3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the treating physician, requires/required the discontinuation of oxaliplatin. Note: As an example, unacceptable toxicity may include (but is not limited to) severe or prolonged neurotoxicity.

4. Has provided to the iCRO at least 1 set of radiographic images taken during the FOLFOX + bevacizumab induction period and at least 42 days prior to the imaging performed during screening. The iCRO must determine the images are of diagnostic quality prior to 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, as detailed in Table 1; all screening laboratory tests should

be performed within 10 days of randomization.

 

Table 1 Adequate Organ Function Values

 

System	Laboratory Value
Hematological
Absolute neutrophil count (ANC)	≥1500/μL
Platelets	≥100 000/μL
Hemoglobin	≥10.0 g/dL or ≥ 5.6mmol/L
Renal
Estimated creatinine clearance using the Cockroft-Gault equation	≥51 mL/min
Hepatic
Total bilirubin	≤1.5 × ULN OR direct bilirubin ≤ULN for  participants with total bilirubin levels  >1.5 × ULN
AST (SGOT) and ALT (SGPT)	≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
Coagulation
International normalized ratio (INR) OR prothrombin time (PT)    Activated partial thromboplastin time (aPTT)	≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); ULN=upper limit of normal. 1 Criteria must be met without packed red blood cell (pRBC) transfusion within last 2 weeks. 2 Estimated creatinine clearance using Cockcroft-Gault:   (140-age [years] × weight [kg]) (× F)* (× F)* Serum creatinine (mg/dL) × 72     *where F = 0.85 for females and F = 1 for males Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

 

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 signing the informed consent.

 

Male Participants

 

Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

 

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 3) 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 [Appendix 5]) 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. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.

 

• 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. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

 

• 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 Appendix 5 during the intervention period and for at least 30 days (if on Arm 2) or 180 days (if on Arm 1 or Arm 3) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the

potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.

 

• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.

 

• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

 

• Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2.

 

The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

 

 

12. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.

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:

 

 

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:

 

https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers

 

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.

 

 

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:

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.