Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Reshma Rangwala; Robert Leone; Yunyoung C. Chang; Leslie A. Fecher; Lynn M. Schuchter; Amy Kramer; Kay See Tan; Daniel F. Heitjan; Glenda Rodgers; Maryann Gallagher; Shengfu Piao; Andrea B. Troxel; Tracey L. Evans; Angela M. DeMichele; Katherine L. Nathanson; Peter J. O'Dwyer; Jonathon Kaiser; Laura Pontiggia; Lisa E. Davis; Ravi K. Amaravadi

doi:10.4161/auto.29118

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Reshma Rangwala, Robert Leone, Yunyoung C. Chang, Leslie A. Fecher, Lynn M. Schuchter, Amy Kramer, Kay See Tan, Daniel F. Heitjan, Glenda Rodgers, Maryann Gallagher, Shengfu Piao, Andrea B. Troxel, Tracey L. Evans, Angela M. DeMichele, Katherine L. Nathanson, Peter J. O'Dwyer, Jonathon Kaiser, Laura Pontiggia, Lisa E. Davis, Ravi K. Amaravadi

School of Medicine

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202 Scopus citations

Abstract

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/m² 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.

Original language	English (US)
Pages (from-to)	1369-1379
Number of pages	11
Journal	Autophagy
Volume	10
Issue number	8
DOIs	https://doi.org/10.4161/auto.29118
State	Published - Aug 2014

Keywords

Autophagy
Chemotherapy
Clinical trial
Hydroxychloroquine
Melanoma

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.4161/auto.29118

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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), 1369-1379. https://doi.org/10.4161/auto.29118

Rangwala, R, Leone, R, Chang, YC, Fecher, LA, Schuchter, LM, Kramer, A, Tan, KS, Heitjan, DF, Rodgers, G, Gallagher, M, Piao, S, Troxel, AB, Evans, TL, DeMichele, AM, Nathanson, KL, O'Dwyer, PJ, Kaiser, J, Pontiggia, L, Davis, LE & Amaravadi, RK 2014, 'Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma', Autophagy, vol. 10, no. 8, pp. 1369-1379. https://doi.org/10.4161/auto.29118

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title = "Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma",

abstract = "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/m2 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.",

keywords = "Autophagy, Chemotherapy, Clinical trial, Hydroxychloroquine, Melanoma",

author = "Reshma Rangwala and Robert Leone and Chang, {Yunyoung C.} and Fecher, {Leslie A.} and Schuchter, {Lynn M.} and Amy Kramer and Tan, {Kay See} and Heitjan, {Daniel F.} and Glenda Rodgers and Maryann Gallagher and Shengfu Piao and Troxel, {Andrea B.} and Evans, {Tracey L.} and DeMichele, {Angela M.} and Nathanson, {Katherine L.} and O'Dwyer, {Peter J.} and Jonathon Kaiser and Laura Pontiggia and Davis, {Lisa E.} and Amaravadi, {Ravi K.}",

note = "Funding Information: Investigational temozolomide was provided free of charge to patients by Schering-Plough/Merck. No monetary funding was provided by Schering-Plough or Merck. The conduct of this trial was supported by the Abramson Cancer Center. This research was also supported by NCI SPORE Career Development Award 5 P50 CA 93372-04, NCI-K23-CA-120862, RO1 CA169134 (RKA). The authors would like to thank Ray Meade in the UPENN electron microscopy facility. We would like to thank Kurt D{\textquoteright}Andrea, Richard Letrero, and Christopher Watt for providing genotyping analysis for patients in the study.",

year = "2014",

month = aug,

doi = "10.4161/auto.29118",

language = "English (US)",

volume = "10",

pages = "1369--1379",

journal = "Autophagy",

issn = "1554-8627",

publisher = "Landes Bioscience",

number = "8",

}

TY - JOUR

T1 - Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

AU - Rangwala, Reshma

AU - Leone, Robert

AU - Chang, Yunyoung C.

AU - Fecher, Leslie A.

AU - Schuchter, Lynn M.

AU - Kramer, Amy

AU - Tan, Kay See

AU - Heitjan, Daniel F.

AU - Rodgers, Glenda

AU - Gallagher, Maryann

AU - Piao, Shengfu

AU - Troxel, Andrea B.

AU - Evans, Tracey L.

AU - DeMichele, Angela M.

AU - Nathanson, Katherine L.

AU - O'Dwyer, Peter J.

AU - Kaiser, Jonathon

AU - Pontiggia, Laura

AU - Davis, Lisa E.

AU - Amaravadi, Ravi K.

N1 - Funding Information: Investigational temozolomide was provided free of charge to patients by Schering-Plough/Merck. No monetary funding was provided by Schering-Plough or Merck. The conduct of this trial was supported by the Abramson Cancer Center. This research was also supported by NCI SPORE Career Development Award 5 P50 CA 93372-04, NCI-K23-CA-120862, RO1 CA169134 (RKA). The authors would like to thank Ray Meade in the UPENN electron microscopy facility. We would like to thank Kurt D’Andrea, Richard Letrero, and Christopher Watt for providing genotyping analysis for patients in the study.

PY - 2014/8

Y1 - 2014/8

N2 - 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/m2 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.

AB - 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/m2 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.

KW - Autophagy

KW - Chemotherapy

KW - Clinical trial

KW - Hydroxychloroquine

KW - Melanoma

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ER -

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Abstract

Keywords

ASJC Scopus subject areas

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