Randomized, phase Ib/II study of M6620 + avelumab + carboplatin vs standard care (sc) in patients (pts) with platinum-sensitive poly (ADP-ribose) polymerase inhibitor-(PARPi)-resistant ovarian cancer

Abstract

Background: Maintenance PARPis are standard of care for pts with recurrent ovarian cancer. Optimal treatment following PARPi resistance is currently unknown. PARPi‐resistant recurrent ovarian cancer with expected platinum sensitivity is associated with high mutational load and homologous recombination deficiency. Ataxia telangiectasia and rad3‐related (ATR) inhibition combined with immune checkpoint inhibition and DNA‐damaging agents, such as carboplatin, has potential for activity following PARPi resistance by increasing DNA damage, immunologic cell death and potential immunological targets. Trial design: NCT03704467 is an open‐label, multicentre, international, 2‐part study including participants with PARPi‐resistant, recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer. Pts must have received ≥2 platinum‐based tx (and responded to the last platinum‐based tx); last platinum dose ≥ 6 months prior; ≥4 months PARPi maintenance tx before progression (PD) and known BRCA1/2 mutation status. Part A is a safety run‐in, with dose de‐escalation to find a recommended phase 2 dose (RP2D) of 3weekly carboplatin + M6620 (an ATR inhibitor) + avelumab (a programmed death ligand‐blocking mAB; all iv). Planned starting doses are carboplatin AUC 5; M6620 90 mg/m2; avelumab 1600 mg. In Part B, pts will be randomized (stratified by BRCA gene status) to carboplatin + M6620 (at the RP2D from Part A) + avelumab or SC (platinum‐based doublet ± bevacizumab; investigator's choice). After completion of ≤ 6 triplet cycles in Part A/B, pts can receive avelumab maintenance tx (800 mg every 2 weeks) until PD, unacceptable toxicity, withdrawal of consent, death, or ≥ 12 months tx following confirmed complete response. The primary objective of Part B is progression‐free survival. Secondary objectives for Part A/B include safety/tolerability; pharmacokinetics, immunogenicity, antitumor activity (BOR, duration of response, time to progression/subsequent tx). Planned enrolment: Part A 3–18 pts (modified 3 + 3 design); Part B ∼72 pts. Enrolment began in Nov 2018 and the first patient is enrolled. Clinical trial identification: NCT03704467. Editorial acknowledgement: Lisa Jolly, PhD, of Bioscript Science Macclesfield, UK, funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study: Merck KGaA. Funding: Merck KGaA. Disclosure: S. Banerjee: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis; Honoraria (self): Merck Serono; Honoraria (self): Nucana; Honoraria (self): Immunogen; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Gamamabs. I. Vergotte: Advisory / Consultancy: Advaxis, Inc.; Advisory / Consultancy: Eisai Inc.; Advisory / Consultancy: MSD Belgium; Advisory / Consultancy: Roche NV; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: F. Hoffmann‐La Roche Ltd; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy: Clovis Oncology Inc.; Advisory / Consultancy: AstraZeneca NV; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): Oncoinvent AS; Advisory / Consultancy: Immunogen Inc; Advisory / Consultancy: Sotio; Research grant / Funding (institution): Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Stichting tegen Kanker; Travel / Accommodation / Expenses: Takeda Oncology; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Clovis; Travel / Accommodation / Expenses: Immunogen. N. Colombo: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: BIOCAD; Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Leadership role, Subject Editor: ESMO Clinical Guidelines; Non‐remunerated activity/ies, Chair Scientific Committee: ACTO Onlus. R. Grisham: Advisory / Consultancy: Clovis; Advisory / Consultancy: Mateon. K.T. Mehr: Full / Part‐time employment: Merck KGaA. M. Falk: Full / Part‐time employment: Merck KGaA. F. Beier: Full / Part‐time employment: Merck KGaA. M. Hennessy: Full / Part‐time employment: EMD Serono. A. Schroeder: Full / Part‐time employment: Merck KGaA. All other authors have declared no conflicts of interest.