Tamrintamab pamozirine (SC-003) in patients with platinum-resistant/refractory ovarian cancer: Findings of a phase 1 study

Abstract

Objective: Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC (NCT02539719).

Methods: Patients received SC-003 at 1 of 6 dose levels (0.025-0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab.

Results: Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression.

Conclusions: SC-003 lacked the requisite safety profile and antitumor activity to warrant further development.

Keywords: Antibody-drug conjugate; Dipeptidase 3; Epithelial ovarian carcinoma; Pyrrolobenzodiazepine; SC-003; Tumor-initiating cells.

Conflict of interest statement

Declaration of competing interest Erika Hamilton: Consulting/advisory roles for Pfizer, Genentech/Roche, Flatiron Health, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics; institutional research funding from Seattle Genetics, Puma, AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, StemcentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc., Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta Pharma, Takeda, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Torque Therapeutics. David O'Malley: Reports personal fees and other from AstraZeneca, personal fees and other from Clovis, personal fees and other from Tesaro, personal fees and other from ImmunoGen, personal fees from Ambry, personal fees and other from Janssen/J&J, personal fees and other from AbbVie, personal fees and other from Regeneron, personal fees and other from Amgen, personal fees from Novocure, personal fees and other from Genentech/Roche, other from VentiRx, other from Array BioPharma, other from EMD Serono, other from Ergomed, other from Ajinomoto Inc., other from Ludwig Cancer Research, other from Stemcentrx, Inc., other from Cerulean Pharma personal fees and other from GOG Foundation, other from Bristol-Myers Squibb Co, other from Serono Inc., other from TRACON Pharmaceuticals, other from Yale University, other from New Mexico Cancer Care Alliance, other from INC Research, Inc., other from inVentiv Health Clinical, other from Iovance Biotherapeutics, Inc., other from PRA Intl, personal fees from Myriad Genetics, personal fees and other from Eisai, personal fees and other from Agenus, personal fees and other from GSK, personal fees from Tarveda, personal fees and other from Merck. Roisin O'Cearbhaill: Research support from NIH/NCI Cancer Center Support Grant (P30 CA008748); honoraria from Clovis, TESARO, Inc., and GlaxoSmithKline. Mihaela Cristea: Consultant for AbbVie, Inc., speaker/consultant for AstraZeneca. Gini Fleming: Advisory board for GSK; honoraria from Curio Science, UpToDate; research support (institutional) from Corcept, AbbVie, Genentech, Tesaro, Syndax, Forty Seven, Inc., Iovance, Syros, Astex, Merck, Sanofi, Sermonix, Compugen, Incyte, Leap Therapeutics, F. Hoffman-La Roche, Eisai, Sanofi. Bilal Tariq: Former employee of AbbVie and may own stock. Kathleen Moore: Consultant/advisory role for AstraZeneca, Genentech/Roche, ImmunoGen, Clovis, Tesaro, Pfizer, Janssen, Aravive, VBL Therapeutics, Onco Med, Samumed, Eisai, GSK, Vavotar, Tarveda, AbbVie; institutional research funding from Genentech/Roche, ImmunoGen, Clovis, Tesaro, Lilly. A. Fong, D. French, M. Rossi, D. Brickman: AbbVie employees and may own stock.

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