A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and Safety of Olaparib Alone or in Combination With Bevacizumab Compared to Bevacizumab With 5-FU in Participants With Unresectable or Metastatic Colorectal Cancer Who Have Not Progressed Following First-line Induction of FOLFOX With Bevacizumab (LYNK-003)
This is an efficacy and safety study of olaparib alone or in combination with bevacizumab being compared to bevacizumab with Fluorouracil (5-FU) in participants with unresectable or metastatic colorectal cancer (CRC) who have not progressed following first-line induction of FOLFOX with bevacizumab. Hypothesis 1 - Olaparib + Bevacizumab is superior to 5-FU + Bevacizumab with respect to progression-free survival (PFS) using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) in the treatment of CRC. Hypothesis 2 - Olaparib is superior to 5-FU + Bevacizumab with respect to PFS using RECIST 1.1 as assessed by BICR) in the treatment of CRC.
18 Years and up
Accepting Healthy Volunteers?
1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by American Joint Committee on Cancer (AJCC eighth edition) colorectal adenocarcinoma (National Comprehensive Cancer Network [NCCN] 2018).
2. Has not progressed (ie, achieved a stable disease [SD], partial response [PR], or complete response [CR]) after a first-line induction course of at least 6 cycles of FOLFOX with bevacizumab as first-line therapy.
- Participants must not have received an investigational agent during their FOLFOX + bevacizumab induction course.
- Determination of SD/PR/CR will be made by the investigator.
- "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 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. Note: As an example, unacceptable toxicity may include (but is not limited to) severe or prolonged neurotoxicity.
• Participants must be randomized within a minimum of 2 weeks and a maximum of 6 weeks after their last dose of FOLFOX + bevacizumab (last dose is the day of the last infusion).
4. Has provided to the imaging contract research organization (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 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to randomization.
1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU or olaparib.
2. Has known active central nervous system (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 human immunodeficiency virus (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 surface antigen (HBsAg reactive) or hepatitis C ribonucleic acid (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 myelodysplastic syndrome/acute myeloid leukemia (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 high-resolution computed tomography (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 (systolic blood pressure [SBP] >150 mm Hg or diastolic blood pressure [DBP] >100 mm Hg) 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 possible reversible encephalopathy syndrome (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. Participants with persistent alopecia or Grade ≤3 neuropathy may be eligible.
14. Has received prior therapy with olaparib or with any other polyadenosine 5'-diphosphoribose polymerase (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 cytochrome P450 3A4 (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.
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.