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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04456699




Registration number
NCT04456699
Ethics application status
Date submitted
1/07/2020
Date registered
2/07/2020
Date last updated
6/05/2021

Titles & IDs
Public title
Efficacy and Safety of Olaparib, Olaparib + Bevacizumab Compared to Bevacizumab + 5-Fluorouracil (FU)
Scientific 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)
Secondary ID [1] 0 0
MK-7339-003
Secondary ID [2] 0 0
7339-003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Olaparib
Treatment: Drugs - 5-FU
Treatment: Drugs - Bevacizumab

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

Experimental: Olaparib - Olaparib (300 mg BID) oral, until progressive disease or end of study

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


Treatment: Drugs: Olaparib
300 mg BID, oral until progressive disease or end of study

Treatment: Drugs: 5-FU
2400 mg/m2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study

Treatment: Drugs: Bevacizumab
5 mg/kg Q2W IV infusion until progressive disease or end of study

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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) - 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.
Timepoint [1] 0 0
Up to approximately 6 years
Secondary outcome [1] 0 0
Overall Survival (OS) - Overall survival is the time from randomization to death due to any cause.
Timepoint [1] 0 0
Up to approximately 6 years
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Up to approximately 6 years
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Up to approximately 6 years
Secondary outcome [4] 0 0
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
Timepoint [4] 0 0
Up to approximately 6 years
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Up to approximately 6 years

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
St George Hospital ( Site 0052) - Kogarah
Recruitment hospital [2] 0 0
Liverpool Hospital ( Site 0055) - Liverpool
Recruitment hospital [3] 0 0
Royal Brisbane and Women s Hospital ( Site 0054) - Herston
Recruitment hospital [4] 0 0
Queen Elizabeth Hospital ( Site 0053) - Woodville South
Recruitment hospital [5] 0 0
Monash Health ( Site 0050) - Clayton
Recruitment hospital [6] 0 0
Peninsula Health Frankston Hospital ( Site 0056) - Frankston
Recruitment postcode(s) [1] 0 0
2217 - Kogarah
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
4029 - Herston
Recruitment postcode(s) [4] 0 0
5011 - Woodville South
Recruitment postcode(s) [5] 0 0
3168 - Clayton
Recruitment postcode(s) [6] 0 0
3199 - Frankston
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Kentucky
Country [6] 0 0
United States of America
State/province [6] 0 0
Louisiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
Nebraska
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Pennsylvania
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Virginia
Country [15] 0 0
Belgium
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Antwerpen
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Belgium
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Bruxelles-Capitale, Region De
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Belgium
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Oost-Vlaanderen
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Belgium
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Vlaams-Brabant
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Belgium
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West-Vlaanderen
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Canada
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Ontario
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Canada
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Quebec
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Chile
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Araucania
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Chile
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Region M. De Santiago
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Colombia
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Cesar
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Colombia
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Distrito Capital De Bogota
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Colombia
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Santander
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Colombia
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France
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France
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Doubs
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France
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Gironde
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France
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France
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Germany
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Berlin
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Germany
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Hamburg
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Hungary
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Borsod-Abauj-Zemplen
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Hungary
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Hajdu-Bihar
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Hungary
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Jasz-Nagykun-Szolnok
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Hungary
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Zala
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Hungary
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Budapest
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Aichi
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Chiba
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Ehime
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Kanagawa
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Saitama
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Fukuoka
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Taegu-Kwangyokshi
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Seoul
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Russian Federation
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Arkhangel Skaya Oblast
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Moskva
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Sankt-Peterburg
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Gauteng
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South Africa
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Limpopo
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South Africa
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Western Cape
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Spain
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Alicante
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Spain
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Asturias
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Spain
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Barcelona
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Spain
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Madrid
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Adana
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Ankara
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Edirne
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Istanbul
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Izmir
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Turkey
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Konya
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Ukraine
State/province [68] 0 0
Dnipropetrovska Oblast
Country [69] 0 0
Ukraine
State/province [69] 0 0
Kharkivska Oblast
Country [70] 0 0
Ukraine
State/province [70] 0 0
Kyivska Oblast
Country [71] 0 0
Ukraine
State/province [71] 0 0
Zaporizka Oblast
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Ukraine
State/province [72] 0 0
Kyiv

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT04456699
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck, Sharpe & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04456699