Reference Detail

Ref Type

Journal Article

PMID

(38865673)

Authors

Tsang ES, Dhawan MS, Pacaud R, Thomas S, Grabowsky J, Wilch L, Karipineni S, Kelley RK, Ko AH, Collisson E, Chapman JS, Ueda S, Bergsland EK, Munster P

Title

Synthetic Lethality Beyond BRCA: A Phase I Study of Rucaparib and Irinotecan in Metastatic Solid Tumors With Homologous Recombination-Deficiency Mutations Beyond BRCA1/2.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	8		2024 Jun	e2300494	JCO Precis Oncol

URL

Abstract Text

Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency.This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks.Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer).Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATM inact mut	Advanced Solid Tumor	sensitive	Irinotecan + Rucaparib	Phase I	Actionable	In a Phase I trial, Rubraca (rucaparib) and Camptosar (irinotecan) combination therapy was well tolerated and resulted in a clinical benefit rate of 35% (6/17, 2 partial responses, 4 stable diseases over 6 months) in patients with advanced solid tumors harboring BRCA1 (n=3), BRCA2 (n=4), PALB2 (n=1), or ATM (n=11) mutations, including partial responses in a patient with PALB2-mutated peritoneal carcinoma and in a patient with ATM-mutated small bowel carcinoma (PMID: 38865673; NCT03318445).	38865673