| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The treatment of participants with unresectable or metastatic CRC that has not progressed following an induction course of FOLFOX + bevacizumab |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Metastatic Colorectal Cancer (Has not progressed after completing at least 6 prior induction cycles of FOLFOX + Bevacizumab and can no longer tolerate any components of FOLFOX) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1. To compare progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR) |
|
| E.2.2 | Secondary objectives of the trial |
1.To compare overall survival (OS)
2.To evaluate objective response rate (ORR) using RECIST 1.1 as assessed by BICR
3.To evaluate duration of response (DOR) using RECIST 1.1 as assessed by BICR
4.To evaluate the safety and tolerability
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by AJCC eighth edition) colorectal adenocarcinoma.
2. Has not progressed 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.
3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the treating physician, requires/required the discontinuation of oxaliplatin. 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 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 ECOG performance status of 0 to 1 within 10 days prior to randomization.
6. Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption.
7. Has adequate organ function
8. Has provided a tumor tissue sample deemed acceptable by the central lab for biomarker analysis.
If a sample is not available at screening, a new tissue sample is required to be collected during screening.
Demographics
9. Is male or female, at least 18 years of age, at the time of signing the informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days (if on Arm 2) or 180 days (if on Arm 1 or Arm 3) after the last dose of study intervention:
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic vasectomized or secondary to medical cause as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
• Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
Female Participants
11. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in the protocol during the intervention period and for at least 30 days (if on Arm 2) or 180 days (if on Arm 1 or Arm 3) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
12. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
|
|
| E.4 | Principal exclusion criteria |
1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, or olaparib
2. Has known active 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 HIV infection
5. Has a known history of or is positive for hepatitis B or hepatitis C
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 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, non-malignant 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 HRCT scan or any psychiatric disorder that prohibits obtaining informed consent.
12. Has 1 or more conditions that, in the opinion of the physician, make the participant ineligible for treatment with bevacizumab. These conditions may include:
•Uncontrolled hypertension (SBP >150 mm Hg or DBP >100 mm Hg) or a history of hypertensive crisis or hypertensive encephalopathy
•History of:
-nephrotic syndrome or moderate proteinuria
-gastrointestinal perforation
-non-gastrointestinal fistula formation
-RPLS
13. Has received prior systemic anticancer therapy (other than FOLFOX + bevacizumab induction) including investigational agents within 28 days prior to randomization
14. Has received prior therapy with olaparib or with any other PARP inhibitor
15. Is currently receiving either strong or moderate inhibitors of 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 or moderate 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.
18. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Prior/Concurrent Clinical Study Experience
19. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study intervention.
Diagnostic Assessments
20. Has a known additional malignancy that is progressing or has required active therapy within the past 5 years.
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
22. Has clinically significant (eg, active) cardiovascular disease, including:
•Myocardial infarction or unstable angina within ≤ 6 months of randomization
•CHF ≥Grade 2 (as per New York Heart Association)
•Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG (eg, QTC ≥450 msec detected on 2 or more time points within a 24-hour period)
•Peripheral vascular disease ≥Grade 3 (eg, symptomatic and interfering with activities of daily living requiring repair or revision)
23. Has known dihydropyrimidine dehydrogenase (DPD) deficiency
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study intervention.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progressive-free Survival (PFS) Using RECIST 1.1 as Assessed by BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 6 years |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
2. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by BICR
3. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by BICR
4. Number of Participants with One or More Adverse Events (AE)
5. Number of Participants Discontinuing Study Intervention Due to an AE
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 6 years
2. Up to approximately 6 years
3. Up to approximately 6 years
4. Up to approximately 6 years
5. Up to approximately 6 years
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health-related Quality of Life (HRQoL) scores: EQ-5D-5L, QLQ-C30 and QLQ-CR29; Health Utility Scores |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Chile |
| China |
| Colombia |
| France |
| Hungary |
| Japan |
| Korea, Republic of |
| Russian Federation |
| South Africa |
| Turkey |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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