Evaluation of Pembrolizumab and Olaparib in Homologous-Recombination Deficient Metastatic Colorectal Cancer: A Phase II Clinical Trial
- Trial ID
- 2023-509095-42-00
- Protocol
- GEMCAD 2102
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II trial is to determine the **Objective Response Rate (ORR)** of pembrolizumab in combination with olaparib, as assessed by the investigator using RECIST criteria v1.1, in patients with refractory metastatic colorectal cancer (mCRC) exhibiting DNA homologous-recombination-repair deficiency (HRD). This objective is clinically relevant as it evaluates the efficacy of the combination therapy in inducing tumor response in a specific subset of colorectal cancer patients, potentially offering a new therapeutic option for those with limited treatment alternatives.
Secondary objectives include:
- Determining the **Disease Control Rate (DCR)**, defined as the percentage of patients achieving complete response, partial response, or stable disease.
- Assessing **Progression-Free Survival (PFS)**.
- Evaluating **Overall Survival (OS)**.
- Measuring the **Duration of Response (DOR)**.
- Assessing the safety and tolerability of the combination therapy.
Participants
The clinical trial involves participants diagnosed with **colorectal cancer**, specifically those with refractory metastatic colorectal cancer exhibiting DNA homologous-recombination-repair deficiency. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include having an unresectable locally-advanced or metastatic condition with progressive disease confirmed by radiologic assessment. Participants must have received at least two and no more than five prior lines of systemic therapy, including specific chemotherapeutic agents. The trial population is characterized by their sensitivity to oxaliplatin-based therapy, with a progression-free survival of at least nine months following the last oxaliplatin-based treatment. Both microsatellite stable (MSS) and microsatellite instability-high (MSI-H) advanced colorectal cancer patients are eligible. The trial includes a vulnerable population, and all participants must provide written informed consent. Lifestyle factors such as diet and physical activity are not specified in the trial data.
Plans and Procedures
The clinical trial is designed to evaluate the **objective response rate** of **pembrolizumab** in combination with **olaparib** in patients with refractory metastatic **colorectal cancer** exhibiting DNA homologous-recombination-repair deficiency. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until February 14, 2025, with recruitment having commenced on November 15, 2022. Participants will be involved in the study for a maximum treatment period of 42 weeks, depending on the specific treatment arm they are assigned to.
The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as age, performance status, and disease characteristics. Following successful screening, participants will undergo a baseline visit to confirm eligibility and collect baseline data. Subsequent visits will occur at regular intervals to monitor treatment response and safety, with assessments conducted according to RECIST criteria v1.1. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy, with primary and secondary endpoints including disease control rate, progression-free survival, overall survival, and duration of response.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose of pembrolizumab is 200 mg, with a total treatment period not exceeding 24 weeks. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The administration of this medication is conducted under controlled conditions to ensure participant compliance and safety.
In addition to pembrolizumab, the trial includes the administration of **olaparib**, which is available in the form of a film-coated tablet. Olaparib is administered orally, with a maximum daily dose of 600 mg, and the treatment period can extend up to 42 weeks. Olaparib is a chemical-based therapeutic agent, and its administration is monitored to ensure adherence to the dosing schedule. The trial does not involve any placebo or comparator treatment, as the focus is on evaluating the combination of pembrolizumab and olaparib in patients with homologous-recombination deficient advanced colorectal cancer.
Efficacy
The efficacy of the clinical trial involving **pembrolizumab** and **olaparib** in patients with homologous-recombination deficient advanced colorectal cancer will be assessed using several endpoints. The primary endpoint is the Objective Response Rate (ORR), which will be evaluated by the investigator according to RECIST criteria version 1.1. Secondary endpoints include Disease Control Rate, Progression-Free Survival (PFS), Overall Survival (OS), and Duration of Response. These parameters will provide a comprehensive assessment of the treatment's impact on the disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male/female participants must be at least 18 years of age on the day of signing informed consent and have histologically confirmed diagnosis of colorectal cancer.
- Have an unresectable locally-advanced or metastatic colorectal cancer and have progressive disease confirmed by radiologic assessment.
- Have DNA HRD defined as either having a BRCA/PALB2 known deleterious mutation (germline or somatic, in this case with a minimum allelic mutation fraction >5%) and/or RAD 51 score < 10%, and be sensitive to oxaliplatin-based therapy (see inclusion criteria 6 for definition). For those patients with no BRCA/PALB2 deleterious mutations or unknown BRCA/PALB2 status, archival tumor tissue will be necessary for a first RAD-51 test. If the first RAD-51 test is positive the patient will be potentially eligible for the trial, but a newly obtained biopsy must be performed before study treatment initiation if the first one was done on tissue obtained prior to the last disease progression before study entry. This new biopsy must be done post-progression to the latest line of treatment and it is mandatory for a second RAD51 test. If the obtention of a new biopsy were not feasible, inclusion must be consulted with the Sponsor, in a case by case manner. For patients with extraordinary sensitivity to oxaliplatin-based chemotherapy (progression-free survival with last line of oxaliplatin-based therapy ≥ 12 months), molecular confirmation of HRD (BRCA, PALB2 or RAD51 test) will not be required for eligibility, but baseline newly obtained tumor biopsy will be mandatory before study entry for HRD characterization.
- Archival tumor tissue sample adequate for HRD status confirmation by a validated test (i.e. myChoice® CDx from Myriad Genetics) of a not previously irradiated tumor lesion will be also mandatory for all DNA HRD cases as defined in eligibility criteria #3 that meet all other eligibility criteria and are included in the trial (tissue specific technical requirements will be provided in a lab manual).
- Have received at least 2 and no more than 5 prior lines of systemic therapy (including adjuvant treatment). Patients must have priorly received at least: fluoropyrimidines, oxaliplatin and irinotecan, with or without anti-VEGF or anti-EGFR therapy if RAS wild type.
- Must have received oxaliplatin-based chemotherapy in the non-resectable metastatic setting and 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) in the last line received in the metastatic setting, and a progression free survival to the last oxaliplatin-based therapy ≥ 9 months. Patients that have received oxaliplatin in the adjuvant setting and/or have been retreated with oxaliplatin in the metastatic setting, may be eligible for the trial as long as they have a disease progression free interval ≥ 9 months after the last oxaliplatin regimen received in the metastatic 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 as defined in the following table (Table 4). Blood samples must be collected within 7 days prior to the start of study intervention.
Exclusion Criteria
- 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. o 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.
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease of any etiology.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV) infection. - No HIV testing is required
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. - No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease or any other non-reversible cause.
- Patient has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of trial treatment.
- Has had an allogenic tissue/solid organ transplant.
- Other severe acute or chronic medical conditions, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for study entry.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 15 Nov 2022 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 42 | PRD9414227 |
Olaparib | Test | FILM-COATED TABLET | INTRAVENOUS INFUSION | 600 | 42 | PRD9414228 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 24 | PRD4323105 |