Pembrolizumab and Olaparib in Homologous-recombination Deficient (HRD) Advanced Colorectal Cancer (CRC).

NCT05201612 | Unknown Phase 2

• 2 other identifiers: GEMCAD-21022021-003767-10
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 15

Brief 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.

Conditions

Metastatic Colorectal Cancer

Keywords

HRD deficient colorectal cancer (CRC)

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Objective response rate (ORR) according to investigator assessment following RECIST criteria version 1.1. ORR has been defined as the number of participants with a best overall response (BOR) of confirmed CR or PR divided by the number of enrolled participants. BOR is defined as the best response designation, determined by the investigator, recorded between the date of treatment start and the date of objectively documented progression per RECIST 1.1 or, the date of initiation of subsequent anti-cancer therapy, whichever occurs first. Complete or partial responses may be claimed only if the criteria for each are met at a subsequent time point of ≥ 4 weeks later.

  Throughout the study period, approximately 10 months per patient from first study dose.

Secondary Outcomes (4)

• Disease Control Rate (DCR)

  Throughout the study period, approximately 10 months per patient from first study dose.

• Progression-free survival (PFS)

  Throughout the study period, approximately 10 months per patient from first study dose.

• Overall survival (OS)

  Throughout the study period, approximately 10 months per patient from first study dose.

• Duration of response (DOR)

  Throughout the study period, approximately 10 months per patient from first study dose.

Other Outcomes (2)

• HRD score as per the Myriad MyChoice HRD test

  Throughout the study period, approximately 10 months per patient from first study dose.

• Biomarker molecular substudy

  Throughout the study period, approximately 10 months per patient from first study dose.

Study Arms (1)

Pembrolizumab plus olaparib

EXPERIMENTAL

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).

Drug: Olaparib; Drug: Pembrolizumab

Interventions

Olaparib DRUG

Olaparib 300 mg, orally (po), twice a day (BID) continuously

Also known as: Lynparza

Pembrolizumab plus olaparib

Pembrolizumab DRUG

Pembrolizumab 200 mg, intravenously (IV), every 21 days. Max 2 years (i.e. 35 cycles)

Also known as: Keytruda

Pembrolizumab plus olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male/female participants must be at least 18 years of age on the day of signing informed consent and have a histologically confirmed diagnosis of colorectal cancer.
• Have an unresectable locally-advanced or metastatic colorectal cancer and have progressive disease confirmed by radiologic assessment.
• Have provided an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
• Have DNA HRD defined as either having a BRCA known deleterious mutation (somatic or germinal) and/or RAD 51 score \< 10%.
• Have received at least 2 and no more than 4 prior lines of systemic therapy (including adjuvant treatment). Patients must have received at least: fluoropyrimidines, oxaliplatin and irinotecan, with or without anti-VEGF or anti-EGFR therapy if RAS wild type.
• Must be oxaliplatin-sensitive defined as having received a minimum of 8 cycles of FOLFOX (fluorouracil, folinic acid and oxaliplatin) or 6 cycles of XELOX (capecitabine and oxaliplatin) as first line therapy, and a progression free survival ≥ 9 months in the first line setting.
• Patients with both MSS or MSI-H advanced colorectal cancer will be suitable to participate in the trial.
• The participant (or legally acceptable representative if applicable) provides written informed consent to participate in the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions after radiotherapy.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Have adequate organ function. Blood samples must be collected within 7 days prior to the start of study intervention.
• A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 28 days prior to any study treatment administration plus an additional 180 days after the last dose of study treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 180 days after the last dose of study treatment.

You may not qualify if:

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) or with any PARP inhibitor.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Participation in an observational (non-interventional) study is allowed.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.
• Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known CNS metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab or olaparib and/or any of its excipients.

Sponsors & Collaborators

• Grupo Espanol Multidisciplinario del Cancer Digestivo: lead
• Merk Sharp & Dohme España S.A.: collaborator

Study Sites (15)

Hospital Universitario Virgen del Rocío

Seville, Andalusia, 41013, Spain

RECRUITING

Hospital Universitario Miguel Servet

Zaragoza, Aragon, 50009, Spain

RECRUITING

Hospital Universitario Marques de Valdecilla

Santander, Cantabria, 39015, Spain

RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, Catalonia, 08035, Spain

RECRUITING

Hospital Clinic de Barcelona

Barcelona, Catalonia, 08036, Spain

RECRUITING

Hospital de la Santa Creu i Sant Pau

Barcelona, Catalonia, 08041, Spain

RECRUITING

Hospital Universitari Arnau de Vilanova de Lleida

Lleida, Catalonia, 25198, Spain

RECRUITING

Hospital de Sabadell

Sabadell, Catalonia, 08208, Spain

RECRUITING

Complexo Hospitalario Universitario A Coruña

A Coruña, Galicia, 15006, Spain

RECRUITING

Hospital Universitario 12 de Octubre

Madrid, Madrid, 28041, Spain

RECRUITING

Hospital Universitario La Paz

Madrid, Madrid, 28046, Spain

RECRUITING

Hospital General Universitario de Elche

Elche, Valencia, 03203, Spain

RECRUITING

Fundacion Instituto Valenciano de Oncología

Valencia, Valencia, 46009, Spain

RECRUITING

Hospital Clínico Universitario de Valencia

Valencia, Valencia, 46010, Spain

RECRUITING

Hospital Universitari i Politècnic La Fe

Valencia, Valencia, 46026, Spain

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

olaparib; pembrolizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Rocío García Carbonero, M.D.; Ph.D.

  Hospital Universitario 12 de Octubre

  PRINCIPAL INVESTIGATOR

• María del Carmen Riesco Martinez, M.D.; Ph.D.

  Hospital Universitario 12 de Octubre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

A responsible person Delegated by the Sponsor

CONTACT

0034934344412; investigacion@mfar.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All patients will receive pembrolizumab 200 mg IV every 3 weeks and olaparib 300 mg, po, bid continuously until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first.

Study Record Dates

• First Submitted: January 7, 2022
• First Posted: January 21, 2022
• Study Start: July 7, 2022
• Primary Completion: September 1, 2024
• Study Completion: March 1, 2025
• Last Updated: February 24, 2023

Record last verified: 2023-02

Locations

ES (15)