Clinical Trials /

Efficacy and Safety of Olaparib, Olaparib + Bevacizumab Compared to Bevacizumab + 5-Fluorouracil (FU)

NCT04456699

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of Olaparib, Olaparib + Bevacizumab Compared to Bevacizumab + 5-Fluorouracil (FU)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 7339-003
  • SECONDARY ID: MK-7339-003
  • SECONDARY ID: LYNK-003
  • SECONDARY ID: jRCT2031200146
  • NCT ID: NCT04456699

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
OlaparibLYNPARZA^TMOlaparib
5-FUFluorouracil, Adrucil, EfudexBevacizumab + 5-FU
BevacizumabMVASI^TM, AvastinBevacizumab + 5-FU

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Olaparib + BevacizumabExperimentalOlaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study
  • Olaparib
  • Bevacizumab
OlaparibExperimentalOlaparib (300 mg BID) oral, until progressive disease or end of study
  • Olaparib
Bevacizumab + 5-FUActive ComparatorBevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W) until progressive disease or end of study
  • 5-FU
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          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.

        Exclusion Criteria:

          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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 6 years
Safety Issue:
Description:Overall survival is the time from randomization to death due to any cause.
Measure:Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.
Measure:Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.
Measure:Number of Participants with One or More Adverse Events (AE)
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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
Measure:Number of Participants Discontinuing Study Intervention Due to an AE
Time Frame:Up to approximately 6 years
Safety Issue:
Description:Tolerability is defined by the degree to which overt AEs of a drug can be tolerated by a participant without discontinuing from the study.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • colorectal cancer
  • CRC
  • Olaparib
  • Bevacizumab
  • FOLFOX
  • 5-FU
  • fluorouracil
  • folinic acid
  • oxaliplatin

Last Updated

April 19, 2021