Lisa Davis
- Clinical Professor
- Member of the Graduate Faculty
Contact
- (520) 626-5625
- Roy P. Drachman Hall, Rm. B207Q
- Tucson, AZ 85721
- lisadavis@arizona.edu
Degrees
- Pharm.D. Pharmacy
- University of Kentucky, Lexington, Kentucky, United States
- B.S. Pharmacy
- University of Arizona, Tucson, Arizona, United States
Work Experience
- University of Arizona, Tucson, Arizona (2016 - Ongoing)
- University of the Sciences (2011 - 2015)
- Philadelphia College of Pharmacy (2005 - 2015)
- University of Pennsylvania, Philadelphia, Pennsylvania (2003 - 2019)
- Philadelphia College of Pharmacy (1993 - 2011)
- Philadelphia College of Pharmacy (1987 - 1993)
Awards
- Educator of the Year Class of 2024
- Spring 2024 (Award Nominee)
Licensure & Certification
- Pharmacotherapy Specialist, Board of Pharmaceutical Specialties (1994)
- Oncology Pharmacy Specialist, Board of Pharmaceutical Specialties (2000)
- Registered Pharmacist Immunizer, Arizona Board of Pharmacy (2016)
- Registered Pharmacist, Arizona Board of Pharmacy (1983)
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
2024-25 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2025) -
Drug Metabolism + Dsptn
CBIO 550 (Spring 2025) -
Drug Metabolism + Dsptn
PCOL 550 (Spring 2025) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2025) -
Pharmacotherapeutics V
PHPR 860E (Spring 2025) -
Intro to Pharmacy Practice
PHPR 805 (Fall 2024) -
Introduction to Pharmacology
PCOL 501 (Fall 2024) -
Introduction to Pharmacology
PHSC 501 (Fall 2024) -
Pharmacokinetics
PHPR 818 (Fall 2024)
2023-24 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2024) -
Drug Metabolism + Dsptn
PCOL 550 (Spring 2024) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2024) -
Pharmacotherapeutics V
PHPR 860E (Spring 2024) -
Introduction to Pharmacology
PCOL 501 (Fall 2023) -
Pharmacokinetics
PHPR 818 (Fall 2023) -
Pharmacy Practice
PHPR 809 (Fall 2023)
2022-23 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2023) -
Drug Metabolism + Dsptn
PCOL 550 (Spring 2023) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2023) -
Pharmacotherapeutics V
PHPR 860E (Spring 2023) -
Introduction to Pharmacology
PCOL 501 (Fall 2022) -
Introduction to Pharmacology
PHSC 501 (Fall 2022) -
Pharmacokinetics
PHPR 818 (Fall 2022) -
Pharmacy Practice
PHPR 809 (Fall 2022)
2021-22 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2022) -
Drug Metabolism + Dsptn
CBIO 550 (Spring 2022) -
Drug Metabolism + Dsptn
PCOL 550 (Spring 2022) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2022) -
Pharmacotherapeutics V
PHPR 860E (Spring 2022) -
Introduction to Pharmacology
PCOL 501 (Fall 2021) -
Introduction to Pharmacology
PHSC 501 (Fall 2021) -
Pharmacokinetics
PHPR 818 (Fall 2021) -
Pharmacy Practice
PHPR 809 (Fall 2021) -
Techniques in Pharm Sci
PCOL 505 (Fall 2021) -
Techniques in Pharm Sci
PHSC 505 (Fall 2021)
2020-21 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2021) -
Drug Dsptn+Metabolism
CBIO 550 (Spring 2021) -
Drug Dsptn+Metabolism
PCOL 550 (Spring 2021) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2021) -
Pharmacotherapeutics V
PHPR 860E (Spring 2021) -
Introduction to Pharmacology
PCOL 501 (Fall 2020) -
Introduction to Pharmacology
PHSC 501 (Fall 2020) -
Pharmacokinetics
PHPR 818 (Fall 2020) -
Pharmacy Practice
PHPR 809 (Fall 2020) -
Techniques in Pharm Sci
PCOL 505 (Fall 2020) -
Techniques in Pharm Sci
PHSC 505 (Fall 2020)
2019-20 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2020) -
Drug Dsptn+Metabolism
PCOL 550 (Spring 2020) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2020) -
Oncologic Diseases
PHPR 825 (Spring 2020) -
Pharmacotherapeutics
PHPR 875C (Spring 2020) -
Basic Pharmacokinetics
PHPR 807A (Fall 2019) -
Basic Pharmacokinetics
PHSC 507A (Fall 2019) -
Pharmacokinetics Disc
PHPR 808A (Fall 2019) -
Pharmacokinetics Disc
PHSC 508A (Fall 2019)
2018-19 Courses
-
Appl Pharmgenet &Precision Med
PHPR 887 (Spring 2019) -
Drug Dsptn+Metabolism
CBIO 550 (Spring 2019) -
Drug Dsptn+Metabolism
PCOL 550 (Spring 2019) -
Intro to Pharmacology/MedChem
PCOL 824 (Spring 2019) -
Oncologic Diseases
PHPR 825 (Spring 2019) -
Pharmacotherapeutics
PHPR 875A (Spring 2019) -
Pharmacotherapeutics
PHPR 875C (Spring 2019) -
Basic Pharmacokinetics
PHPR 807A (Fall 2018) -
Basic Pharmacokinetics
PHSC 507A (Fall 2018) -
Case Dis Med Chem+Pharm
PHPR 822 (Fall 2018) -
Pharmacokinetics Disc
PHPR 808A (Fall 2018) -
Pharmacokinetics Disc
PHSC 508A (Fall 2018) -
Pharmacology I
PCOL 571A (Fall 2018) -
Pharmacology I
PCOL 871A (Fall 2018)
2017-18 Courses
-
Drug Dsptn+Metabolism
CBIO 550 (Spring 2018) -
Drug Dsptn+Metabolism
PCOL 550 (Spring 2018) -
Indv Med:Appl Pharmgenet
PHPR 887 (Spring 2018) -
Oncologic Diseases
PHPR 825 (Spring 2018) -
Pharmacotherapeutics
PHPR 875C (Spring 2018) -
Basic Pharmacokinetics
PHPR 807A (Fall 2017) -
Basic Pharmacokinetics
PHSC 507A (Fall 2017) -
Case Dis Med Chem+Pharm
PHPR 822 (Fall 2017) -
Pharmacokinetics Disc
PHPR 808A (Fall 2017) -
Pharmacokinetics Disc
PHSC 508A (Fall 2017) -
Pharmacology I
PCOL 571A (Fall 2017) -
Pharmacology I
PCOL 871A (Fall 2017)
2016-17 Courses
-
Indv Med:Appl Pharmgenet
PHPR 887 (Spring 2017) -
Pharmacotherapeutics
PHPR 875C (Spring 2017) -
Basic Pharmacokinetics
PHPR 807A (Fall 2016) -
Basic Pharmacokinetics
PHSC 507A (Fall 2016) -
Case Dis Med Chem+Pharm
PHPR 822 (Fall 2016) -
Pharmacokinetics Disc
PHPR 808A (Fall 2016) -
Pharmacokinetics Disc
PHSC 508A (Fall 2016) -
Pharmacology I
PCOL 571A (Fall 2016) -
Pharmacology I
PCOL 871A (Fall 2016)
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.
- 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.
Journals/Publications
- Erstad, B. L., & Davis, L. E. (2024). Fixed Versus Body-Sized-Based Dosing of Monoclonal Antibodies. The Annals of pharmacotherapy, 58(1), 91-95.More infoMonoclonal 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.
- 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. (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/zxab457More infoIn 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
- 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.More info: 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.More infoHigh-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.More infoA 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.
- 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-18-2204More infoPurpose 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.
- 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.More infoIn 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.
- 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.More infoWe 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.More infoThe 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.More infoBlocking 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.More infoPreclinical 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.More infoThe 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.
Poster Presentations
- 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.