TY - JOUR
T1 - A Phase I dose-escalation study to evaluate the safety and tolerability of evofosfamide in combination with ipilimumab in advanced solid malignancies
AU - Hegde, Aparna
AU - Jayaprakash, Priyamvada
AU - Couillault, Coline A.
AU - Piha-Paul, Sarina
AU - Karp, Daniel
AU - Rodon, Jordi
AU - Pant, Shubham
AU - Fu, Siqing
AU - Dumbrava, Ecaterina E.
AU - Yap, Timothy A.
AU - Subbiah, Vivek
AU - Bhosale, Priya
AU - Coarfa, Cristian
AU - Higgins, Jack P.
AU - Williams, Eric T.
AU - Wilson, Thomas F.
AU - Lim, Jo Ann
AU - Meric-Bernstam, Funda
AU - Sumner, Elizabeth
AU - Zain, Hira
AU - Nguyen, Di
AU - Nguyen, Ly M.
AU - Rajapakshe, Kimal
AU - Curran, Michael A.
AU - Hong, David S.
N1 - Funding Information:
S. Piha-Paul reports other support from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Inc., Eli lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmune, LLC., Medivation, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, and NCI/NIH P30CA016672 outside the submitted work. J. Rodon reports grants and personal fees from Novartis, Spectrum Pharmaceuticals, Inc., and Pfizer; personal fees from Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Roche Pharmaceuticals, Ellipses Pharma, Certera, NovellusDX, and IONCTURA SA; personal fees and other support from Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, and Molecular Partners; grants, personal fees, and other support from Bayer; grants from Blueprint Pharmaceuticals, Tocagen, Symphogen, BioAlta, GenMab, CytomX, Kelun-Biotech, Ipsen, and Takeda-Millenium; grants and other support from GlaxoSmithKline; and other support from ESMO, Department of Defense, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe,
Funding Information:
Karolinska Cancer Institute, King Abdullah International Medical Research Center, WIN Consortium, Janssen, European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, and Elsevier outside the submitted work. T.A. Yap reports grants from Artios, Constellation, Cyteir, Eli Lilly, Forbius, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyo-pharm, Kyowa, Novartis, Ribon Therapeutics, Regeneron, Sanofi, Scholar Rock, Tesaro, and Vertex Pharmaceuticals; grants and personal fees from AstraZeneca, Bayer, Clovis, EMD Serono, F-Star, Merck, Pfizer, Repare, and Seattle Genetics; and personal fees from Almac, Aduro, Atrin, Axiom, Bristol Myers Squibb, Calithera, Cybrexa, Guidepoint, Ignyta, I-Mab, Janssen, Roche, Rubius, Schrodinger, Varian, and Zai Labs outside the submitted work. V. Subbiah reports grants from LOXO Oncology/Eli Lilly during the conduct of the study. V. Subbiah also reports consulting or advisory role with MedImmune, Helsinn Therapeutics, Loxo, R-Pharma-US, and QED Pharma; research funding from Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Roche (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst), Amgen (Inst), and Turningpoint Therapeutics (Inst); travel, accommodations, and expenses support from PharmaMar, Bayer, Novartis, and Helsinn Therapeutics; and other relationship support from Medscape. J.P. Higgins reports personal fees from Molecular Templates during the conduct of the study, as well as personal fees from Molecular Templates outside the submitted work. E.T. Williams reports other support from Molecular Templates outside the submitted work, as well as employment with Molecular Templates. F. Meric-Bernstam reports personal fees from Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Ltd., Genentech, IBM Watson, Jackson Laboratory, Kolon Life Sciences, OrgiMed, PACT Pharma, Parexl International, Pfizer Inc., Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, Chugai Biopharmaceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey; grants from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc., CytomX Therapeutics, Daiichi Sanko Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant, Millennium Pharmaceuticals, Novartis, Puma Biotechnology, and Taiho Pharmaceutical; and nonfinancial support from Beth Israel Deaconess Medical Center outside the submitted work. M.A. Curran reports personal fees from ImmunoGenesis, Inc. and Agenus, Inc. during the conduct of the study. M.A. Curran also reports personal fees from ImmunoGenesis, Inc., Agenus, Inc., Alligator Bioscience, Inc., ImmunOs, Inc., Oncoresponse, Inc., Pieris, Inc., Nurix, Inc., Aptevo, Inc., Servier, Inc., Kineta, Inc., Salarius, Inc., Kineta, Inc., Xencor, Inc., and Mereo, Inc., as well as grants and personal fees from ImmunoMet, Inc. outside the submitted work; in addition, M.A. Curran has a patent for Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies issued to multiple licensees. D.S. Hong reports grants from NIH and Molecular Templates
Funding Information:
This trial and associated correlative studies were supported by Molecular Templates, Inc.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. Patients and Methods: In a phase I, 3þ3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. Results: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n ¼ 11), pancreatic cancer (n ¼ 7), immunotherapy-resistant melanoma (n ¼ 2), and human papillomavirus-negative head and neck cancer (n ¼ 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. Conclusions: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
AB - Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. Patients and Methods: In a phase I, 3þ3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. Results: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n ¼ 11), pancreatic cancer (n ¼ 7), immunotherapy-resistant melanoma (n ¼ 2), and human papillomavirus-negative head and neck cancer (n ¼ 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. Conclusions: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
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UR - http://www.scopus.com/inward/citedby.url?scp=85106981404&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4118
DO - 10.1158/1078-0432.CCR-20-4118
M3 - Article
C2 - 33771853
AN - SCOPUS:85106981404
SN - 1078-0432
VL - 27
SP - 3050
EP - 3060
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -