Efficacy and Safety of Olaparib (MK-7339) With or Without Bevacizumab Compared to Bevacizumab With a Fluoropyrimidine in Unresectable or Metastatic Colorectal Cancer (CRC) (MK-7339-003/LYNK-003)

Study Overview
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Brief Summary
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This is an efficacy and safety study of olaparib alone or in combination with bevacizumab being compared to bevacizumab with a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer who have not progressed following first-line induction. The primary hypotheses are: Olaparib + Bevacizumab is superior to a fluoropyrimidine + 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); Olaparib is superior to a fluoropyrimidine + Bevacizumab with respect to PFS using RECIST 1.1 as assessed by BICR. As of amendment 5 study enrollment is being discontinued and study participants randomized to one of the two experimental arms (olaparib plus bevacizumab or olaparib monotherapy) must discontinue study intervention. Participants who are still on study treatment will no longer have tumor response assessments by BICR.

Official Title
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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 a Fluoropyrimidine in Participants With Unresectable or Metastatic Colorectal Cancer Who Have Not Progressed Following First-line Induction (LYNK-003)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Olaparib
* Drug: 5-FU
* Drug: Bevacizumab
* Drug: Capecitabine
* Drug: Leucovorin/ levoleucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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 + 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 imaging contract research organization (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. 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 CAPOX + bevacizumab or FOLFOX + bevacizumab (last dose is the day of the last infusion that contained oxaliplatin). 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. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to randomization. Exclusion Criteria: Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, capecitabine, or olaparib. 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. Has an active infection requiring systemic therapy. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 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. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Has myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or with features suggestive of MDS/AML. Has hemoptysis or hematemesis within 28 days prior to randomization. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation). Has clinically significant bleeding within 28 days prior to randomization. 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. 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 Arterial thromboembolic events (eg, myocardial infarction, cerebral infarction) History of nephrotic syndrome or moderate proteinuria History of gastrointestinal perforation History of non-gastrointestinal fistula formation History of possible reversible encephalopathy syndrome (RPLS) Has received prior systemic anticancer therapy (other than CAPOX + bevacizumab or 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 are eligible. Has received prior therapy with olaparib or with any other polyadenosine 5'-diphosphoribose polymerase (PARP) inhibitor. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaparib + bevacizumab<br>Participants will receive olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study. | Drug: Olaparib<br>* 300 mg BID, oral until progressive disease or end of study<br>* Other names: LYNPARZA^TM;Drug: Bevacizumab<br>* 5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study<br>* Other names: Avastin;|
| Experimental: Olaparib<br>Participants will receive olaparib (300 mg BID) oral, until progressive disease or end of study. | Drug: Olaparib<br>* 300 mg BID, oral until progressive disease or end of study<br>* Other names: LYNPARZA^TM;|
| Active Comparator: Bevacizumab + chemotherapy<br>Participants will receive investigator's choice of either bevacizumab (7.5mg/kg IV once every three weeks (Q3W)) + capecitabine (1000mg/m^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5FU (400mg/m2) can be added prior to infusional 5FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) Q2W IV infusion may be added per investigator's discretion. Treatment will continue until progressive disease or end of study. | Drug: 5-FU<br>* 2400 mg/m^2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study; bolus 5FU (400mg/m2) can be added prior to infusional 5FU, per local standards and at the investigator's discretion<br>* Other names: Efudex;Drug: Bevacizumab<br>* 5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study<br>* Other names: Avastin;Drug: Capecitabine<br>* 1000mg/m^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study<br>* Other names: XELODA^®;Drug: Leucovorin/ levoleucovorin<br>* 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) may be added to Bevacizumab + 5FU per investigator's discretion Q2W IV infusion until progressive disease or end of study<br>* Other names: Khapzory^TM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Using RECIST 1.1 as Assessed by BICR | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions is also considered PD. | Up to  6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is the time from randomization to death due to any cause. | Up to  6 years | 
| Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR | ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to  6 years | 
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | For participants who demonstrate a confirmed CR or confirmed PR per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. | Up to  6 years | 
| Number of Participants with One or More Adverse Events (AE) | An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention | Up to  6 years | 
| Number of Participants Discontinuing Study Intervention Due to an AE | Tolerability is defined by the degree to which overt AEs of a drug can be tolerated by a participant without discontinuing from the study. | Up to  6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, oxaliplatin, CAPOX, capecitabine, colorectal cancer, Olaparib, Bevacizumab, FOLFOX, 5-FU, fluorouracil, folinic acid