PAVO: A phase-II, open label, single arm study of niraparib in patients with locally advanced/metastatic PALB2 mutated tumors

Authors Tian Zhang, Thomas Weart, Matthias Weiss, Drew Murray, Minaxi Jhawer, Edward Huynh, Shumei Kato, Amy Cummings, Lydia Usha, Arvinder Bhinder, Rajiv Desai, Brad Johnson, Anjali Avadhani, Cecile Rose T. Vibat, Lauren Lopez, Brynna Driscoll, Annajane Ward, Christie K. Rice, Blathnaid Donovan, Scott Sherrin, Mykel Robble, Stephanie O'Leary, Kimberly Blackwell, Amine Aziez, Stephanie Petrone, Kathleen Harnden, Kimberly Strickland, Sonya Reid, Mark Robson, Andrew S. Paulson, Afshin Dowlati.

Background – Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in treating solid tumors with Homologous Recombination Deficiency (HRD), the inability to repair DNA double-stranded breaks through the Homologous Recombination Repair (HRR) pathway. Specific genetic and epigenetic alterations result in defective HRR function. Bi-allelic loss of BRCA1 or BRCA2 principally drives HRR deficiency. While BRCA1/2 are instrumental to HRR, multiple genes, including PALB2, impact the HRR pathway. PALB2 mutations occur in an estimated 0.97% to 3.66% of solid tumors [AACR GENIE PALB2] and are associated with susceptibility to various cancers. No clinically approved therapies specifically targeting PALB2 currently exist. Emerging evidence suggests that patients with germline or somatic PALB2 mutations may benefit from PARPi treatment, which has potential to be a new tumor agnostic therapy option across a wide range of solid tumors.

Methods – PAVO is a pan-tumor, single-arm, multicenter Phase-II study assessing the safety and efficacy of niraparib (a PARPi) in patients who harbor a confirmed PALB2 mutation. The study plans to enroll up to 110 adult subjects. Eligible participants must have: locally advanced or metastatic solid tumor(s); confirmed pathogenic or likely pathogenic somatic or germline PALB2 mutation; received all standard of care (SOC) therapy for their tumor type, or are unlikely to derive benefit from SOC therapy in the opinion of the treating physician; ECOG performance status of 0 or 1; life expectancy of ≥ 12 weeks with adequate organ/bone marrow function. Exclusion criteria include a confirmed somatic or germline BRCA1/2 mutation, prior treatment with any PARPi, ovarian or prostate cancer, or rapid progression while on platinum-based therapy in the metastatic setting. Niraparib will be administered in 28 day cycles with daily dosing, as outlined in the protocol. Participants will continue study treatment until documented radiographic progression, unacceptable toxicity, death, or consent withdrawal. The primary study endpoint is objective response rate (ORR), defined as the proportion of participants who have partial or complete response to therapy as assessed by Independent Central Review. Secondary endpoints include DOR, PFS, and CBR. PAVO is sponsored by Tempus with support from GSK (GlaxoSmithKline). The trial opened in March 2022. Tempus molecular data tracking (integrated NGS and EMR data) and the TIME Trial program (rapid match of patients to Just in TIME sites for clinical trials), enable patient identification and prescreening. Enrollment occurs through a combination of TIME and prospective clinical sites, where individualized prescreening models are in development. New site identification and referral of molecularly eligible patients to enrolling centers are ongoing.

Clinical Trial Registry: NCT05169437



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