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

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ClinicalTrials.gov Identifier: NCT04456699
Recruitment Status : Recruiting
First Posted : July 2, 2020
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE July 1, 2020
First Posted Date  ICMJE July 2, 2020
Last Update Posted Date September 16, 2021
Actual Study Start Date  ICMJE August 19, 2020
Estimated Primary Completion Date January 22, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2020)
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 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2020)
  • Overall Survival (OS) [ Time Frame: Up to approximately 6 years ]
    Overall survival is the time from randomization to death due to any cause.
  • Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 6 years ]
    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.
  • Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 6 years ]
    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.
  • Number of Participants with One or More Adverse Events (AE) [ Time Frame: Up to approximately 6 years ]
    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
  • Number of Participants Discontinuing Study Intervention Due to an AE [ Time Frame: Up to approximately 6 years ]
    Tolerability is defined by the degree to which overt AEs of a drug can be tolerated by a participant without discontinuing from the study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Olaparib, Olaparib + Bevacizumab Compared to Bevacizumab + 5-Fluorouracil (FU)
Official Title  ICMJE 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)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE
  • Drug: Olaparib
    300 mg BID, oral until progressive disease or end of study
    Other Name: LYNPARZA^TM
  • Drug: 5-FU
    2400 mg/m2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study
    Other Names:
    • Fluorouracil
    • Adrucil
    • Efudex
  • Drug: Bevacizumab
    5 mg/kg Q2W IV infusion until progressive disease or end of study
    Other Names:
    • MVASI^TM
    • Avastin
Study Arms  ICMJE
  • Experimental: Olaparib + Bevacizumab
    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
    Interventions:
    • Drug: Olaparib
    • Drug: Bevacizumab
  • Experimental: Olaparib
    Olaparib (300 mg BID) oral, until progressive disease or end of study
    Intervention: Drug: Olaparib
  • Active Comparator: Bevacizumab + 5-FU
    Bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W) until progressive disease or end of study
    Interventions:
    • Drug: 5-FU
    • Drug: Bevacizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 1, 2020)
525
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 22, 2027
Estimated Primary Completion Date January 22, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Chile,   Colombia,   France,   Germany,   Hungary,   Japan,   Korea, Republic of,   Latvia,   Lithuania,   Russian Federation,   South Africa,   Spain,   Turkey,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04456699
Other Study ID Numbers  ICMJE 7339-003
MK-7339-003 ( Other Identifier: Merck Protocol Number )
LYNK-003 ( Other Identifier: Merck )
jRCT2031200146 ( Registry Identifier: jRCT )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck, Sharpe & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP