Phase 1b expansion study of CX-5461 in patients with solid tumors and BRCA2 and/or PALB2 mutation.

Abstract

TPS622 Background: BRCA and PALB2 proteins play important roles in the maintenance of genomic stability as they are essential for error-free repair of double-stranded DNA breaks, while deficiency of these proteins promotes error-prone DNA repair, chromosomal instability and carcinogenesis. Inherited mutations in BRCA genes predispose to various early onset cancers. Poly(ADP-ribose) polymerase inhibitors (PARPi) inducing synthetic lethality in tumors with homologous recombination (HR)-mediated DNA repair deficiencies have been approved for treatment in patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma. Unfortunately, resistance to PARPi associated with multiple mechanisms can be observed over time, suggesting a prominent unmet need for the development of new treatment options. CX-5461, a G-quadruplex stabilizer, employs an alternative mechanism in destabilizing the DNA replication fork to promote DNA damage resulting in cancer cell lethality in HR-deficient (HRD) tumors, thus represent a promising therapeutic strategy for patients with defects in HR-repair. Methods: A prior phase I dose escalation study has been completed for CX-5461 (CCTG IND.231, NCT02719977) but additional safety data are required to define the chronic tolerable dose for phase 2 trials. Therefore, a phase Ib expansion trial was designed for two doses preselected from our previous phase I trial to determine the final recommended phase II dose (RP2D) by evaluating safety, tolerability and objective response rate in a more selected population. This trial will enroll patients in two cohorts; the main cohort recruiting patients with pancreatic, breast, ovarian or prostate cancer with germline BRCA2 and/or PALB2 mutation, and an exploratory cohort recruiting ovarian cancer patients with BRCA1 and/or other HRD-associated mutations. Major eligibility criteria include documented evidence of pathogenic or likely pathogenic germline mutation in BRCA2 and/or PALB2 for main cohort patients, documented evidence of pathogenic or likely pathogenic germline mutation or a clinically actionable somatic mutation in BRCA1 and/or other HRD-associated mutation for exploratory cohort. Patients with non-adenocarcinoma histology of pancreatic cancer, known photosensitivity disorders of the skin, or patients with ophthalmological conditions will not be enrolled. An initial 16 eligible patients for the main cohort and 10 eligible patients for the exploratory cohort will be enrolled in parallel to receive CX-5461 at 250mg/m2, delivered via IV infusion on Day 1 and Day 8 of a 28-day cycle. Upon completion of the initial arms with no safety concerns, another two arms will open to enroll an additional 16 patients for the main cohort and 10 patients for the exploratory cohort to receive CX-5461 at 325mg/m2 of the same dosing schedule. Clinical trial information: NCT04890613.