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)
Metastatic Colorectal Cancer
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring colorectal cancer, CRC, Olaparib, Bevacizumab, FOLFOX, 5-FU, fluorouracil, folinic acid, oxaliplatin, CAPOX, capecitabine
Eligibility Criteria
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.
Sites / Locations
- Providence Saint Joseph Medical Center, Disney Family Cancer ( Site 1392)
- St Joseph Heritage Healthcare-Oncology ( Site 1383)
- UC Health Memorial Hospital ( Site 1401)
- Poudre Valley Health System ( Site 1402)
- University Cancer & Blood Center, LLC ( Site 1381)
- University of Chicago ( Site 1357)
- Illinois Cancer Care, PC ( Site 1352)
- James Graham Brown Cancer Center ( Site 1393)
- University Medical Center New Orleans ( Site 1365)
- New England Cancer Specialists ( Site 1422)
- Cancer & Hematology Centers of Western Michigan ( Site 1358)
- Hattiesburg Clinic Hematology/Oncology ( Site 1418)
- Washington University in St. Louis ( Site 1384)
- St. Vincent Frontier Cancer Center-Research ( Site 1414)
- CHI Health St. Francis ( Site 1406)
- Cancer Partners of Nebraska ( Site 1353)
- Providence Portland Medical Center ( Site 1400)
- Oregon Health & Science University ( Site 1411)
- Allegheny Singer Research Institute ( Site 1364)
- West Cancer Center - East Campus ( Site 1396)
- Vanderbilt University Medical Center ( Site 1362)
- Baylor Scott & White Medical Center - Temple ( Site 1397)
- Blue Ridge Cancer Care ( Site 1374)
- St George Hospital ( Site 0052)
- Liverpool Hospital ( Site 0055)
- Royal Brisbane and Women s Hospital ( Site 0054)
- Queen Elizabeth Hospital ( Site 0053)
- Monash Health ( Site 0050)
- Peninsula Health Frankston Hospital ( Site 0056)
- Imelda vzw ( Site 0110)
- AZ Klina ( Site 0106)
- UZ Antwerpen ( Site 0108)
- UCL Saint Luc ( Site 0100)
- OLV Ziekenhuis ( Site 0109)
- UZ Gent ( Site 0101)
- UZ Gasthuisberg ( Site 0102)
- AZ Groeninge ( Site 0105)
- Dr. Everett Chalmers Regional Hospital ( Site 0204)
- Moncton Hospital - Horizon Health Network ( Site 0201)
- Princess Margaret Cancer Centre ( Site 0209)
- Hopital Cite de la Sante de Laval ( Site 0203)
- McGill University Health Centre ( Site 0207)
- CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0202)
- Centro Investigación del Cáncer James Lind ( Site 0251)
- Sociedad Oncovida S.A. ( Site 0250)
- Clínica San Carlos de Apoquindo Red Salud UC Christus ( Site 0252)
- Sociedad de Oncología Y Hematología del Cesar S.A.S. ( Site 0353)
- Oncomedica S.A. ( Site 0352)
- Administradora Country SA - Clinica del Country ( Site 0350)
- Instituto Nacional de Cancerologia E.S.E ( Site 0362)
- Oncologos del Occidente ( Site 0364)
- Fundacion Cardiovascular de Colombia ( Site 0360)
- Hemato Oncologos S.A. ( Site 0355)
- C.H.U. de Strasbourg Hopital de Hautepierre ( Site 0464)
- Institut de Cancerologie de l Ouest Centre Rene Gauducheau ( Site 0455)
- CHU Jean Minjoz ( Site 0450)
- CHU Bordeaux Haut-Leveque ( Site 0457)
- CHU Saint Eloi ( Site 0467)
- Centre Leon Berard ( Site 0459)
- Hopital Europeen Georges Pompidou ( Site 0452)
- Universitaetsklinikum Ulm ( Site 0500)
- St. Josef und St. Elisabeth Hospital gGmbH-Hematology, oncology and palliative medicine ( Site 0503)
- Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 0504)
- Facharztzentrum Eppendorf ( Site 0501)
- Bekes Megyei Kozponti Korhaz - Pandy Kalman Tagkorhaza ( Site 1432)
- Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Okta-Klinikai Onkológiai és Sugárterápiás Ce
- Debreceni Egyetem Klinikai Kozpont ( Site 1426)
- Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 1427)
- Zala Megyei Szent Rafael Korhaz ( Site 1429)
- Orszagos Onkologiai Intezet ( Site 1431)
- Aichi Cancer Center Hospital ( Site 0658)
- National Cancer Center Hospital East ( Site 0650)
- National Hospital Organization Shikoku Cancer Center ( Site 0652)
- St. Marianna University School of Medicine Hospital ( Site 0657)
- Saitama Cancer Center ( Site 0653)
- Shizuoka Cancer Center Hospital and Research Institute ( Site 0655)
- Chiba Cancer Center ( Site 0656)
- National Hospital Organization Kyushu Cancer Center ( Site 0654)
- National Cancer Center Hospital ( Site 0651)
- The Cancer Institute Hospital of JFCR ( Site 0659)
- Asan Medical Center ( Site 0952)
- Kyungpook National University Chilgok Hospital ( Site 0956)
- Korea University Anam Hospital ( Site 0955)
- Seoul National University Hospital ( Site 0950)
- Severance Hospital Yonsei University Health System ( Site 0951)
- Samsung Medical Center ( Site 0954)
- The Catholic University of Korea St. Mary s Hospital ( Site 0953)
- Daugavpils Regional Hospital ( Site 1502)
- P. Stradina Clinical University Hospital ( Site 1500)
- Riga East Clinical University Hospital ( Site 1501)
- LSMUL Kauno Klinikos ( Site 1528)
- Nacionalinis Vezio Institutas ( Site 1527)
- Vilniaus Universiteto Ligonine Santaros Klinikos ( Site 1526)
- Arkhangelsk Clinical Oncological Dispensary ( Site 1113)
- GBUZ Republican Clinical Oncological Dispensary-Antitumor drug therapy department ( Site 1130)
- Krasnoyarsk Regional Clinical Oncological Dispensary ( Site 1121)
- MEDSI Clinical Hospital on Pyatnitsky Highway-Departmentof Antitumor Drug therapy ( Site 1129)
- National Medical and Surgical Center n.a. N.I.Pirogov ( Site 1126)
- N.N. Blokhin NMRCO ( Site 1106)
- First Moscow State Medical University n.a. I.M.Sechenov ( Site 1127)
- MROI n.a. P.A. Herzen - branch of FSBI NMICR of MoH of Russia ( Site 1128)
- City Clinical Oncology Center ( Site 1114)
- Sandton Oncology Medical Group PTY LTD ( Site 0900)
- The Oncology Centre ( Site 0903)
- Cancercare Rondebosch Oncology ( Site 0904)
- Hospital General Universitario de Elche ( Site 1155)
- Hospital Universitario Central de Asturias ( Site 1153)
- Hospital Vall D Hebron ( Site 1151)
- Hospital Universitario Gregorio Maranon ( Site 1152)
- Hospital 12 de Octubre de Madrid ( Site 1150)
- Inonu Universitesi Medical Fakultesi ( Site 1207)
- Baskent University Adana Training Hospital ( Site 1205)
- Hacettepe University Faculty of Medicine ( Site 1200)
- Gazi Universitesi Tip Fakultesi ( Site 1215)
- Trakya Universitesi Tip Fakultesi ( Site 1210)
- Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 1202)
- Prof. Dr. Cemil Tascioglu Sehir Hastanesi ( Site 1216)
- Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 1214)
- Kartal Dr. Lutfi Kirdar Egitim ve Arast Hast ( Site 1211)
- Ege Universitesi Tip Fakultesi Tulay Aktas Onkoloji Hastanesi ( Site 1204)
- Necmettin Erbakan Universitesi Meram Tip Fakultesi ( Site 1203)
- Medical center Medikal Plaza of Ecodnipro LLC ( Site 1317)
- Communal non profit enterprise Regional Clinical Oncology Center ( Site 1304)
- Medical Center of Yuriy Spizhenko LLC.-Clinical Trial ( Site 1319)
- Medical Center Asklepion LLC ( Site 1309)
- Medical Center Verum ( Site 1318)
- Shalimov s NI of Surgery and Transplantation ( Site 1321)
- Medical center of the Limited Liability Company Yulis ( Site 1314)
- Dobrobut Medical Center ( Site 1320)
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Experimental
Active Comparator
Olaparib + bevacizumab
Olaparib
Bevacizumab + chemotherapy
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.
Participants will receive olaparib (300 mg BID) oral, until progressive disease or end of study.
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.