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 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04456699
• Other study ID #: 7339-003
• Secondary ID: MK-7339-003LYNK-
• Status: Completed
• Phase: Phase 3
• Start date: August 19, 2020
• Est. completion date: November 6, 2023

Study information

• Verified date: March 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 335
• Est. completion date: November 6, 2023
• Est. primary completion date: March 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 + 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.

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 CAPOX + bevacizumab or FOLFOX + bevacizumab (last dose is the day of the last infusion that contained oxaliplatin).

4. 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.

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, capecitabine, 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 anticoagulation).

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

• 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)

13. 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.

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Olaparib
300 mg BID, oral until progressive disease or end of study
• 5-FU
2400 mg/m^2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study; bolus 5-FU (400mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator's discretion
• Bevacizumab
5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study
• Capecitabine
1000 mg/m^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study
• Leucovorin/ levoleucovorin
400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) may be added to Bevacizumab + 5-FU per investigator's discretion Q2W IV infusion until progressive disease or end of study

Locations

Country	Name	City	State
Australia	Monash Health ( Site 0050)	Clayton	Victoria
Australia	Peninsula Health Frankston Hospital ( Site 0056)	Frankston	Victoria
Australia	Royal Brisbane and Women s Hospital ( Site 0054)	Herston	Queensland
Australia	St George Hospital ( Site 0052)	Kogarah	New South Wales
Australia	Liverpool Hospital ( Site 0055)	Liverpool	New South Wales
Australia	Queen Elizabeth Hospital ( Site 0053)	Woodville South	South Australia
Belgium	OLV Ziekenhuis ( Site 0109)	Aalst	Oost-Vlaanderen
Belgium	Imelda vzw ( Site 0110)	Bonheiden	Antwerpen
Belgium	AZ Klina ( Site 0106)	Brasschaat	Antwerpen
Belgium	UCL Saint Luc ( Site 0100)	Brussels	Bruxelles-Capitale, Region De
Belgium	UZ Antwerpen ( Site 0108)	Edegem	Antwerpen
Belgium	UZ Gent ( Site 0101)	Gent	Oost-Vlaanderen
Belgium	AZ Groeninge ( Site 0105)	Kortrijk	West-Vlaanderen
Belgium	UZ Gasthuisberg ( Site 0102)	Leuven	Vlaams-Brabant
Canada	Dr. Everett Chalmers Regional Hospital ( Site 0204)	Fredericton	New Brunswick
Canada	Hopital Cite de la Sante de Laval ( Site 0203)	Laval	Quebec
Canada	Moncton Hospital - Horizon Health Network ( Site 0201)	Moncton	New Brunswick
Canada	McGill University Health Centre ( Site 0207)	Montreal	Quebec
Canada	CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0202)	Sherbrooke	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0209)	Toronto	Ontario
Chile	Clínica San Carlos de Apoquindo Red Salud UC Christus ( Site 0252)	Santiago	Region M. De Santiago
Chile	Sociedad Oncovida S.A. ( Site 0250)	Santiago	Region M. De Santiago
Chile	Centro Investigación del Cáncer James Lind ( Site 0251)	Temuco	Araucania
Colombia	Administradora Country SA - Clinica del Country ( Site 0350)	Bogota	Distrito Capital De Bogota
Colombia	Instituto Nacional de Cancerologia E.S.E ( Site 0362)	Bogota	Distrito Capital De Bogota
Colombia	Fundacion Cardiovascular de Colombia ( Site 0360)	Bucaramanga	Santander
Colombia	Hemato Oncologos S.A. ( Site 0355)	Cali	Valle Del Cauca
Colombia	Oncomedica S.A. ( Site 0352)	Monteria	Cordoba
Colombia	Oncologos del Occidente ( Site 0364)	Pereira	Risaralda
Colombia	Sociedad de Oncología Y Hematología del Cesar S.A.S. ( Site 0353)	Valledupar	Cesar
France	CHU Jean Minjoz ( Site 0450)	Besancon	Doubs
France	Centre Leon Berard ( Site 0459)	Lyon	Rhone-Alpes
France	CHU Saint Eloi ( Site 0467)	Montpellier	Herault
France	Hopital Europeen Georges Pompidou ( Site 0452)	Paris
France	CHU Bordeaux Haut-Leveque ( Site 0457)	Pessac Cedex	Gironde
France	Institut de Cancerologie de l Ouest Centre Rene Gauducheau ( Site 0455)	Saint-Herblain	Bretagne
France	C.H.U. de Strasbourg Hopital de Hautepierre ( Site 0464)	Strasbourg	Bas-Rhin
Germany	Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 0504)	Berlin
Germany	St. Josef und St. Elisabeth Hospital gGmbH-Hematology, oncology and palliative medicine ( Site 0503)	Bochum	Nordrhein-Westfalen
Germany	Facharztzentrum Eppendorf ( Site 0501)	Hamburg
Germany	Universitaetsklinikum Ulm ( Site 0500)	Ulm	Baden-Wurttemberg
Hungary	Orszagos Onkologiai Intezet ( Site 1431)	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont ( Site 1426)	Debrecen	Hajdu-Bihar
Hungary	Bekes Megyei Kozponti Korhaz - Pandy Kalman Tagkorhaza ( Site 1432)	Gyula	Bekes
Hungary	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Okta-Klinikai Onkológiai és Sugárterápiás Ce	Miskolc	Borsod-Abauj-Zemplen
Hungary	Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 1427)	Szolnok	Jasz-Nagykun-Szolnok
Hungary	Zala Megyei Szent Rafael Korhaz ( Site 1429)	Zalaegerszeg	Zala
Japan	Chiba Cancer Center ( Site 0656)	Chiba
Japan	National Hospital Organization Kyushu Cancer Center ( Site 0654)	Fukuoka
Japan	National Cancer Center Hospital East ( Site 0650)	Kashiwa	Chiba
Japan	St. Marianna University School of Medicine Hospital ( Site 0657)	Kawasaki	Kanagawa
Japan	Saitama Cancer Center ( Site 0653)	Kitaadachi-gun	Saitama
Japan	National Hospital Organization Shikoku Cancer Center ( Site 0652)	Matsuyama	Ehime
Japan	Aichi Cancer Center Hospital ( Site 0658)	Nagoya	Aichi
Japan	Shizuoka Cancer Center Hospital and Research Institute ( Site 0655)	Sunto-gun	Shizuoka
Japan	National Cancer Center Hospital ( Site 0651)	Tokyo
Japan	The Cancer Institute Hospital of JFCR ( Site 0659)	Tokyo
Korea, Republic of	Kyungpook National University Chilgok Hospital ( Site 0956)	Daegu	Taegu-Kwangyokshi
Korea, Republic of	Korea University Anam Hospital ( Site 0955)	Seoul
Korea, Republic of	Samsung Medical Center ( Site 0954)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 0950)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0951)	Seoul
Korea, Republic of	The Catholic University of Korea St. Mary s Hospital ( Site 0953)	Seoul
Korea, Republic of	Asan Medical Center ( Site 0952)	Songpagu	Seoul
Latvia	Daugavpils Regional Hospital ( Site 1502)	Daugavpils
Latvia	P. Stradina Clinical University Hospital ( Site 1500)	Riga
Latvia	Riga East Clinical University Hospital ( Site 1501)	Riga
Lithuania	LSMUL Kauno Klinikos ( Site 1528)	Kaunas
Lithuania	Nacionalinis Vezio Institutas ( Site 1527)	Vilnius
Lithuania	Vilniaus Universiteto Ligonine Santaros Klinikos ( Site 1526)	Vilnius
Russian Federation	Arkhangelsk Clinical Oncological Dispensary ( Site 1113)	Arkhangelsk	Arkhangel Skaya Oblast
Russian Federation	MEDSI Clinical Hospital on Pyatnitsky Highway-Departmentof Antitumor Drug therapy ( Site 1129)	Krasnogorsk	Moskovskaya Oblast
Russian Federation	Krasnoyarsk Regional Clinical Oncological Dispensary ( Site 1121)	Krasnoyarsk	Krasnoyarskiy Kray
Russian Federation	First Moscow State Medical University n.a. I.M.Sechenov ( Site 1127)	Moscow	Moskva
Russian Federation	MROI n.a. P.A. Herzen - branch of FSBI NMICR of MoH of Russia ( Site 1128)	Moscow	Moskva
Russian Federation	N.N. Blokhin NMRCO ( Site 1106)	Moscow	Moskva
Russian Federation	National Medical and Surgical Center n.a. N.I.Pirogov ( Site 1126)	Moscow	Moskva
Russian Federation	City Clinical Oncology Center ( Site 1114)	Saint Petersburg	Sankt-Peterburg
Russian Federation	GBUZ Republican Clinical Oncological Dispensary-Antitumor drug therapy department ( Site 1130)	Ufa	Baskortostan, Respublika
South Africa	The Oncology Centre ( Site 0903)	Durban	Limpopo
South Africa	Cancercare Rondebosch Oncology ( Site 0904)	Rondebosch	Western Cape
South Africa	Sandton Oncology Medical Group PTY LTD ( Site 0900)	Sandton	Gauteng
Spain	Hospital Vall D Hebron ( Site 1151)	Barcelona
Spain	Hospital General Universitario de Elche ( Site 1155)	Elche	Alicante
Spain	Hospital 12 de Octubre de Madrid ( Site 1150)	Madrid
Spain	Hospital Universitario Gregorio Maranon ( Site 1152)	Madrid
Spain	Hospital Universitario Central de Asturias ( Site 1153)	Oviedo	Asturias
Turkey	Baskent University Adana Training Hospital ( Site 1205)	Adana
Turkey	Gazi Universitesi Tip Fakultesi ( Site 1215)	Ankara
Turkey	Hacettepe University Faculty of Medicine ( Site 1200)	Ankara
Turkey	Trakya Universitesi Tip Fakultesi ( Site 1210)	Edirne
Turkey	Göztepe Prof. Dr. Süleyman Yalçin Sehir Hastanesi-oncology ( Site 1214)	Istanbul
Turkey	Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 1202)	Istanbul
Turkey	Kartal Dr. Lutfi Kirdar Egitim ve Arast Hast ( Site 1211)	Istanbul
Turkey	Prof. Dr. Cemil Tascioglu Sehir Hastanesi ( Site 1216)	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Tulay Aktas Onkoloji Hastanesi ( Site 1204)	Izmir
Turkey	Necmettin Erbakan Universitesi Meram Tip Fakultesi ( Site 1203)	Konya
Turkey	Inonu Universitesi Medical Fakultesi ( Site 1207)	Malatya	Adana
Ukraine	Medical center Medikal Plaza of Ecodnipro LLC ( Site 1317)	Dnipro	Dnipropetrovska Oblast
Ukraine	Medical Center of Yuriy Spizhenko LLC.-Clinical Trial ( Site 1319)	Kapitanivka Village	Kyivska Oblast
Ukraine	Communal non profit enterprise Regional Clinical Oncology Center ( Site 1304)	Kharkiv	Kharkivska Oblast
Ukraine	Medical Center Asklepion LLC ( Site 1309)	Khodosivka	Kyivska Oblast
Ukraine	Dobrobut Medical Center ( Site 1320)	Kyiv
Ukraine	Medical Center Verum ( Site 1318)	Kyiv	Kyivska Oblast
Ukraine	Shalimov s NI of Surgery and Transplantation ( Site 1321)	Kyiv	Kyivska Oblast
Ukraine	Medical center of the Limited Liability Company Yulis ( Site 1314)	Zaporizhzhia	Zaporizka Oblast
United States	University Cancer & Blood Center, LLC ( Site 1381)	Athens	Georgia
United States	St. Vincent Frontier Cancer Center-Research ( Site 1414)	Billings	Montana
United States	Providence Saint Joseph Medical Center, Disney Family Cancer ( Site 1392)	Burbank	California
United States	University of Chicago ( Site 1357)	Chicago	Illinois
United States	UC Health Memorial Hospital ( Site 1401)	Colorado Springs	Colorado
United States	Poudre Valley Health System ( Site 1402)	Fort Collins	Colorado
United States	St Joseph Heritage Healthcare-Oncology ( Site 1383)	Fullerton	California
United States	West Cancer Center - East Campus ( Site 1396)	Germantown	Tennessee
United States	CHI Health St. Francis ( Site 1406)	Grand Island	Nebraska
United States	Cancer & Hematology Centers of Western Michigan ( Site 1358)	Grand Rapids	Michigan
United States	Hattiesburg Clinic Hematology/Oncology ( Site 1418)	Hattiesburg	Mississippi
United States	Cancer Partners of Nebraska ( Site 1353)	Lincoln	Nebraska
United States	James Graham Brown Cancer Center ( Site 1393)	Louisville	Kentucky
United States	Vanderbilt University Medical Center ( Site 1362)	Nashville	Tennessee
United States	University Medical Center New Orleans ( Site 1365)	New Orleans	Louisiana
United States	Illinois Cancer Care, PC ( Site 1352)	Peoria	Illinois
United States	Allegheny Singer Research Institute ( Site 1364)	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University ( Site 1411)	Portland	Oregon
United States	Providence Portland Medical Center ( Site 1400)	Portland	Oregon
United States	Blue Ridge Cancer Care ( Site 1374)	Roanoke	Virginia
United States	Washington University in St. Louis ( Site 1384)	Saint Louis	Missouri
United States	New England Cancer Specialists ( Site 1422)	Scarborough	Maine
United States	Baylor Scott & White Medical Center - Temple ( Site 1397)	Temple	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Chile,  Colombia,  France,  Germany,  Hungary,  Japan,  Korea, Republic of,  Latvia,  Lithuania,  Russian Federation,  South Africa,  Spain,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR).	PFS was 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 was 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 was also considered PD. PFS using RECIST 1.1 as assessed by BICR is presented.	Up to approximately 30 months
Secondary	Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause. The OS is presented.	Up to approximately 30 months
Secondary	Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR	ORR was 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. Per protocol, ORR of all randomized participants who entered the with measurable disease is presented.	Up to approximately 30 months
Secondary	Number of Participants With One or More Adverse Events (AE)	An AE was 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. The percentage of participants who experienced at least one AE was reported for each arm.	Up to approximately 30 months
Secondary	Number of Participants Discontinuing Study Intervention Due to an AE	An AE was 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. The percentage of participants who discontinued study intervention due to an AE was reported for each arm.	Up to approximately 30 months

External Links

•   Merck Clinical Trials Information