Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

Reshma Rangwala, Yunyoung C. Chang, Janice Hu, Kenneth M. Algazy, Tracey L. Evans, Leslie A. Fecher, Lynn M. Schuchter, Drew A. Torigian, Jeffrey T. Panosian, Andrea B. Troxel, Kay See Tan, Daniel F. Heitjan, Angela M. DeMichele, David J. Vaughn, Maryann Redlinger, Abass Alavi, Jonathon Kaiser, Laura Pontiggia, Lisa E. Davis, Peter J. O'DwyerRavi K. Amaravadi

Research output: Contribution to journalArticle

198 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1391-1402
Number of pages12
JournalAutophagy
Volume10
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Hydroxychloroquine
Autophagy
Melanoma
Neoplasms
Maximum Tolerated Dose
Anorexia
Nausea
Fatigue
temsirolimus
Stomatitis
Physiological Stress
Exanthema
Positron-Emission Tomography
Disease-Free Survival
Weight Loss
Cell Death
Pharmacokinetics

Keywords

  • Autophagy
  • Clinical trial
  • Hydroxychloroquine
  • Melanoma
  • MTOR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Rangwala, R., Chang, Y. C., Hu, J., Algazy, K. M., Evans, T. L., Fecher, L. A., ... Amaravadi, R. K. (2014). Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy, 10(8), 1391-1402. https://doi.org/10.4161/auto.29119

Combined MTOR and autophagy inhibition : Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. / Rangwala, Reshma; Chang, Yunyoung C.; Hu, Janice; Algazy, Kenneth M.; Evans, Tracey L.; Fecher, Leslie A.; Schuchter, Lynn M.; Torigian, Drew A.; Panosian, Jeffrey T.; Troxel, Andrea B.; Tan, Kay See; Heitjan, Daniel F.; DeMichele, Angela M.; Vaughn, David J.; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E.; O'Dwyer, Peter J.; Amaravadi, Ravi K.

In: Autophagy, Vol. 10, No. 8, 01.01.2014, p. 1391-1402.

Research output: Contribution to journalArticle

Rangwala, R, Chang, YC, Hu, J, Algazy, KM, Evans, TL, Fecher, LA, Schuchter, LM, Torigian, DA, Panosian, JT, Troxel, AB, Tan, KS, Heitjan, DF, DeMichele, AM, Vaughn, DJ, Redlinger, M, Alavi, A, Kaiser, J, Pontiggia, L, Davis, LE, O'Dwyer, PJ & Amaravadi, RK 2014, 'Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma', Autophagy, vol. 10, no. 8, pp. 1391-1402. https://doi.org/10.4161/auto.29119
Rangwala, Reshma ; Chang, Yunyoung C. ; Hu, Janice ; Algazy, Kenneth M. ; Evans, Tracey L. ; Fecher, Leslie A. ; Schuchter, Lynn M. ; Torigian, Drew A. ; Panosian, Jeffrey T. ; Troxel, Andrea B. ; Tan, Kay See ; Heitjan, Daniel F. ; DeMichele, Angela M. ; Vaughn, David J. ; Redlinger, Maryann ; Alavi, Abass ; Kaiser, Jonathon ; Pontiggia, Laura ; Davis, Lisa E. ; O'Dwyer, Peter J. ; Amaravadi, Ravi K. / Combined MTOR and autophagy inhibition : Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. In: Autophagy. 2014 ; Vol. 10, No. 8. pp. 1391-1402.
@article{b7f6297cffe04159b99f5fcca70ca997,
title = "Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma",
abstract = "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.",
keywords = "Autophagy, Clinical trial, Hydroxychloroquine, Melanoma, MTOR",
author = "Reshma Rangwala and Chang, {Yunyoung C.} and Janice Hu and Algazy, {Kenneth M.} and Evans, {Tracey L.} and Fecher, {Leslie A.} and Schuchter, {Lynn M.} and Torigian, {Drew A.} and Panosian, {Jeffrey T.} and Troxel, {Andrea B.} and Tan, {Kay See} and Heitjan, {Daniel F.} and DeMichele, {Angela M.} and Vaughn, {David J.} and Maryann Redlinger and Abass Alavi and Jonathon Kaiser and Laura Pontiggia and Davis, {Lisa E.} and O'Dwyer, {Peter J.} and Amaravadi, {Ravi K.}",
year = "2014",
month = "1",
day = "1",
doi = "10.4161/auto.29119",
language = "English (US)",
volume = "10",
pages = "1391--1402",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "8",

}

TY - JOUR

T1 - Combined MTOR and autophagy inhibition

T2 - Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

AU - Rangwala, Reshma

AU - Chang, Yunyoung C.

AU - Hu, Janice

AU - Algazy, Kenneth M.

AU - Evans, Tracey L.

AU - Fecher, Leslie A.

AU - Schuchter, Lynn M.

AU - Torigian, Drew A.

AU - Panosian, Jeffrey T.

AU - Troxel, Andrea B.

AU - Tan, Kay See

AU - Heitjan, Daniel F.

AU - DeMichele, Angela M.

AU - Vaughn, David J.

AU - Redlinger, Maryann

AU - Alavi, Abass

AU - Kaiser, Jonathon

AU - Pontiggia, Laura

AU - Davis, Lisa E.

AU - O'Dwyer, Peter J.

AU - Amaravadi, Ravi K.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - Clinical trial

KW - Hydroxychloroquine

KW - Melanoma

KW - MTOR

UR - http://www.scopus.com/inward/record.url?scp=84905826525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905826525&partnerID=8YFLogxK

U2 - 10.4161/auto.29119

DO - 10.4161/auto.29119

M3 - Article

C2 - 24991838

AN - SCOPUS:84905826525

VL - 10

SP - 1391

EP - 1402

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 8

ER -