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Clinical Trial Summary

Colorectal Cancer (CRC) is a leading cause of cancer-related death. Around 30% of patients present with advanced disease and 50% of those that attempt curative surgery will eventually relapse. The potential synergism of combining PARP inhibitor and PD-L1 is based on the hypothesis that pharmacological inhibition of PARP by olaparib will result in enhanced immunogenicity which can be further enhanced with an immune checkpoint inhibitor such as pembrolizumab. This may occur through a number of mechanisms, such as increased production of cytokines and chemokines that have the potential to promote antitumour immunity, upregulation of surface receptors which render tumour cells more visible to detection by cytotoxic T cells thereby leading to death of tumour cells and release of neoantigens, that help promote antigen presentation and immune priming. This hypothesis is supported by preclinical studies in mouse models of cancer, demonstrating that administration of a PARP inhibitor to sensitive tumour types resulted in increased T cell infiltration and immune activation within tumours. The primary hypothesis is that Olaparib and pembrolizumab combination will lead to an increase in objective response rate in patients with refractory metastatic colorectal cancer (mCRC) with DNA homologous-recombination-repair deficiency (HRD) from 1.5% in benchmark studies to up to >10%. The primary objective of the study is to determine the objective response rate (ORR) of pembrolizumab in combination with olaparib, assessed by the investigator per RECIST criteria version 1.1. Secondary objectives include efficacy in terms of disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR); safety and an exploratory study of biomarkers associated with treatment efficacy and disease prognosis.

Clinical Trial Description

This study is a phase 2, open-label, multicentric, single arm trial designed to evaluate the response to olaparib in combination with pembrolizumab in patients with metastatic colorectal cancer (mCRC) with homologous-recombination repair deficiency (HRD), defined as the presence of a BRCA deleterious mutation and/or a low RAD51 score (cut-off <10% ) [Castroviejo-Bermejo, 2018]. Patients will be required to provide a sample of the most recent archival tumor tissue for HRD determination. A functional score evaluating HRD deficiency will be performed, the RAD51 score. This score will be determined in FFPE tumor samples. Oxaliplatin-sensitivity and a low RAD51 score (cut-off <10%) will be required for patients to continue the screening process. Oxaliplatin-sensitivity is defined as a progression free survival ≥ 9 months in the first line setting, having received at least 8 cycles of FOLFOX (fluorouracil, folinic acid and oxaliplatin) or 6 cycles of XELOX (capecitabine and oxaliplatin) treatment as first line therapy. All patients will undergo screening assessments within 4 weeks prior to enrollment. Screening assessments will include demographics and medical history, prior anticancer treatments and sensibility to oxaliplatin therapy, prior and current medications, 12-lead ECG, ECOG performance status, hematology and serum/plasma chemistry, urinalysis, physical examination, vital signs measurements, and baseline radiologic assessment by whole body computed tomography (CT). All patients included in the study will undergo the Myriad MyChoice HRD test, but no specific cut-off value will be requested to participate in the trial. Treatment cycles will be 21 days in length. All participants will receive treatment as follows: Olaparib 300 mg, orally (po), twice a day (BID) continuously. Pembrolizumab 200 mg, intravenously (IV), every 21 days. Treatment will be continued in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Pembrolizumab will be administered up to a maximum of 2 years (35 cycles). All patients will be monitored for efficacy as well as safety throughout this phase. Assessments will include physical examination, vital signs and weight assessment, hematology, serum chemistry, urinalysis, concomitant medications, ECOG performance status, disease status assessment, 12-lead ECG, AEs with any associated therapies and procedures, study drug administration and accountability. Disease response to study treatment will be evaluated by imaging methods, with tumor scans being done every 9 weeks of treatment (± 7 days). Disease progression will be determined by RECIST v1.1. Patients experiencing disease progression by RECIST v1.1, as assessed by the investigator, will be discontinued from study treatment and continue follow-up. However, if the patient has met criteria for radiologic progression by RECIST, but is still benefiting from the study drugs, according to the investigator, the decision to continue will be made jointly between the investigator and the sponsor. Upon treatment discontinuation (with the exception of withdrawal of consent or death), patients will have an End of Treatment Visit. All patients will be followed for at least 28 days after the last dose of study drug and will then be followed every 3 months for survival. ;

Study Design

Related Conditions & MeSH terms

NCT number NCT05201612
Study type Interventional
Source Grupo Espanol Multidisciplinario del Cancer Digestivo
Contact A responsible person Delegated by the Sponsor
Phone 0034934344412
Status Recruiting
Phase Phase 2
Start date July 7, 2022
Completion date March 2025

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