The participant must be excluded from the study if the participant:
1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, 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. No HIV testing is required unless mandated by local health authority.
5. Has a known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA [qualitative] is detected).
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
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 coagulation).
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, nonmalignant 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 treating physician, make the participant ineligible for treatment with bevacizumab. These conditions may include:
- Uncontrolled hypertension or a history of hypertensive crisis or hypertensive encephalopathy
- History of nephrotic syndrome or moderate proteinuria
- History of gastrointestinal perforation.
- History of non-gastrointestinal fistula formation
- History of RPLS
13. Has received prior systemic anticancer therapy (other than FOLFOX + bevacizumab induction) including investigational agents within 28 days prior to randomization.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.
14. Has received prior therapy with olaparib or with any other PARP inhibitor.
15. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) 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 (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg. bosentan, efavirenz, modafinil) 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.
Note: A current list of strong/moderate inhibitors or inducers of CYP3A4 can be found at the following website:
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 or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study intervention.
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 28 days after the last dose of the previous investigational agent.
20. Has a known additional malignancy that is progressing or has required active therapy within the past 5 years.
Note: 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.
21. 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.
22. Has clinically significant (eg, active) cardiovascular disease, including:
- Myocardial infarction or unstable angina within ≤ 6 months of randomization
- CHF ≥Grade 2 (as per New York Heart Association)
- Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG (eg, QTC ≥450 msec detected on 2 or more time points within a 24-hour period)
- Peripheral vascular disease ≥Grade 3 (eg, symptomatic and interfering with activities of daily living requiring repair or revision)
23. Has DPD deficiency
24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study intervention.