Metastatic Colorectal Cancer
Conditions
Keywords
colorectal cancer, CRC, Olaparib, Bevacizumab, FOLFOX, 5-FU, fluorouracil, folinic acid, oxaliplatin, CAPOX, capecitabine
Brief 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.
Interventions
DRUGOlaparib
300 mg BID, oral until progressive disease or end of study
DRUG5-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
DRUGBevacizumab
5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study
DRUGCapecitabine
1000 mg/m\^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study
DRUGLeucovorin/ 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
Sponsors
AstraZeneca
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 folinic acid/fluorouracil/oxaliplatin (FOLFOX) + bevacizumab or 4 cycles of capecitabine and oxaliplatin (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-Progressive Disease (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 colorectal cancer (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 30 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 30 months | OS was defined as the time from randomization to death due to any cause. The OS is presented. |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 30 months | 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. |
| Number of Participants With One or More Adverse Events (AE) | Up to approximately 30 months | 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 number of participants who experienced at least one AE was reported for each arm. |
| Number of Participants Discontinuing Study Intervention Due to an AE | Up to approximately 30 months | 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 number of participants who discontinued study intervention due to an AE was reported for each arm. |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 30 months | For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. DOR is defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis will be censored at the date of their last tumor assessment. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions is also considered PD. DOR assessments will be based on BICR with confirmation. The DOR as assessed using RECIST 1.1 for all participants who experience a confirmed CR or PR will be presented. |
Countries
Australia, Belgium, Canada, Chile, Colombia, France, Germany, Hungary, Japan, Latvia, Lithuania, Russia, South Africa, South Korea, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Pre-assignment details
Eligible participants were randomized 1:1:1 to receive either Olaparib + Bevacizumab, Olaparib, or Bevacizumab + chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Olaparib + Bevacizumab Participants received 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. | 111 |
| Olaparib Participants received olaparib (300 mg BID) oral, until progressive disease or end of study. | 115 |
| Bevacizumab + Chemotherapy Participants received investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/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 5-FU (400 mg/m2) was added prior to infusional 5-FU, 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 was added per investigator's discretion. Treatment continued until progressive disease or end of study. | 109 |
| Total | 335 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 48 | 50 | 52 |
| Overall Study | Physician Decision | 0 | 0 | 2 |
| Overall Study | Sponsor Decision | 55 | 61 | 50 |
| Overall Study | Withdrawal by Subject | 8 | 4 | 5 |
Baseline characteristics
| Characteristic | Olaparib + Bevacizumab | Olaparib | Bevacizumab + Chemotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 12.8 | 61.1 Years STANDARD_DEVIATION 10.7 | 63.2 Years STANDARD_DEVIATION 11.3 | 61.3 Years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 16 Participants | 10 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 88 Participants | 93 Participants | 94 Participants | 275 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 5 Participants | 16 Participants |
| Mutation Status BRAF and RAS all wild type | 32 Participants | 33 Participants | 29 Participants | 94 Participants |
| Mutation Status BRAF or RAS Mutation | 79 Participants | 82 Participants | 80 Participants | 241 Participants |
| Number of Induction Cycles 6-8 cycles for FOLFOX + bevacizumab or 4-6 cycles for CAPOX + bevacizumab | 53 Participants | 57 Participants | 53 Participants | 163 Participants |
| Number of Induction Cycles >8 cycles for FOLFOX + bevacizumab or >6 cycles for CAPOX + bevacizumab | 58 Participants | 58 Participants | 56 Participants | 172 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 10 Participants | 5 Participants | 4 Participants | 19 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 40 Participants | 30 Participants | 95 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 71 Participants | 64 Participants | 66 Participants | 201 Participants |
| Response to Prior Induction CR/PR | 49 Participants | 48 Participants | 47 Participants | 144 Participants |
| Response to Prior Induction SD | 62 Participants | 67 Participants | 62 Participants | 191 Participants |
| Sex: Female, Male Female | 50 Participants | 49 Participants | 44 Participants | 143 Participants |
| Sex: Female, Male Male | 61 Participants | 66 Participants | 65 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 49 / 111 | 51 / 115 | 52 / 109 |
| other Total, other adverse events | 94 / 111 | 74 / 113 | 86 / 108 |
| serious Total, serious adverse events | 16 / 111 | 13 / 113 | 14 / 108 |
Outcome results
Primary
Progression Free Survival (PFS) Per 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.
Time frame: Up to approximately 30 months
Population: The analysis population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib + Bevacizumab | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR) | 3.7 Months |
| Olaparib | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR) | 3.6 Months |
| Bevacizumab + Chemotherapy | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR) | 5.5 Months |
p-value: 0.977495% CI: [1, 1.97]Log Rank
p-value: 0.999395% CI: [1.23, 2.49]Log Rank
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. DOR is defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis will be censored at the date of their last tumor assessment. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions is also considered PD. DOR assessments will be based on BICR with confirmation. The DOR as assessed using RECIST 1.1 for all participants who experience a confirmed CR or PR will be presented.
Time frame: Up to approximately 30 months
Population: All randomized participants who received at least one dose of treatment and had either a CR or a PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib + Bevacizumab | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | NA Months |
| Olaparib | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | NA Months |
| Bevacizumab + Chemotherapy | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | NA 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 number of participants who discontinued study intervention due to an AE was reported for each arm.
Time frame: Up to approximately 30 months
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib + Bevacizumab | Number of Participants Discontinuing Study Intervention Due to an AE | 6 Participants |
| Olaparib | Number of Participants Discontinuing Study Intervention Due to an AE | 4 Participants |
| Bevacizumab + Chemotherapy | Number of Participants Discontinuing Study Intervention Due to an AE | 7 Participants |
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 number of participants who experienced at least one AE was reported for each arm.
Time frame: Up to approximately 30 months
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib + Bevacizumab | Number of Participants With One or More Adverse Events (AE) | 101 Participants |
| Olaparib | Number of Participants With One or More Adverse Events (AE) | 91 Participants |
| Bevacizumab + Chemotherapy | Number of Participants With One or More Adverse Events (AE) | 96 Participants |
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.
Time frame: Up to approximately 30 months
Population: The analysis population consisted of all randomized participants who had a measurable disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaparib + Bevacizumab | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | 4.8 Percentage of Participants |
| Olaparib | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | 1.9 Percentage of Participants |
| Bevacizumab + Chemotherapy | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | 4.8 Percentage of Participants |
p-value: 0.527295% CI: [-7, 6.5]Miettinen and Nurminen
p-value: 0.90295% CI: [-9.7, 2.3]Miettinen & Nurminen
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. The OS is presented.
Time frame: Up to approximately 30 months
Population: The analysis population consists of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib + Bevacizumab | Overall Survival (OS) | 21.2 Months |
| Olaparib | Overall Survival (OS) | 21.6 Months |
| Bevacizumab + Chemotherapy | Overall Survival (OS) | 19.9 Months |
p-value: 0.152795% CI: [0.54, 1.21]Log Rank
p-value: 0.249195% CI: [0.59, 1.3]Log Rank