Phase II trial of Pembrolizumab and Olaparib in homologous-recombination deficient (HRD) advanced colorectal cancer (CRC).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol Multidisciplinar En Cancer Digestivo

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jul 2022 → 10 Nov 2025

Decision date (initial)

2024-07-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

GEMCAD

External identifiers

EU CT number

2023-509095-42-00

EudraCT number

2021-003767-10

ClinicalTrials.gov

NCT05201612

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Therapy, Safety

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 v1.1, in patients with refractory metastatic colorectal cancer (mCRC) with DNA homologous-recombination-repair deficiency (HRD)

Secondary objectives 5

1. To determine Disease Control Rate (DCR), defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD).
2. To determine Progression-Free Survival (PFS).
3. To determine Overall Survival (OS).
4. To determine Duration of Response (DOR).
5. To determine the safety and tolerability of the combination.

Conditions and MedDRA coding

Colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. Have an unresectable locally-advanced or metastatic colorectal cancer and have progressive disease confirmed by radiologic assessment.
3. 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.
4. 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).
5. 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.
6. 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.
7. Patients with both MSS or MSI-H advanced colorectal cancer will be suitable to participate in the trial.
8. The participant (or legally acceptable representative if applicable) provides written informed consent to participate in the trial.
9. 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.
10. 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.
11. 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 23

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Has known CNS metastases and/or carcinomatous meningitis.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or olaparib and/or any of its excipients.
11. 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.
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease of any etiology.
13. Has an active infection requiring systemic therapy.
14. Has a known history of Human Immunodeficiency Virus (HIV) infection. - No HIV testing is required
15. 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.
16. 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.
17. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
18. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease or any other non-reversible cause.
19. Patient has any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. 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.
22. Has had an allogenic tissue/solid organ transplant.
23. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate.

Secondary endpoints 4

1. Disease Control Rate.
2. PFS.
3. OS.
4. Duration of response.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol Multidisciplinar En Cancer Digestivo

Sponsor organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Address

Calle Balmes No 243 Escalera A Planta 5 Puerta 1

City

Barcelona

Postcode

08006

Country

Spain

Scientific contact point

Organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Contact name

A person designed by the Sponsor

Public contact point

Organisation

Grupo Espanol Multidisciplinar En Cancer Digestivo

Contact name

A person designed by the Sponsor

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications