The treatment of participants with unresectable or metastatic CRC that has not progressed following an induction course of FOLFOX + bevacizumab MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by AJCC eighth edition) colorectal adenocarcinoma. 2. Has not progressed after a first-line induction course of at least 6 cycles of FOLFOX with bevacizumab or 4 cycles of CAPOX + bevacizumab as first-line therapy. -Participants must not have received an investigational agent during their induction course. -Determination of best overall response (SD/PR/CR) will be made by the investigator. -Non-PD will be verified by BICR prior to randomization based on the images submitted to iCRO as described in inclusion criterion 4. -"First-line therapy" is defined as the first systemic chemotherapy regimen given for the diagnosis of unresectable or metastatic CRC. Participants may have received prior adjuvant/neoadjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to initiation of first-line CAPOX + bevacizumab or FOLFOX + bevacizumab induction treatment. 3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the treating physician, requires/required the discontinuation of oxaliplatin. Participants must be randomized within a minimum of 2 weeks and a maximum of 6 weeks after their last dose of CAPOX + bevacizumab or FOLFOX + bevacizumab (last dose is the day of the last infusion that contained oxaliplatin). 4. Has provided to the iCRO 1 set of baseline radiographic images taken before or during the CAPOX + bevacizumab or FOLFOX + bevacizumab induction period and at least 42 days prior to the imaging performed during Screening. Tumor imaging at Screening must be performed within 28 days prior to the date of randomization 5. Has an ECOG performance status of 0 to 1 within 10 days prior to randomization. 6. Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption. 7. Has adequate organ function 8. Has provided a tumor tissue sample deemed acceptable by the central lab for biomarker analysis. 9. Is male or female, at least 18 years of age, at the time of providing documented informed consent. 10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days (if on Arm 2) or 180 days (if on Arm 1 or Arm 3a or Arm3b) after the last dose of study intervention: • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception unless confirmed to be azoospermic vasectomized or secondary to medical cause as detailed below: Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. • Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex. 11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a WOCBP OR • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Append
Exclusion criteria
Exclusion criteria: 1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, capecitabine, or olaparib 2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression for at least 28 days by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid intervention for at least 14 days prior to first dose of study intervention) 3. Has an active infection requiring systemic therapy 4. Has a known history of HIV infection 5. Has a known history of or is positive for hepatitis B or hepatitis C 6. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study 7. Has MDS/AML or with features suggestive of MDS/AML 8. Has hemoptysis or hematemesis within 28 days prior to randomization 9. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation) 10. Has clinically significant bleeding within 28 days prior to randomization 11. Is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent. 12. Has 1 or more conditions that, in the opinion of the physician, make the participant ineligible for treatment with bevacizumab. These conditions may include: •Uncontrolled hypertension (SBP >150 mm Hg or DBP >100 mm Hg) or a history of hypertensive crisis or hypertensive encephalopathy •Arterial thromboembolic events (eg, myocardial infarction, cerebral infarction) •History of: -nephrotic syndrome or moderate proteinuria -gastrointestinal perforation -non-gastrointestinal fistula formation -RPLS 13. Has received prior systemic anticancer therapy (other than CAPOX + bevacizumab or FOLFOX + bevacizumab induction) including investigational agents within 28 days prior to randomization 14. Has received prior therapy with olaparib or with any other PARP inhibitor 15. Is currently receiving either strong or moderate inhibitors of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to randomization is 2 weeks 16. Is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to randomization is 5 weeks for phenobarbital and 3 weeks for other agents 17. Has undergone major surgery within 2 weeks of randomization or has not recovered adequately from toxicities and/or complications from any major surgery prior to randomization. 18. 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. Prior/Concurrent Clinical Study Experience 19. Is currently participating in
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Progressive-free Survival (PFS) Using RECIST 1.1 as Assessed by BICR;Timepoint(s) of evaluation of this end point: Up to 6 years;Main Objective: 1. To compare progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR) between the following treatments: - Olaparib + Bevacizumab versus a fluoropyrimidine + Bevacizumab - Olaparib versus a fluoropyrimidine + Bevacizumab;Secondary Objective: 1.To compare overall survival (OS) between the following treatments: - Olaparib + Bevacizumab versus a fluoropyrimidine + Bevacizumab - Olaparib versus a fluoropyrimidine + Bevacizumab 2.To evaluate objective response rate (ORR) using RECIST 1.1 as assessed by BICR following administration of: - Olaparib + Bevacizumab - Olaparib - Fluoropyrimidine + Bevacizumab 3.To evaluate duration of response (DOR) using RECIST 1.1 as assessed by BICR following administration of: - Olaparib + Bevacizumab - Olaparib - Fluoropyrimidine + Bevacizumab 4.To evaluate the safety and tolerability - Olaparib + Bevacizumab - Olaparib | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1. Up to 6 years 2. Up to 6 years 3. Up to 6 years 4. Up to 6 years 5. Up to 6 years ;Secondary end point(s): 1. Overall Survival (OS) 2. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by BICR 3. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by BICR 4. Number of Participants with One or More Adverse Events (AE) 5. Number of Participants Discontinuing Study Intervention Due to an AE | — |
Countries
Australia, Belgium, Canada, Chile, China, Colombia, France, Germany, Hungary, Japan, Korea, Republic of, Latvia, Lithuania, Russian Federation, South Africa, Spain, Turkey, Ukraine, United States
Contacts
Public ContactMayo
Merck Sharp & Dohme LLC
Outcome results
None listed