Synthetic Lethality Beyond BRCA: A Phase I Study of Rucaparib and Irinotecan in Metastatic Solid Tumors with Homologous Recombination-Deficiency Mutations

Pharmacy Medicine Basic Medical Sciences Oncology
Rucaparib Irinotecan Metastatic solid tumors Homologous recombination deficiency Phase I trial

Research Background

In recent years, Poly ADP-ribose Polymerase (PARP) inhibitors have shown significant efficacy as a key approach to treat hereditary BRCA1/2 mutation cancers. However, their effectiveness on tumors with other homologous recombination deficiency (HRD) gene mutations such as ATM, CDK12, and CHEK2 has been less satisfactory. Hence, researchers have begun exploring the combined use of PARP inhibitors with other drugs to enhance therapeutic effects and extend the inhibition of DNA damage repair.

Previous preclinical studies have shown a notable synergistic effect when PARP inhibitors are used in combination with topoisomerase I inhibitors like Irinotecan. Irinotecan and its active metabolite SN-38 can interfere with the DNA-topoisomerase I complex, thereby preventing DNA strand repair. The use of PARP inhibitors combined with this method of DNA damage enhances the cytotoxic effects on tumor cells. Based on these preclinical studies, scientists conducted this Phase I clinical trial to evaluate the tolerance and preliminary efficacy of the combined use of Rucaparib and Irinotecan in patients with HRD mutations in multiple metastatic solid tumors.

Source of the Paper

This study was conducted by Erica S. Tsang (MD, MPH), Mallika S. Dhawan (MD), Romain Pacaud (PhD), and others, affiliated with the University of California San Francisco. The paper was published in the June 12, 2024 issue of JCO Precision Oncology, DOI: https://doi.org/10.1200/po.23.00494.

Study Process

Study Design and Process

This study is a Phase I, open-label, dose-escalation trial. The trial is divided into three cohorts:

  • Cohort 1: Rucaparib 400 mg orally twice daily (Days 1-7 and Days 15-21) + Irinotecan 65 mg/m^2 every two weeks
  • Cohort 2: Rucaparib 400 mg orally twice daily (Days 1-7 and Days 15-21) + Irinotecan 100 mg/m^2 every two weeks
  • Cohort 3: Rucaparib 400 mg orally twice daily (Days 1-7) + Irinotecan 100 mg/m^2 every three weeks

The primary objective of the trial was to determine the maximum tolerated dose and recommended Phase II dose of the combination of Rucaparib and Irinotecan and to assess its safety and toxicity.

Subjects and Methodology

A total of 20 patients with metastatic solid tumors harboring HRD mutations, including but not limited to BRCA1/2 and ATM mutations, were enrolled in this study. All patients had to meet the following baseline criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, absolute neutrophil count ≥ 1.5 x 10^9/L, total bilirubin ≤ 1.5 times the upper limit, creatinine ≤ 1.5 times the upper limit or creatinine clearance > 50 ml/min, and measurable disease as per RECIST 1.1 criteria. Previous treatment history was unrestricted, including those who had previously received Rucaparib or Irinotecan.

Data and Results

Maximum Tolerated Dose and Recommended Dose

In Cohort 1 (Rucaparib 400 mg, Irinotecan 65 mg/m^2 every two weeks), there was one case of grade 4 neutropenia (dose-limiting toxicity). In Cohort 2 (Rucaparib 400 mg, Irinotecan 100 mg/m^2 every two weeks), three patients experienced grade 3-4 neutropenia. Therefore, researchers adjusted to the Cohort 3 regimen: Rucaparib 400 mg twice daily on Days 1-7, and Irinotecan 100 mg/m^2 every three weeks. Under this regimen, no dose-limiting toxicity was observed. Thus, the recommended Phase II dose is Rucaparib 400 mg twice daily on Days 1-7, and Irinotecan 100 mg/m^2 every three weeks.

Safety and Toxicity

Common grade 3-4 treatment-related adverse events included neutropenia (25%), and other grade 1-2 adverse events included nausea (45%), diarrhea (45%), fatigue (30%), and vomiting (30%). No treatment-related grade 5 adverse events were reported. Dose delays occurred in some patients (8 cases), with 4 cases due to cytopenia, indicating acceptable tolerance within a reasonable range.

Efficacy Analysis

Among the 17 evaluable patients, 2 showed partial responses (one with primary peritoneal cancer with PALB2 mutation and one with small intestine cancer with ATM mutation), accounting for 12%. Six patients (35%) maintained partial response or disease stability six months after treatment. Notably, three patients (18%) remained in the study after more than a year of treatment, with long-term responses particularly observed in patients with BRCA-, PALB2-, and ATM-mutations, especially those previously responsive to platinum-based treatments.

Conclusion and Value

This study illustrates that through pulse dosing (21-day cycle, Rucaparib given on Days 1-7 and Irinotecan on Day 21), the combination can achieve long-term tolerance and efficacy in various tumor types, particularly those traditionally less sensitive to PARP inhibitors. This study not only extends the application scope of PARP inhibitors beyond BRCA mutations but also provides a scientific basis for future verification of this combination regimen in larger sample sizes and more tumor types.

Research Highlights

  1. Innovative Regimen: By using pulse dosing, the toxicity of the drug combination is reduced, and treatment tolerance is improved.
  2. Applicability to Multiple Mutations: Effective not only in BRCA mutations but also in other HRD mutations such as PALB2 and ATM.
  3. Long-term Efficacy: Some patients showed lasting treatment responses even after more than a year of treatment.

Potential Impact

Due to the demonstrated anticancer activity of Irinotecan in various tumor types and the long-term tolerance and efficacy shown in this study when combined with PARP inhibitors, further follow-up studies and clinical trials are expected to be of significant clinical importance, potentially leading to widespread application in a broader patient population with HRD-mutated tumors.