Lisa Davis

Interests

Teaching

Team learning, learning assessments, cancer therapeutics, cancer pharmacogenomics, pharmacokinetics

Research

Oncology, new drug development, Phase I clinical trials, medication adherence, supportive care, precision oncology, pharmacokinetics, pharmacogenomics, drug resistance, autophagy

Courses

Scholarly Contributions

Chapters

• Davis, L. E. (2023). Colon Cancer. In: Schwinghammer TL et al, eds.. In Pharmacotherapy Casebook: A Patient-Focused Approach. 12th ed.. McGraw-Hill.
• Holle, L. M., Clement, J. M., & Davis, L. E. (2023). Colorectal Cancer. In DiPiro's Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw-Hill.
• Bhattacharjee, S., & Davis, L. E. (2021). Role of the pharmacist in research. In Remington The Science and Practice of Pharmacy, 23rd Edition(pp 789-800). Academic Press. doi:10.1016/b978-0-12-820007-0.00043-x
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  Abstract Pharmacists are uniquely positioned to lead and support research in pharmacy disciplines and for decades have been instrumental in drug development due to the basic and applied science foundation and clinical training in their curriculum, and access to research-focused training programs. They perform critical functions within the pharmaceutical industry and regulatory services within the industry and government organizations. Academic and practice settings provide many opportunities for pharmacists to excel as independent and collaborating investigators in basic, translational, clinical, and outcomes research. Postgraduate training programs, including residencies, fellowships, internships, sabbaticals, masters, and doctorate-level research programs in the pharmaceutical sciences, pharmacology/toxicology, health outcomes, pharmacoepidemiology, pharmacoeconomics, and pharmacy administration can provide pharmacists with the knowledge and skills to pursue many avenues of research.
• Davis, L. (2020). Colon Cancer. In Pharmacotherapy Casebook: A Patient-Focused Approach.
• Holle, L., Clement, J., & Davis, L. (2020). Colorectal Cancer. In Pharmacotherapy: A Pathophysiologic Approach, 11th Edition.
• Tenneti, P., Davis, L., & Mahadevan, D. (2018). Novel Aurora Kinase inhibitor based combination therapies for PTCL. In T-cell Lymphomas. IntechOpen.
• Davis, L. (2017). Colon Cancer. In Pharmacotherapy Casebook: A Patient-Focused Approach.
• Holle, L., Clement, J., & Davis, L. (2017). Colorectal Cancer. In Pharmacotherapy: A Pathophysiologic Approach, 10th Edition.
• Alberts, D. S., Roe, D. J., Plezia, P. M., Kuhn, J. G., & Davis, L. E. (1992). Prospective Evaluation of a Predictive Model for Plasma Concentration-Versus-Time Profiles of Investigational Anticancer Drugs in Patients. In Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development(pp 237-245). Springer, Boston, MA. doi:10.1007/978-1-4615-3492-1_14
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  Several models have been proposed to predict target plasma concentrations for new anticancer drugs in humans. Collins et al. (1) have suggested a dose-escalation scheme based on the optimally determined plasma concentration-versus-time (CXT) product in mouse models. Phase I human studies are initiated at a dose of onetenth the LD10 in mice. Then, human pharmacology studies are conducted to determine plasma CXT data in patients. The dose is then escalated to approach a plasma CXT equal to that achieved in the mouse model.

Journals/Publications

• Campbell, A. M., Antwo, P. B., Davis, L., & Warholak, T. (2025).

  Fixed, Systematically Formed versus Continuously Changing Random Team Assignments and Outcomes in a Therapeutics Course.

  . American Journal of Pharmaceutical Education, 89(3), 101370. doi:10.1016/j.ajpe.2025.101370
• Warholak, T. L., Davis, L., Antwi, P. B., & Campbell, A. M. (2023). Fixed versus random weekly team assignments and student outcomes in a therapeutics course. American Journal of Pharmaceutical Education.
• Cracchiolo, M. J., Davis, L., Matiatos, A. P., Davini, D. W., Husnain, M., Simpson, R. J., Voudouris, V., & Katsanis, E. (2024). Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies. Cancer Chemotherapy Pharmacology. doi:10.21203/rs.3.rs-3848777/v1
• Erstad, B. L., & Davis, L. E. (2024). Fixed Versus Body-Sized-Based Dosing of Monoclonal Antibodies. The Annals of pharmacotherapy, 58(1), 91-95.
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  Monoclonal antibody products are an increasing portion of novel drug approvals. The labeling of initial drug approvals frequently involves body-size-based rather than fixed-dose administration regimens for adults without clear rationale for doing so. This presents challenges when prescribing these products for patients with extremes of body habitus who constitute a small portion of enrollment in pre-approval investigations. Fixed-dose regimens allow for standardized preparation with the potential to reduce the risk of calculation errors, drug waste, and make home administration more practical. Fixed-dose rather than body-size-based monoclonal antibody regimens should serve as the initial approach in early phase 1 clinical trials.
• Erstad, B. L., & Davis, L. E. (2023). Fixed Versus Body-Sized-Based Dosing of Monoclonal Antibodies. Annals of Pharmacotherapy, 58(1), 106002802311706. doi:10.1177/10600280231170650
• Buie, L. W., Davis, L. E., Finnes, H. D., Hough, S., Iannucci, A., Kennedy, L., Lawson, A. P., Mackler, E., & Seung, A. H. (2022). Hematology‐oncology pharmacists: We hear you, we see you, we support you. JACCP: JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY, 5(12), 1325-1326. doi:10.1002/jac5.1707
• Davis, L., Matthias, K. R., & Nix, D. E. (2022). The relationship of vancomycin 24-hour AUC and trough concentration. American Journal of Health-System Pharmacy, 79(7), 534-539.
• Finnes, H. D., Kennedy, L., Buie, L. W., Lawson, A. P., Amy, S. H., Davis, L. E., Mackler, E. E., Iannucci, A., & Hough, S. (2022). Hematology-oncology Pharmacists: We Hear You, We See You, We Support You. Journal of the American College of Clinical Pharmacy, 5(12), 1325-1326.
• Garland, L. L., Guillen-Rodriguez, J., Hsu, C., Davis, L. E., Szabo, E., Husted, C., Liu, H., LeClerc, A., Alekseyev, Y., Liu, G., Bauman, J. E., Spira, A., Beane, J., Wojtowicz, M., & Chow, H. (2022). Clinical study of aspirin and zileuton on biomarkers of tobacco-related carcinogenesis in current smokers. Cancer (Basel), 14(12).
• Matthias, K. R., Davis, L., & Nix, D. E. (2022). Response to Rybak et al. American Journal of Health-System Pharmacy. doi:https://doi.org/10.1093/ajhp/zxac126
• Nix, D. E., Davis, L. E., & Matthias, K. R. (2022). Response to Rybak et al. American Journal of Health-System Pharmacy, 79(16), 1308-1311. doi:10.1093/ajhp/zxac126
• Nix, D. E., Davis, L. E., & Matthias, K. R. (2021). The relationship of vancomycin 24-hour AUC and trough concentration. American Journal of Health-System Pharmacy, 79(7), 534-539. doi:10.1093/ajhp/zxab457
• Nix, D. E., Davis, L. E., & Matthias, K. R. (2021). The relationship of vancomycin 24-hour AUC and trough concentration. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. doi:10.1093/ajhp/zxab457
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  In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
• Anderson, E. J., Mollon, L. E., Dean, J. L., Warholak, T. L., Aizer, A., Platt, E. A., Tang, D. H., & Davis, L. (2020). A Systematic Review of the Prevalence and Diagnsostic Workup of PIK3CA mutations in HER+/HER2- Metastatic Breast Cancer. International Journal of Breast Cancer. doi:10.1155/2020/3759179
• Anderson, E. J., Mollon, L. E., Dean, J. L., Warholak, T. L., Aizer, A., Platt, E. A., Tang, D. H., & Davis, L. E. (2020). A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2– Metastatic Breast Cancer. International Journal of Breast Cancer, 2020, 1-16. doi:10.1155/2020/3759179
• Mollon, L. E., Anderson, E. J., Aguilar, A., Dean, J. L., Warholak, T. L., Aizer, A., Platt, E., Tang, D., & Davis, L. (2020). A Systematic Literature Review of the Prognostic and Predictive Value of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.. Clinical Breast Cancer, 20(3), e232-e243. doi:https://doi.org/10.1016/j.clbc.2019.08.011
• Babiker, H. M., Davis, L., Larson, K., Placencia, C., Swensen, C., Tenneti, P., Lim, M., Cañamar, R., Curtis, J., Castillo, E., Mancuso, J., Rensvold, D., Martinez, S., Macias, L., Recio-Boiles, A., Chandana, S. R., & Mahadevan, D. (2019). A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations. Expert opinion on investigational drugs, 28(8), 675-686.
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  : Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. : This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. : We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.
• Davis, L. E., Nicholls, L. A., Babiker, H. M., Liau, J., & Mahadevan, D. (2019). PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor. Cancer Immunology Research, 7(9), 1396-1400. doi:10.1158/2326-6066.cir-19-0072
• Davis, L. E., Nicholls, L. A., Babiker, H. M., Liau, J., & Mahadevan, D. (2019). PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor. Cancer immunology research, 7(9), 1396-1400.
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  High-grade malignant peripheral nerve sheath tumors (MPNST) have a poor prognosis with limited responsiveness to systemic therapy. We document a case of a complete metabolic response to pembrolizumab monotherapy in metastatic disease. Tumor molecular profiling identified programmed-death ligand-1 (PD-L1) positivity. This characteristic provided a rationale for immune-checkpoint therapy. Treatment with pembrolizumab resulted in a complete metabolic response after four cycles of therapy. Patients with PD-L1-positive, metastatic MPNST may be candidates for immune-checkpoint therapy, which may produce a durable complete remission. Future study of anti-PD-1/PD-L1 therapy is warranted.
• Garland, L. L., Guillen-Rodriguez, J., Hsu, C. H., Yozwiak, M., Zhang, H. H., Alberts, D. S., Davis, L. E., Szabo, E., Merenstein, C., Lel, J., Zhang, X., Liu, H., Liu, G., Spira, A. E., Beane, J. E., Wojtowicz, M., & Chow, H. S. (2019). Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial. Cancer prevention research (Philadelphia, Pa.), 12(11), 809-820.
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  A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Low-dose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of -4.55 ± 11.52 from baseline 15.44 ± 13.79 ng/mg creatinine for arms combined, = 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature ( < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.
• Garland, L. L., Guillen-Rodriguez, J., Hsu, C., Yozwiak, M., Zhang, H. H., Alberts, D. S., Davis, L. E., Szabo, E., Merenstein, C., Lel, J., Zhang, X., Liu, H., Liu, G., Spira, A. E., Beane, J. E., Wojtowicz, M., & Chow, H. S. (2019). Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial. Cancer Prevention Research, 12(11), 809-820. doi:10.1158/1940-6207.capr-19-0036
• Haas, N. B., Appleman, L. J., Stein, M., Redlinger, M., Wilks, M., Xu, X., Onorati, A., Kalavacharla, A., Kim, T., Zhen, C. J., Kadri, S., Segal, J. P., Gimotty, P. A., Davis, L. E., & Amaravadi, R. K. (2019). Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma. Clinical Cancer Research, 25(7), 2080-2087. doi:10.1158/1078-0432.ccr-18-2204
• Haas, N. B., Appleman, L. J., Stein, M., Redlinger, M., Wilks, M., Xu, X., Onorati, A., Kalavacharla, A., Kim, T., Zhen, C. J., Kadri, S., Segal, J. P., Gimotty, P. A., Davis, L. E., & Amaravadi, R. K. (2019). Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. doi:DOI:10.1158/1078-0432.CCR-18-2204
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  Purpose Everolimus inhibits the mechanistic target of rapamycin (mTOR), activating cytoprotective autophagy. Hydroxychloroquine (HCQ) inhibits autophagy. Based on preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and HCQ, to determine its safety and activity in patients with clear cell renal carcinoma (ccRCC). Experimental Design Three centers conducted a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced ccRCC. The objectives were to determine the maximum tolerated dose of HCQ with daily everolimus, and to estimate the rate of 6 month progression-free survival (PFS) in ccRCC patients receiving everolimus/HCQ after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy and next generation tumor sequencing. Results No DLT was observed in the phase I trial. The recommended phase II dose of HCQ 600 mg bid with everolimus was identified. Disease control (Stable disease (SD) + partial response (PR)) occurred in 22/33 (67%) evaluable patients. Partial response was observed in 2/33 patients (6%). PFS ≥6 months was achieved in 15/33 (45%) of patients who achieved disease control. Conclusion Combined HCQ 600mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6 month PFS rate was met. HCQ is a tolerable autophagy inhibitor in future RCC or other trials.
• Aguilar, A., Aizer, A. A., Anderson, E. J., Bardia, A., Davis, L. E., Dean, J. L., Mollon, L., Platt, E., Tang, D. H., & Warholak, T. L. (2018). A systematic literature review of the clinical prognosis of HR+/HER2- advanced or metastatic breast cancer with and without PIK3CA mutation.. Journal of Clinical Oncology, 36(15_suppl), e13037-e13037. doi:10.1200/jco.2018.36.15_suppl.e13037
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  e13037Background: The predictive and prognostic value of PIK3CA mutation in HR+/HER2–metastatic breast cancer (mBC) is not known. This study aimed to assess clinical prognosis for patients with HR+...
• Anderson, E., Aguilar, A., Aizer, A. A., Anderson, E. J., Bardiya, A., Davis, L. E., Dean, J. L., Mollon, L., Platt, E., Tang, D. H., & Warholak, T. L. (2018). Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer. Cancer Research, 78(13_Supplement), 1207-1207. doi:10.1158/1538-7445.am2018-1207
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  Introduction: Clinical research on the predictive value of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) metastatic breast cancer (mBC) has advanced in recent years. However, knowledge of epidemiological prevalence has not been systematically evaluated. This study aimed to report prevalence of PIK3CA mutation using different biopsy techniques as well as specific hotspot mutations across the available literature. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm”, “PIK3CA protein”, “hormone receptor positive”, and “metastases”. English-language studies in HR+, HER2– mBC detailing the prevalence of PIK3CA mutations and published between January 1993 through August 2017 were included. Content analysis was employed to quantify collected data elements. Results: Of 558 studies included for full-text review, 36 met inclusion criteria. Most included studies (n = 18) were observational in nature. A total of 4,247 samples were tested for genetic mutations. Most studies used tissue biopsy samples (n = 33; 89%). Tumor samples accounted for 84.6% of all samples (n = 3597). Liquid biopsies were performed in 4 studies (11%) and accounted for 15.3% of all samples (n = 650). One study reported both liquid and tumor biopsy data. Overall, reported prevalence of the PIK3CA mutation ranged from 13.3% to 61.5%. Median prevalence was 36.4% (25th percentile = 28.6%; 75th percentile = 48.4%). Among studies using tissue biopsies, the majority reported prevalence from 16.7% to 61.5%. Among studies using liquid biopsies, the majority (n = 3) reported prevalence from 43.3% to 46.8%; one other study reported 13.3%. The most commonly tested hotspot mutations were H1047R and E545K. Among studies reporting specific hotspot mutation prevalence (n = 9), the H1047R hotspot mutation prevalence in these studies ranged between 25% and 75% while the E545K prevalence ranged between 11.1% and 50%. Conclusions: Although discrepancies exist with respect to mutation prevalence estimated across various tissue vs. liquid biopsy techniques, PIK3CA mutations and mutation hotspots (specifically H1047R and E545K) frequently occur in HR+/HER2– mBC. Citation Format: Lea Mollon, Alejandra Aguilar, Elizabeth Anderson, Joni Dean, Lisa Davis, Terri Warholak, Ayal A. Aizer, Emma Platt, Aditya Bardiya, Derek Tang. A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1207.
• Anderson, E., Aguilar, A., Aizer, A. A., Anderson, E. J., Bardiya, A., Davis, L. E., Dean, J. L., Mollon, L., Platt, E., Tang, D. H., & Warholak, T. L. (2018). Abstract 2193: Biopsy and analytical testing methods used to identify PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer: A systematic literature review. Cancer Research, 78(13_Supplement), 2193-2193. doi:10.1158/1538-7445.am2018-2193
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  Introduction: This study aimed to identify biopsy and analytical testing methods for PIK3CA mutation in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) via a systematic literature review. Understanding the available biopsy and analytical methods for PIK3CA mutation and its publication trends over time may support understanding of emerging technology trends. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm,” “PIK3CA protein,” “hormone receptor positive,” and “metastases.” English-language studies in HR+, HER2- mBC reporting either biopsy or analytical testing methods for PIK3CA mutation and published between January 1993 through August 2017 were included. Content analysis was employed to quantify collected data elements. Results: Of 558 studies included for full-text review, 36 met inclusion criteria. Total number of samples tested among this subgroup were 4,247 (tumor = 3,597; liquid = 650). Sample size ranged from 9 to 618 (median = 47). The most common methods used for identifying PIK3CA mutations were tumor biopsies (n = 33) while liquid biopsies only occurred in four studies. One study reported both liquid and tumor biopsy data. Formalin-fixed, paraffin-embedded (FFPE) tissue samples were used in most studies examining tumor samples (n = 28). Among liquid biopsies, circulating tumor cells (CTC) (n = 2), cell-free DNA (cfDNA) (n = 1), and circulating tumor DNA (ctDNA) (n = 1) were used. Techniques for DNA analyses included PCR (n = 14), NGS (n = 14), Sanger (n = 7), mass spectrometry (n = 5) and liquid chip technology (n = 1). Some studies used multiple methods (n = 5). Most studies using NGS were cross-sectional (n = 9); other studies using NGS (n=4) were clinical trials. Among clinical trials (n = 9), four used PCR only (sample size range 30 to 550), two used NGS only (sample size range 16 to 28), one used Sanger sequencing only (sample size = 21) and two used both NGS and PCR methods (sample size range 26 to 55). Of fourteen studies using NGS, thirteen were published from 2015 to 2017, which may be indicative of a transition to newer methodology. While PCR remained a commonly used analytical method regardless of sample size, NGS has become more common than PCR in recent publication years. Conclusions: The majority of studies utilized PCR for PIK3CA analytical testing despite newer technologies available. NGS methodology was used more frequently in more recent publications. However, the relative accuracy between PCR and NGS testing is yet to be fully understood. Citation Format: Elizabeth Anderson, Lea Mollon, Alejandra Aguilar, Joni Dean, Lisa Davis, Terri Warholak, Ayal Aizer, Emma Platt, Aditya Bardiya, Derek Tang. Biopsy and analytical testing methods used to identify PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer: A systematic literature review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2193.
• Anderson, E., Aguilar, A., Aizer, A. A., Anderson, E. J., Bardiya, A., Davis, L. E., Dean, J. L., Mollon, L., Platt, E., Tang, D. H., & Warholak, T. L. (2018). Abstract 2217: Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review. Cancer Research, 78(13_Supplement), 2217-2217. doi:10.1158/1538-7445.am2018-2217
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  Introduction: This systematic literature review sought to determine the concordance of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm,” “PIK3CA protein,” “hormone receptor positive,” and “metastases.” Databases were searched for English-language publications in HR+, HER2- mBC published between January 1993 through August 2017. Studies were included if results reported were specific to patients with HR+, HER2- mBC and reported data comparing PIK3CA mutations from liquid biopsies versus tumor biopsies or primary tumor samples versus metastatic lesion samples. Concordance was assessed between tissue samples (mutations found in primary tumors versus those from metastatic lesions) and between biopsy methods (i.e., tumor biopsy versus liquid biopsy) when the assessment was done at a variety of time points including time of initial diagnosis and time of diagnosis at disease progression. Content analysis was employed to quantify collected data elements. Results: Of 558 studies included for full-text review, four met inclusion criteria (number of patient samples [n]=358). One study (n = 9) found the concordance between the mutation status of primary breast tumors to the mutation status of metastatic lesions to be 100%. Three studies (n = 47; n = 55; n = 247) determined the concordance of PIK3CA mutations between tumor biopsies and liquid biopsies with concordance ranging from 70.4% to 94%. One study found that the concordance of circulating tumor DNA (ctDNA) against tumor biopsy was higher among metastatic lesions only (81.6%) relative to using all tumor samples (either primary or metastatic lesions) (70.4%). Conclusions: Available evidence suggested high level of concordance across sampling methods as well as across time. However, additional evidence is needed to increase study generalizability as well as to assess other possible confounding factors, such as differential timing between tumor and liquid biopsies. Citation Format: Alejandra Aguilar, Joni Dean, Elizabeth Anderson, Lea Mollon, Lisa Davis, Terri Warholak, Ayal Aizer, Emma Platt, Aditya Bardiya, Derek Tang. Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2217.
• Davis, L. E. (2018). The evolution of biomarkers to guide the treatment of metastatic colorectal cancer. The American journal of managed care, 24(7 Suppl), S107-S117.
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  In the United States, colon cancer is one of the leading causes of death and cancer-related death. There is a critical need to improve clinical outcomes in patients with metastatic colorectal cancer (mCRC), as current survival rates are unsatisfactory. There have been significant advances in the treatment of mCRC over the past decade. Molecular characteristics of mCRC and identification of mutations can serve predictive and prognostic indicators of disease response to treatment. These biomarkers can be incorporated into clinical decision making when developing an individualized treatment plan. Targeted therapies have improved the survival of patients with mCRC. As we learn about the various molecular alterations in this disease, additional emerging therapies can be developed to improve clinical outcomes in patients with mCRC.
• Davis, L. E., Hsu, P., Mahadevan, D., Park, S., & Persky, D. O. (2017). Phase II/1b Trial of Ibrutinib Plus Prednisone and Rituximab Induction Followed By Venetoclax Plus Ibrutinib Maintenance in Newly Diagnosed High-Risk Chronic Lymphocytic Leukemia. Blood, 130, 5351-5351. doi:10.1182/blood.v130.suppl_1.5351.5351
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  Introduction: Therapy options for chronic lymphocytic leukemia (CLL) are rapidly changing with the approval of ibrutinib, an irreversible Bruton9s tyrosine kinase inhibitor, and venetoclax, a Bcl2 inhibitor. In the RESONATE studies, ibrutinib showed significant improvements in overall response rates (ORR), progression-free-survival (PFS), and overall survival (OS). Nonetheless, complete response (CR) rates were only about 4%. During the first few weeks of treatment, ibrutinib will mobilize CLL cells from tissue sites into peripheral blood. Rituximab, a chimeric monoclonal CD20 antibody, when used with ibrutinib, has shown to immediately clear CLL from the blood with durable responses but with CR9s of only 8%. Venetoclax is approved for relapsed or refractory CLL with 17p deletion. In a phase 2 study, at a median follow-up of 12.1 months, the ORR was ~79%, but with only 16% CR9s. Amongst the 45 patients of whom minimal residual disease (MRD) was assessed, 24 were negative for MRD. In vitro studies have shown that nurse-like cells (NLCs) will protect CLL cells against spontaneous apoptosis by producing chemokines and interleukins such as SDF1, suggestive of a mechanism of ibrutinib resistance. SDF1 was shown to bind to its receptor CXCR4 located on CLL cells and activate a signal transduction pathway that would reduce spontaneous apoptosis. Dexamethasone was found to decrease NLC viability. This suggests that a combined therapy of ibrutinib plus steroids along with rituximab and venetoclax may be necessary to achieve deeper CR9s in high-risk CLL. In addition, CLL with overexpression of exosome miR-155 is associated with a poor response to chemoimmunotherapy. In prior preclinical studies, exosome miR-150 and miR-155 have been shown to increase with BCR activation via α-IgM stimulation. We hope that via next generation microRNA sequencing from our patients9 CLL plasma cells we will observe a decrease in the levels of exosome miR-150 and miR-155 in response to inhibition of BCR-pathway by ibrutinib as seen in preclinical studies. Methods: Patients with newly diagnosed high-risk CLL per FISH studies will be enrolled. Ibrutinib will be administered orally 420 mg daily, rituximab will be dosed at 375 mg/m2 intravenously on days 1, 8, 15, 22 of cycle 1 and on day 1 for cycle 2-6. Prednisone will be administered as 10 mg one week on, one week off per cycle. Each cycle will last 28 days. After 6 cycles, if patients have MRD, venetoclax will be added in on a weekly schedule with weekly ramp up from 20mg to 50mg, 100mg, and 200mg for a total duration of 6 months plus ibrutinib at 420mg as maintenance until disease progression or drug intolerance. There is the option to reintroduce venetoclax, prednisone, or rituximab if patients progress during maintenance. Results: The primary objectives of this study are to evaluate safety and MRD negative CR rates based on IWG-CLL criteria. For the evaluation of safety, the proportions of the 29 subjects with any adverse events, each specific adverse event, and study-related adverse events will be reported along with the 95% confidence intervals. The proportion of the 29 subjects who demonstrate a MRD negative CR will be reported along with the 95% confidence interval. A sample size of 29 will produce a two-sided 95% confidence interval with a width≤ 0.380. In addition, Kaplan-Meier method will be performed to evaluate time to first MRD negativity (TTMN), time to first relapse (TTFR), PFS and OS, respectively. Based on the Kaplan-Meier curve, the median time to TTMN, TTFR, PFS and OS, respectively, will be reported along with the 95% confidence interval if it exists. Correlation coefficients will be derived to describe the relationship between continuous endpoints and Kendall9s tau will be derived to describe the relationship between categorical endpoints. There is no planned interim analysis for the CR rate. However, at any time point if an excessive number of adverse events are observed, the study will be terminated. Conclusion: In this Phase IB/II clinical trial, we seek to observe prolonged response rates of ibrutinib via inhibiting NLC9s by adding prednisone. Also, we anticipate that rituximab will further amplify the CR9s. For maintenance therapy, we hope that by combining venetoclax with ibrutinib in high-risk CLL patients who were unable to achieve negative MRD9s, we will be able to induce deeper remissions. Disclosures Persky: Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.
• Blustein, L., Davis, L. E., Hartman, R., & Morel, D. W. (2014). A pharmaceutical industry elective course on practice experience selection and fellowship pursuit by pharmacy students.. American journal of pharmaceutical education, 78(6), 126. doi:10.5688/ajpe786126
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  To design and implement 2 pharmaceutical industry elective courses and assess their impact on students' selection of advanced pharmacy practice experiences (APPEs) and pursuit of pharmaceutical industry fellowships..Two 2-credit-hour elective courses that explored careers within the prescription and nonprescription pharmaceutical drug industries were offered for second- and third-year pharmacy students in a doctor of pharmacy (PharmD) degree program..The impact of the courses on pharmacy students' pursuit of a pharmaceutical industry fellowship was evaluated based on responses to annual graduating students' exit surveys. A greater percentage (17.9%) of students who had taken a pharmaceutical industry elective course pursued a pharmaceutical industry fellowship compared to all PharmD graduates (4.8%). Of the students who enrolled in pharmaceutical industry APPEs, 31% had taken 1 of the 2 elective courses..Exposure to a pharmaceutical industry elective course within a college or school of pharmacy curriculum may increase students' interest in pursuing pharmaceutical industry fellowships and enrolling in pharmaceutical industry APPEs.
• Blustein, L., Davis, L. E., Kuffner, E., & Shah, R. (2014). Communicating doses of pediatric liquid medicines to parents/caregivers: a comparison of written dosing directions on prescriptions with labels applied by dispensed pharmacy.. The Journal of pediatrics, 164(3), 596-601.e1. doi:10.1016/j.jpeds.2013.11.007
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  To identify and compare volumetric measures used by healthcare providers in communicating dosing instructions for pediatric liquid prescriptions to parents/caregivers..Dosing instructions were retrospectively reviewed for the 10 most frequently prescribed liquid medications dispensed from 4 community pharmacies for patients aged ≤ 12 years during a 3-month period. Volumetric measures on original prescriptions (ie, milliliters, teaspoons) were compared with those utilized by the pharmacist on the pharmacy label dispensed to the parent/caregiver..Of 649 prescriptions and corresponding pharmacy labels evaluated, 68% of prescriptions and 62% of pharmacy labels communicated dosing in milliliters, 24% of prescriptions and 29% of pharmacy labels communicated dosing in teaspoonfuls, 7% of prescriptions and 0% of pharmacy labels communicated dosing in other measures (ie, milligrams, cubic centimeters, "dose"), and 25% of dispensed pharmacy labels did not reflect units as written in the prescription..Volumetric measures utilized by healthcare professionals in dosing instructions for prescription pediatric oral liquid medications are not consistent. Healthcare professionals and parents/caregivers should be educated on safe dosing practices for liquid pediatric medications. Generalizability to the larger pediatric population may vary depending on pharmacy chain, location, and medications evaluated.
• Mahalingam, D., Mita, M., Sarantopoulos, J., Wood, L., Amaravadi, R. K., Davis, L. E., Mita, A. C., Curiel, T. J., Espitia, C. M., Nawrocki, S. T., Giles, F. J., & Carew, J. S. (2014). Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy, 10(8), 1403-14.
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  We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.
• Rangwala, R., Chang, Y. C., Hu, J., Algazy, K. M., Evans, T. L., Fecher, L. A., Schuchter, L. M., Torigian, D. A., Panosian, J. T., Troxel, A. B., Tan, K. S., Heitjan, D. F., DeMichele, A. M., Vaughn, D. J., Redlinger, M., Alavi, A., Kaiser, J., Pontiggia, L., Davis, L. E., , O'Dwyer, P. J., et al. (2014). Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy, 10(8), 1391-402.
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  The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.
• Rangwala, R., Leone, R., Chang, Y. C., Fecher, L. A., Schuchter, L. M., Kramer, A., Tan, K. S., Heitjan, D. F., Rodgers, G., Gallagher, M., Piao, S., Troxel, A. B., Evans, T. L., DeMichele, A. M., Nathanson, K. L., O'Dwyer, P. J., Kaiser, J., Pontiggia, L., Davis, L. E., & Amaravadi, R. K. (2014). Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy, 10(8), 1369-79.
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  Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.
• Rosenfeld, M. R., Ye, X., Supko, J. G., Desideri, S., Grossman, S. A., Brem, S., Mikkelson, T., Wang, D., Chang, Y. C., Hu, J., McAfee, Q., Fisher, J., Troxel, A. B., Piao, S., Heitjan, D. F., Tan, K. S., Pontiggia, L., O'Dwyer, P. J., Davis, L. E., & Amaravadi, R. K. (2014). A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy, 10(8), 1359-68.
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  Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.
• Vogl, D. T., Stadtmauer, E. A., Tan, K. S., Heitjan, D. F., Davis, L. E., Pontiggia, L., Rangwala, R., Piao, S., Chang, Y. C., Scott, E. C., Paul, T. M., Nichols, C. W., Porter, D. L., Kaplan, J., Mallon, G., Bradner, J. E., & Amaravadi, R. K. (2014). Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy, 10(8), 1380-90.
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  The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
• Amaravadi, R. K., Davis, L. E., Levi, S. M., Lynch, J. P., Ma, X. H., Mcafee, Q., Piao, S., Samanta, A., Sepulveda, A. R., Uehara, T., Winkler, J. D., & Zhang, Z. (2012). Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency.. Proceedings of the National Academy of Sciences of the United States of America, 109(21), 8253-8. doi:10.1073/pnas.1118193109
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  Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.
• Davis, L. E. (2012). Book Review: Stockley's Drug Interactions Pocket Companion 2012:. Annals of Pharmacotherapy, 46(10), 1444-1444. doi:10.1345/aph.1r125
• Davis, L. E., Davis, L. E., Luger, S. M., Luger, S. M., Mick, R., Mick, R., Paul, T. M., Paul, T. M., Porter, D. L., Porter, D. L., Raguza-lopez, M., Raguza-lopez, M., Salazar, G., Salazar, G., Stadtmauer, E. A., Stadtmauer, E. A., Stoopler, E. T., Stoopler, E. T., Vogl, D. T., & Vogl, D. T. (2012). Effect of Body Composition and Renal Function on the Pharmacokinetics of High-Dose Melphalan for Multiple Myeloma. Biology of Blood and Marrow Transplantation, 18(2), S248. doi:10.1016/j.bbmt.2011.12.131
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  s from the 2012 BMT Tandem Meetings. Poster presentation in San Diego, CA. This paper is posted at ScholarlyCommons. http://repository.upenn.edu/dental_papers/34 For more information, please contact repository@pobox.upenn.edu. Recommended Citation Vogl, D. T., Mick, R., Stoopler, E. T., Davis, L. E., Paul, T. M., Salazar, G., Raguza-Lopez, M., Porter, D. L., Luger, S. M., & Stadtmauer, E. A. (2012). Effect of Body Composition and Renal Function on the Pharmacokinetics of High-Dose Melphalan for Multiple Myeloma. Biology of Blood and Marrow Transplantation, 18 (2), S248-. http://dx.doi.org/10.1016/j.bbmt.2011.12.131 Effect of Body Composition and Renal Function on the Pharmacokinetics of High-Dose Melphalan for Multiple Myeloma Disciplines Biological Factors | Other Pharmacy and Pharmaceutical Sciences | Pharmaceutical Preparations | Surgical Procedures, Operative Comments Abstracts from the 2012 BMT Tandem Meetings. Poster presentation in San Diego, CA. Author(s) Dan T. Vogl, Rosemarie Mick, Eric T. Stoopler, Lisa E. Davis, Thomas M. Paul, German Salazar, Maria Raguza-Lopez, David L. Porter, Selina M. Luger, and Edward A. Stadtmauer This other is available at ScholarlyCommons: http://repository.upenn.edu/dental_papers/34
• Davis, L. E., Stadtmauer, E. A., & Vozniak, J. M. (2012). Multi-Dose Pharmacokinetic Study of Plerixafor in a Morbidly Obese Patient with Multiple Myeloma and Dialysis-Dependent Renal Impairment. Biology of Blood and Marrow Transplantation, 18(2), S256-S257. doi:10.1016/j.bbmt.2011.12.153
• Algazy, K. M., Algazy, K. M., Amaravadi, R. K., Amaravadi, R. K., Chang, C. Y., Chang, C. Y., David, V. J., David, V. J., Davis, L. E., Davis, L. E., Demichele, A. M., Demichele, A. M., O'dwyer, P. J., O'dwyer, P. J., Redlinger, M., Redlinger, M., Schuchter, L. M., Schuchter, L. M., Torigian, D. A., & Torigian, D. A. (2011). Abstract 4500: Combined mTOR inhibition and autophagy inhibition: Phase I trial of temsirolimus and hydroxchloroquine in patients with advanced solid tumors. Cancer Research, 71, 4500-4500. doi:10.1158/1538-7445.am2011-4500
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  Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Therapy-induced autophagy may be a key resistance mechanism that explains the low rates of clinical benefit observed in trials of mTOR inhibitors in multiple cancers. For example, the mTOR inhibitor temsirolimus produced a 0% stable disease rate in a prior phase II trial in patients with metastatic melanoma. Hydroxychloroquine (HCQ) is an autophagy inhibitor that augments the antitumor efficacy of a number of anticancer therapies including mTOR inhibitors in preclinical models. To determine the safety and pharmacodynamic (PD) effects of combining an mTOR inhibitor with an autophagy inhibitor, we report the results of a phase I clinical trial of temsirolimus and HCQ in patients with advanced solid tumors. Methods: We conducted a traditional 3+3 phase I dose escalation clinical trial in which patients were treated with 1 week single agent temsirolimus 25 mg IV weekly followed by combined weekly temsirolimus with increasing doses of daily continuous HCQ. Patients with advanced solid tumors with any number of prior therapies were eligible. The primary objective was to determine the maximal tolerated dose (MTD) of HCQ in this combination. Secondary objectives included toxicity rate, response rate, measurement of therapy-induced accumulation of autophagic vesicles (AV) in serial peripheral blood mononuclear cells (PBMC) and tumor tissue, and pharmacokinetic (PK) analysis of temsirolimus, sirolimus and HCQ to explore drug interactions and establish a PK-PD relationship. A 12 patient expansion at the MTD or HCQ 600 mg bid (final planned dose level) in patients with metastatic melanoma with serial FDG-PET scans is planned. Results: 23 patients were enrolled with 14 evaluable for response and toxicity. The median number of prior treatments was 4. HCQ was successfully dose escalated from 200 mg daily to 600 mg bid in 4 cohorts. There was one dose limiting toxicity (DLT) at 200 mg HCQ, grade 4 thrombocytopenia with bleeding, that lead to dose expansion. The 800 mg dose cohort was also expanded due to a death from streptococcal pneumonia in month 3 of treatment. No additional bleeding, infections, or other DLTs were observed. Anorexia, nausea, and fatigue were common grade 2 toxicities. Stable disease was achieved in 10/14 evaluable patients, including 4/5 patients with metastatic melanoma. After 6 weeks of treatment, a significant accumulation of AV was observed in PBMC of patients treated with this combination compared to pretreatment samples providing PD evidence of consistent autophagy inhibition. Conclusions: The combination of temsirolimus and HCQ demonstrated significant clinical activity, and a manageable safety profile in a highly treatment-refractory patient population. PD evidence of autophagy inhibition was observed. The recommended phase II dose, PK-PD analysis, response rate, and FDG-PET results in the melanoma expansion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2011-4500
• Amaravadi, R. K., Bradner, J. E., Carroll, M., Davis, L. E., Kaplan, J., Mallon, G., Mangan, P. A., Nichols, C. W., Paul, T. M., Porter, D. L., Scott, E. C., Shelly, B. K., Stadtmauer, E. A., Swider, C. R., & Vogl, D. T. (2011). Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Final Results of a Phase 1 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Patients with Relapsed or Refractory Myeloma. Blood, 118(21), 1869-1869. doi:10.1182/blood.v118.21.1869.1869
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  Abstract 1869 BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m 2 , (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm 3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS: We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naive patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION: Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures: Vogl: Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll: Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi: Millennium Pharmaceuticals: Honoraria, Research Funding.
• Basel-brown, L., Basel-brown, L., Davis, L. E., Davis, L. E., Jackson, G., Jackson, G., Kapoor, S., Kapoor, S., Paul, T. M., Paul, T. M., Salazar, G., Salazar, G., Stoopler, E. T., Stoopler, E. T., Vogl, D. T., Vogl, D. T., Yudkoff, M., Yudkoff, M., Zemel, B. S., & Zemel, B. S. (2011). Impact of Obesity and Renal Insufficiency on Oral Mucositis Associated with High-Dose Melphalan. Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 112(6), e127-e128. doi:10.1016/j.tripleo.2011.07.015
• Amaravadi, R. K., Brem, S., Davis, L. E., Grossman, S. A., Mikkelsen, T., O'dwyer, P. J., Piao, S., Rosenfeld, M. R., & Wang, D. (2010). Pharmacokinetic analysis and pharmacodynamic evidence of autophagy inhibition in patients with newly diagnosed glioblastoma treated on a phase I trial of hydroxychloroquine in combination with adjuvant temozolomide and radiation (ABTC 0603).. Journal of Clinical Oncology, 28(15_suppl), 3086-3086. doi:10.1200/jco.2010.28.15_suppl.3086
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  3086 Background: Preclinical studies indicate autophagy inhibition by hydroxychloroquine (HCQ) can augment the efficacy of DNA damaging cancer therapy. The primary objective of this trial was to de...
• Davis, L. E., & Mccluggage, L. K. (2010). Book Review: Stockley's Drug Interactions 2010: Pocket Companion. Annals of Pharmacotherapy, 44(7-8), 1355-1355. doi:10.1345/aph.1p048
• Davis, L. E., Luger, S. M., Paul, T. M., Porter, D. L., Raguza-lopez, M., Salazar, G., Stadtmauer, E. A., Stoopler, E. T., & Vogl, D. T. (2010). Effect of Pharmacokinetic Variability on the Toxicity and Efficacy of High-Dose Melphalan for Multiple Myeloma. Blood, 116(21), 1349-1349. doi:10.1182/blood.v116.21.1349.1349
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  Abstract 1349 Background: High dose melphalan is the most common conditioning regimen for patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). However, toxicity and efficacy of this treatment are variable, with the sources of variability poorly understood. We hypothesized that variation in melphalan pharmacokinetics would explain differences in outcomes after transplant. Methods: We evaluated 41 patients with MM undergoing ASCT with high-dose melphalan conditioning. Patients received melphalan on day -2 at a dose of 200 mg/m 2 (one patient with poor renal function received 180 mg/m 2 ) and ASCT on day 0. Melphalan dose was calculated using ideal body weight (IBW), with adjusted IBW used for patients weighing >120% of IBW. We assessed toxicity on day +7 using the Oral Mucositis Assessment Scale (OMAS), a physician evaluated measurement of erythema and ulceration (on a scale of 0–5, with higher scores indicating more severe mucositis). Patients reported the severity of mouth soreness on a scale of 0–10 using the Mucositis Daily Questionnaire (MDQ) on days 0, +3, +7, +11, +19, and +28. Melphalan concentrations were measured using HPLC/tandem mass spectrometry in plasma samples obtained during infusion and 2, 4, 8, 15, and 30 minutes, and 1, 2, 3.5, 8, and 14 hours after its completion, as well as immediately prior to stem cell infusion. Melphalan area under the curve (AUC) was estimated by non-compartmental analysis. Results: Patients9 median age was 57 years (range 39–72); 59% were male. We observed significant variation in melphalan exposure, with a range of 7.6–26.6 mg*h/L (median 13.5). Severity of oral mucositis was directly related to AUC (with an increase of 0.1 on the OMAS score for every 1 unit increase in AUC, p=0.003). The most severe mucositis was seen in the 4 patients with an AUC ≥17.5 (75% had OMAS scores >1), while severe mucositis was rarely seen in the 18 patients with AUC ≤12.5 (only 1 of 18 had an OMAS score >1). The association between AUC and maximum reported mouth soreness was not statistically significant (an increase of 0.2 on the MDQ scale for every 1 unit increase in AUC, p=0.17), but there was a trend toward higher maximum reported mouth soreness in the 4 patients with AUC≥17.5 (mean 7.5 vs. 4 for other patients, p=0.07). Eight patients had detectable melphalan concentrations at the time of stem cell infusion (mean 3.8 ng/mL, range 1.8–7.1), though time to neutrophil and platelet recovery did not differ for these patients compared with those with undetectable melphalan levels. Of 19 patients with measurable disease at the time of transplant, 8 had stable disease (SD), 9 partial response (PR), and 2 complete response (CR) at day +100. The 2 patients with CR had higher melphalan exposure than patients without a CR (mean AUC 19 vs 11.6, p= 0.002), but there was no discernable difference in melphalan levels between patients with a PR or SD. Conclusion: Using standard dosing calculations in a representative sample of patients with myeloma, melphalan drug exposure was highly varied. Drug exposure was correlated with severity of oral mucositis, and complete responses were seen only in patients with high drug exposure. Further analyses are planned into the effect of obesity and renal dysfunction on pharmacokinetics. Exploration of the appropriate target AUC and strategies for reducing variability in drug exposure have the potential to improve both efficacy and toxicity of this effective and commonly used therapy. Disclosures: No relevant conflicts of interest to declare.
• Basel-brown, L., Daikhin, E., Davis, L. E., Jackson, G., Kapoor, S., Paul, T. M., Raguza-lopez, M., Rockwell, K., Salazar, G., Stadtmauer, E. A., Stoopler, E. T., Swider, C. R., Tenhave, T., Vogl, D. T., Washington, J., Yudkoff, M., & Zemel, B. S. (2009). Effect of Obesity and Renal Insufficiency On Toxicity of High-Dose Melphalan for Multiple Myeloma.. Blood, 114(22), 1177-1177. doi:10.1182/blood.v114.22.1177.1177
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  Abstract 1177 Poster Board I-199 BACKGROUND: High dose melphalan followed by an autologous peripheral blood stem cell transplant (ASCT) is standard initial therapy for multiple myeloma (MM). However, toxicity and efficacy of this treatment are variable, with the sources of variability being poorly understood. We hypothesized that obesity and renal insufficiency modulate the pharmacokinetics of melphalan and therefore impact treatment toxicity. METHODS: We evaluated 39 patients with MM undergoing high-dose melphalan followed by ASCT. Patients received melphalan on day -2 at a dose of 200 mg/m2 (one patient with poor renal function received 180 mg/m2) and ASCT on day 0. We assessed body composition using dual energy x-ray absorptiometry (DEXA) and renal function using 24 hour urine creatinine clearance. We assessed toxicity on day +7 using the Oral Mucositis Assessment Scale (OMAS), a physician evaluated measurement of erythema and ulceration (on a scale of 0-5, with higher scores indicating worse mucositis). We also assessed patient reported symptom scores for mouth and throat soreness using the Mucositis Daily Questionnaire (MDQ) periodically during the first month (on a scale of 0-10, with higher scores indicating worse soreness). RESULTS: The median age was 55 years (range 37-70). 59% were male. The median weight was 83 kg (48-128), with median percentage body fat as measured by DEXA of 31% (range 15–53), and the median glomerular filtration rate (GFR) was 105 ml/min (range 28-194). Results from univariate and multivariate analyses are shown in the table below. In univariate analyses, we observed a weak and statistically insignificant direct correlation between percent body fat and toxicity (as measured by OMAS score or peak soreness), and a weak and statistically significant indirect correlation between GFR and OMAS score. In a multi-variable linear regression model including percent body fat, weight, GFR, and actual melphalan dose, we observed a correlation between OMAS score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 0.65 unit increase in OMAS score (p=0.01). In a similar multi-variable model, we observed a correlation between MDQ soreness score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 2.07 increase in MDQ soreness score (p=0.05). CONCLUSION: More obese patients, as measured by percent body fat, have more severe oral mucositis after high dose melphalan, independent of melphalan dose, weight, and renal function. We are measuring melphalan pharmacokinetics in this group of patients, and further research should help guide rational chemotherapy dosing for this highly effective treatment. Disclosures: No relevant conflicts of interest to declare.
• Amaravadi, R. K., Bradner, J. E., Carberry, M., Carroll, M., Davis, L. E., Mangan, P. A., Nichols, C. W., Shank, D., Shelly, B. K., Stadtmauer, E. A., Swider, C. R., Thompson, C. B., & Vogl, D. T. (2008). Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Preliminary Results of a Phase 1/2 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Relapsed or Refractory Myeloma. Blood, 112(11), 3684-3684. doi:10.1182/blood.v112.11.3684.3684
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  BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma are enrolling on a standard 3+3 dose escalation design. Patients receive a 2-week run-in of single-agent oral HCQ (at escalating doses), followed by addition of standard dose bortezomib (on days 1, 4, 8, and 11 of 21-day cycles). Dose-limiting toxicity (DLT) is defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. Response is assessed on day 1 of each cycle according to International Working Group criteria. We use electron microscopy (EM) to characterize changes in autophagic vesicles (AVs) in serial samples of peripheral blood mononuclear cells (PBMCs) and CD138-selected bone marrow plasma cells (BMPCs) RESULTS: Ten patients have enrolled in the first 3 dose levels (see table). The median age is 63.5 (range 43–68), and 5 (50%) are male. The median number of prior lines of therapy is 4 (range 1–8). Seven patients had received prior Bz. No DLTs have been observed. Adverse events have generally been those expected with Bz: thrombocytopenia (30%, grade 3: 20%), anemia (70%, grade 3: 30%), and fatigue (70%, all grade 1/2), as well as neutropenia (20%, grade 3:10%). Grade 2 treatment-emergent peripheral neuropathy occurred in 1 patient (grade 1 in 3 patients). No patients developed retinal toxicity. Four patients had pulmonary infections: 1 viral influenza, 1 H. influenzae, and 2 lobar pneumonias; all resolved with appropriate antibiotics and did not preclude continued therapy. One patient died from complications of C. difficile colitis that occurred at the end of the 4th cycle, after antibiotic therapy for an upper respiratory infection. One patient had a minor response after previously progressing on single-agent Bz. EM analysis of PBMCs and BMPCs show no significant changes in AVs thus far with the lowest dose of HCQ. Enrollment is ongoing at higher doses of HCQ (escalating from 400 to 1200 mg daily). CONCLUSION: At the lowest dose levels tested, combined Bz and HCQ is tolerable, without evidence of synergistic toxicity. EM is a feasible pharmacodynamic assay for patient tumor and normal cells. Further dose escalation will determine whether combined autophagy and proteasome inhibition is achievable and safe with these agents. Updated clinical and correlative results will be presented.
• Berlin, J. A., Berlin, J., Davis, L. E., Giantonio, B. J., Haller, D. G., O'dwyer, P. J., Shults, J., Sun, W., & Veronese, M. L. (2005). A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer.. British journal of cancer, 92(10), 1846-9. doi:10.1038/sj.bjc.6602569
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  Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.
• Bilenker, J. H., Davis, L. E., Flaherty, K. T., Gallagher, M., Giantonio, B. J., O'dwyer, P. J., Rosen, M. A., Schnall, M. D., Stevenson, J. P., Sun, W., Vaughn, D. J., & Zimmer, R. (2005). Phase I trial of combretastatin a-4 phosphate with carboplatin.. Clinical cancer research : an official journal of the American Association for Cancer Research, 11(4), 1527-33. doi:10.1158/1078-0432.ccr-04-1434
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  Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin..Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion..Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles..This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.
• Davis, L. E. (2003). Book Review: Fluoropyrimidines in Cancer Therapy. Annals of Pharmacotherapy, 37(12), 1920-1921. doi:10.1345/aph.1d047
• Davis, L. E., & Li, E. C. (2003). Zoledronic acid: a new parenteral bisphosphonate.. Clinical therapeutics, 25(11), 2669-708. doi:10.1016/s0149-2918(03)80327-2
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  Inhibition of bone resorption using bisphosphonates is an important step in palliation of complications of advanced cancer, such as hypercalcemia and metastatic bone disease..The goal of this article was to describe the pharmacologic properties of zoledronic acid (zoledronate) and discuss findings from preclinical and clinical studies of its use in skeletal disorders..Relevant English-language literature was identified using the terms zoledronic acid, zoledronate, Zometa, and 118072-93-8 through searches of MEDLINE (1966-June 2003) and International Pharmaceutical Abstracts (1970-June 2003), and abstract proceedings from the American Society of Clinical Oncology (1997-2002)..Zoledronic acid is a nitrogen-containing bisphosphonate that inhibits bone resorption. It is indicated for the treatment of hypercalcemia of malignancy and for the treatment of patients with multiple myeloma or documented metastasis from solid tumors, in conjunction with standard antineoplastic therapy. The recommended dosage is 4 mg via IV over >or= 15 minutes every 3 or 4 weeks. Compared with pamidronate 90 mg, zoledronic acid 4 and 8 mg provided a higher complete response rate for hypercalcemia of malignancy by day 10 (88.4% and 86.7% vs 69.7%; P = 0.002 and P = 0.015) and longer duration of action (median time to relapse, 30 and 40 days vs 17 days; P = 0.001 and P = 0.007). In patients with breast cancer or multiple myeloma, zoledronic acid was as effective as pamidronate in delaying time to a first skeletal-related event (373 days vs 363 days). In patients with hormone-refractory prostate cancer and bone metastases, zoledronic acid 4 mg reduced the proportion of patients who experienced a skeletal-related event (33% vs 44% with placebo; P = 0.021) or a skeletal fracture (13% vs 22% with placebo; P = 0.015). In patients with bone metastases from solid tumors, zoledronic acid delayed the median time to a first skeletal-related event (230 days vs 163 days with placebo; P = 0.023). Common adverse events include fever, nausea, constipation, fatigue, and bone pain..Zoledronic acid is an effective and generally well-tolerated treatment for hypercalcemia of malignancy and skeletal complications of metastatic bone disease.
• Baumgart, S., Clancy, R. R., Corcoran, L., Davis, L. E., Delivoria-papadopoulos, M., Marro, P. J., Mcgaurn, S. P., & Zirin, S. (1997). Purine metabolism and inhibition of xanthine oxidase in severely hypoxic neonates going onto extracorporeal membrane oxygenation.. Pediatric research, 41(4 Pt 1), 513-20. doi:10.1203/00006450-199704000-00010
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  The effect of allopurinol to inhibit purine metabolism via the xanthine oxidase pathway in neonates with severe, progressive hypoxemia during rescue and reperfusion with extracorporeal membrane oxygenation (ECMO) was examined. Twenty-five term infants meeting ECMO criteria were randomized in a double-blinded, placebo-controlled trial. Fourteen did not receive allopurinol, whereas 11 were treated with 10 mg/kg after meeting criteria and before cannulation, in addition to a 20-mg/kg priming dose to the ECMO circuit. Infant plasma samples before cannulation, and at 15, 30, 60, and 90 min, and 3, 6, 9, and 12 h on bypass were analyzed (HPLC) for allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid concentrations. Urine samples were similarly evaluated for purine excretion. Hypoxanthine concentrations in isolated blood-primed ECMO circuits were separately measured. Hypoxanthine, xanthine, and uric acid levels were similar in both groups before ECMO. Hypoxanthine was higher in allopurinol-treated infants during the time of bypass studied (p = 0.022). Xanthine was also elevated (p < 0.001), and uric acid was decreased (p = 0.005) in infants receiving allopurinol. Similarly, urinary elimination of xanthine increased (p < 0.001), and of uric acid decreased (p = 0.04) in treated infants. No allopurinol toxicity was observed. Hypoxanthine concentrations were significantly higher in isolated ECMO circuits and increased over time during bypass (p < 0.001). This study demonstrates that allopurinol given before cannulation for and during ECMO significantly inhibits purine degradation and uric acid production, and may reduce the production of oxygen free radicals during reoxygenation and reperfusion of hypoxic neonates recovered on bypass.
• Clancy, R. R., Davis, L. E., Jacobs, M. L., Krawczeniuk, M. M., Mcgaurn, S. P., Mm, K., Murphy, J. D., & Norwood, W. I. (1994). The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome.. Pediatrics, 94(6 Pt 1), 820-3.
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  The purpose of this investigation was to determine the pharmacokinetic disposition of intravenous allopurinol and its metabolite oxypurinol in neonates with the hypoplastic left heart syndrome (HLHS) and to evaluate the subsequent degree of xanthine oxidase inhibition using serum uric acid as a marker..Pharmacokinetic data were evaluated in 12 stable preoperative neonates with HLHS after a single intravenous allopurinol administration of 5 mg/kg or 10 mg/kg. Pharmacokinetic parameters were determined for elimination half-life, clearance, volume of distribution, and mean residence time. Xanthine oxidase inhibition, measured by serum uric acid reduction, was also measured..Pharmacokinetic parameters revealed no statistically significant differences between a 5-mg/kg and 10-mg/kg dose of intravenous allopurinol on elimination half-life, clearance, volume of distribution, and mean residence time. Mean serum uric acid levels were significantly reduced from baseline by 39.99 and 42.94%, respectively, in the 5- and 10-mg/kg treatment groups..The enzyme xanthine oxidase plays a key biochemical role in the generation of toxic oxygen-derived free radicals during ischemia-reperfusion conditions. Allopurinol and its active metabolite oxypurinol inhibit xanthine oxidase, and significantly reduce the conversion of hypoxanthine to xanthine and xanthine to uric acid. Cell injury may be caused by toxic oxygen free radicals produced by ischemia-reperfusion injury such as could occur during the repair of HLHS under hypothermic total circulatory arrest. We hypothesize that allopurinol may provide protection from cellular injury in this clinical context.
• Daly, J. M., Davis, L. E., Kressel, H. Y., Lenkinski, R. E., & Shinkwin, M. A. (1993). The effect of dietary protein depletion on hepatic 5-fluorouracil metabolism.. Cancer, 72(12), 3715-22. doi:10.1002/1097-0142(19931215)72:12<3715::aid-cncr2820721225>3.0.co;2-w
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  Protein calorie malnutrition, which is highly prevalent in tumor-bearing hosts, increases toxicity to 5-fluorouracil (5-FU), but the mechanisms are unclear. This study investigated the effects of protein depletion on 5-FU in vivo hepatic metabolism using F19-nuclear magnetic resonance spectroscopy (19F-NMRS)..Rats received normal (21.5%) or low (2.5%) protein diet for 25 days. 5-FU was injected intraperitoneally, and hepatic fluorine spectra were obtained. Parallel experiments were conducted to determine serum 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) and to measure hepatic dihydropyrimidine dehydrogenase (DPD) activity..The mean time of initial detection of fluoro-beta-alanine and the mean duration of the 5-FU signal in the liver were significantly prolonged in the low-protein group. 5-FU clearance and hepatic DPD activity were significantly lower in the low-protein group. Low-protein animals demonstrated increased toxicity, with diarrhea, weight loss, leukopenia (P < 0.001), and an 85% mortality, compared with regular diet animals, who had mild diarrhea and weight loss but no leukopenia and a 12% mortality..Protein depletion results in increased toxicity to 5-FU, which is associated with a significantly decreased rate of hepatic metabolism and clearance of 5-FU and a significant decrease in hepatic DPD activity. 19F-NMRS can noninvasively identify these alterations of 5-FU metabolism in vivo and may serve as a useful guide to determining chemotherapy dosage adjustments to reduce toxicity.
• Davis, L. E. (1991). Long-Term Complications of Antineoplastic Agents. Journal of Pharmacy Practice, 4(2), 131-150. doi:10.1177/089719009100400208
• Alberts, D. S., Davis, L. E., Griswold, D. P., Plezia, P. M., & Roe, D. J. (1988). Predictive model for plasma concentration-versus-time profiles of investigational anticancer drugs in patients.. Journal of the National Cancer Institute, 80(11), 815-9. doi:10.1093/jnci/80.11.815
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  We report a model that provides a strong correlation between mouse toxicity data [mouse lethal dose 10% (LD10)] and human plasma concentration-versus-time (CXT) data for 22 commonly used anticancer agents. Mouse toxicity data (LD10) from two dosing schedules, daily times one and daily times seven, were evaluated for the two mouse strains BDF/1 and Swiss. Data from BDF/1 mice were selected for analysis because they were more abundant. Strong correlations were found between LD10 and human plasma CXT data for both daily times one and daily times seven dosing schedules--ln (CXT) = -1.6504 + [0.8408 X ln (LD10)], r = .84, P less than .0001, and ln (CXT) = -0.0754 + [0.8954 X ln (LD10)], r = .90, P less than .0001, respectively. These correlations may serve as useful models to predict the maximally tolerated dose of an investigational anticancer agent prior to entry into clinical trials and to assist in the selection of clinically relevant in vitro CXTs for new-agent screening against human tumors.

Poster Presentations

• Nakata, L., Davis, L., Place, S., & Nicholas, S. (2025, March).

  Impact of Dose and Schedule Changes on Clinical Outcomes with Sacituzumab and Govitecan

  . HOPA Annual conference. Portland, Oregon: Hematology Oncology Pharmacy Association.
• Poladia, P., Nix, D. E., Segar, J., & Davis, L. (2024). Correlates of neuropathy in patients with breast cancer receiving taxane-based neoadjuvant or adjuvant chemotherapy. . Trainee research poster presentation at the 2024 Annual Meeting of HOPA, Tampa, FL, Abstract 050..
• Warholak, T. L., Davis, L., Antwi, P. B., & Campbell, A. M. (2023, July). Fixed versus random weekly team assignments and student outcomes in a therapeutics course. American Association of Colleges of Pharmacy Annual Meeting. Aurora, CO.
• Babiker, H. M., Mahadevan, D., Sundrarajeen, S., Placencia, C., Rensvold, D. M., Castillo, E., Davis, L., Shaheen, M., Canamar, R., Lim, M. R., Myers, T. J., & Paradiso, L. J. (2019, Fall). Phase 1 trial of MEK1 inhibitor E6201 Plus Dabrafenib in patients (pts) with BRAF V600-mutated metastatic melanoma (MM) with central nervous system (CNS) metastases (mets).. 17th International Congress of the Society for Melanoma Research. Salt Lake City: ICSMR.