631P - Phase Ib expansion study of CX-5461 in patients with solid tumours and BRCA2 and/or PALB2 mutation

Background

G-quadruplex (G4) structures can enhance propensity for DNA damage and they induce chromosome breaks, which activate homologous recombination (HR) repair pathway. CX-5461, a small molecule G4 stabilizer, selectively attacks HR-deficient cancer cells. We report the preliminary results of an open-label, multi-center, phase Ib expansion assessing CX-5461 in patients (pts) with solid tumours and BRCA2 and/or PALB2 mutation (NCT04890613).

Methods

CX-5461 was administered at two dose levels on Days 1 and 8 of a 28-day cycle to pts with pancreatic, prostate, breast or ovarian cancer (OC). Study comprises two cohorts: main cohort, with arm A (250 mg/m²) and B (325 mg/m²) enrolling pts with BRCA2 / PALB2 mutations, and exploratory cohort incorporating arm C (250 mg/m²) and D (325 mg/m²) for OC pts with BRCA1/ HR mutations. Primary objective is to determine recommended phase II dose of CX-5461. Secondary objectives: assessment of safety, tolerability and its anti-tumor activity.

Results

Of 28 pts enrolled, 22 have completed at least one cycle and were evaluable for DLT. Arm A included 2 OC pts, 5 breast cancer and 2 pancreatic cancer and Arm C and D: 10 and 3 OC pts. Among 22 pts, 36% had BRCA1 somatic, 14% BRCA1 germline, 4.5% somatic/germline BRCA1, 32% BRCA2 germline, 9% PALB2 germline and 4.5% HR mutations. Pts were heavily pretreated with median number of 6 lines (2-10): 77% prior platinum, 41% bevacizumab and 86% PARPi. Pts received median number of 4 doses (2-36) of CX-5461. Overall grade 3/4 adverse events (AE) were reported in 50%. Eight (36%) pts had grade 3/4 AE related to CX-5461. Five (23%) had grade 3 AE of special interest: 2 palmar-plantar erythrodysesthesia, 2 photosensitivity, 1 ocular photosensitivity; no grade 4 AE. Of the fifteen pts evaluable for response, 40% achieved clinical benefit with stable disease (SD) as best response. Of OC pts with SD (n=5), 3 had BRCA1 somatic, 1 BRCA1 germline and 1 HR mutations. All had previously received platinum and PARPi and two had duration of response > 6 months.

Conclusions

This Phase 1b study shows acceptable clinical tolerability and early signals of activity for CX-5461, including post PARP inhibition. Photosensitivity was manageable by preventive measures. Genomic data on resistance mechanisms is being analyzed.

Clinical trial identification

NCT04890613.

Editorial acknowledgement

Legal entity responsible for the study

UHN.

Funding

Senhwa.

Disclosure

H. Han: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: OncLive; Financial Interests, Institutional, Local PI: Zymeworks, Arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, SeaGen, Quantum Leap Healthcare Collaborative, Celcuity, Mersana, Senwha. G. Shapiro: Financial Interests, Institutional, Other, Research funding to Dana-Farber Cancer Institute for conduct of investigator-initiated clinical trials.: Pfizer; Financial Interests, Institutional, Other, Research funding to Dana-Farber Cancer Institute for conduct of investigator-initiated clinical trial.: Eli Lilly; Financial Interests, Personal, Advisory Board, Additional research funding through a Sponsored Research Agreement, paid to Dana-Farber Cancer Institute: Merck KGaA/EMD-Serono; Financial Interests, Personal, Advisory Board: Bicycle Therapeutics, Boehringer Ingelheim, ImmunoMet, Blueprint Medicines, Kymera Therapeutics, Janssen, Xinthera; Financial Interests, Institutional, Other, Research funding through a Sponsored Research Agreement paid to Dana-Farber Cancer Institute: Tango Therapeutics; Financial Interests, Institutional, Other, Research funding through a Sponsored Research Agreement, paid to Dana-Farber Cancer Institute: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Exelixis, Cyteir, AbbVie, Incyte, AstraZeneca, Novartis, Amgen; Financial Interests, Institutional, Funding, For investigator-initiated clinical trials: Pfizer; Financial Interests, Personal and Institutional, Local PI: Bayer, Boehringer Ingelheim, Syros; Financial Interests, Institutional, Funding, For investigator-initiated clinical trial: Lilly; Financial Interests, Institutional, Coordinating PI: Cyclacel; Other, Patent: Dosage regimen for sapacitabine and seliciclib, issued to Geoffrey Shapiro and Cyclacel Pharmaceuticals: Cyclacel; Other, Pending patent: Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition, with Liam Cornell, PhD (Dana-Farber Cancer Institute): Dana-Farber Cancer Institute. L.S. Rosen: Financial Interests, Institutional, Funding, PI at UCLA Health Hem/Onc for Inspirna trial, Institution receives research funding: Inspirna. T. Chao: Financial Interests, Personal, Full or part-time Employment: Senhwa Biosciences, Inc.; Financial Interests, Personal, Stocks/Shares: Tracon Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: BioLineRx. C. Huang: Financial Interests, Personal, Full or part-time Employment: Senhwa Biosciences; Non-Financial Interests, Leadership Role: Senhwa Biosciences. V. Bowering: Non-Financial Interests, Advisory Role, Nurses Advisory board - Lynparza: AstraZeneca; Non-Financial Interests, Advisory Role, Nurses Advisory Role-Niraparib: GSK. All other authors have declared no conflicts of interest.