Germline BRCA1/2 Mutations and, Metastatic Adenocarcinoma of the Pancreas
Conditions
Keywords
BRCA, metastatic adenocarcinoma pancreas, maintenance olaparib monotherapy, first line platinum chemotherapy, pancreatic cancer, PARP inhibitor
Brief summary
A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients with gBRCA Mutated Metastatic Pancreatic Cancer whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy
Detailed description
Approximately 145 patients will be randomised using an Interactive Voice Response System /Interactive Web Response System (IVR/IWR system) in a 3:2 ratio (Olaparib:placebo) to the treatments as specified below: * Olaparib tablets p.o. 300 mg twice daily * Matching placebo tablets p.o. twice daily Eligible patients will be those patients with pancreas cancer previously treated for metastatic disease who have not progressed following completion of at least 16 weeks (can be more) of first line platinum-based chemotherapy. All patients must have a known deleterious or suspected deleterious germline BRCA mutation to be randomised; this may have been determined prior to enrolment into the study or may be assessed as part of the enrolment procedure for the study (via centrally provided MyriadIntegrated BRAC. Patients will be randomised within 6 weeks after their last dose of chemotherapy (last dose is the day of the last infusion) and treatment started as soon as possible but no less than 4 and no more than 8 weeks of the last chemotherapy dose. At the time of starting protocol treatment, all previous chemotherapy treatment should be discontinued. Following randomisation, patients will attend clinic visits weekly for the first 4 weeks of treatment (Days 8, 15, 22 and 29). Patients will then attend clinic visits every 4 weeks whilst on study treatment. Patients should continue to receive study treatment until objective radiological disease progression as per RECIST as assessed by the investigator and as long as in the investigator's opinion they are benefiting from treatment and they do not meet any other discontinuation criteria. Once a patient has progressed the patient will be followed for second progression (PFS2) every 8 weeks and then survival until the final analysis.
Interventions
DRUGOlaparib
Tablet -100mg
DRUGPlacebo
Match Olaparib 100mg placebo
Sponsors
Myriad Genetic Laboratories, Inc.
Merck Sharp & Dohme LLC
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment * Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study. * Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious * Patients are on treatment with a first line platinum-based (cisplatin, carboplatin or oxaliplatin) regimen for metastatic pancreas cancer, have received a minimum of 16 weeks of continuous platinum treatment and have no evidence of progression based on investigator's opinion. * Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreas cancer are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and initiation of the platinum-based chemotherapy for metastatic pancreas cancer. Major
Exclusion criteria
* gBRCA1 and/or gBRCA2 mutations that are considered to be non detrimental (eg, Variants of uncertain clinical significance or Variant of unknown significance or Variant, favour polymorphism or benign polymorphism etc.) * Progression of tumour between start of first line platinum based chemotherapy for metastatic pancreas cancer and randomisation. * Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle 1 Day 1 is not permitted. * Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation * Any previous treatment with a PARP inhibitor, including Olaparib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1) | Up to 4 years | To determine the efficacy of olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomisation to Second Progression (PFS2) | Up to 4 years | To determine efficacy by assessment of PFS2 of olaparib maintenance monotherapy compared to placebo. The PFS2 was defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or death. |
| Time From Randomisation to Second Subsequent Therapy or Death (TSST) | Up to 4 years | To determine the efficacy by assessment of TSST of olaparib maintenance monotherapy compared to placebo. The TSST was defined as time to second subsequent therapy or death. |
| Time From Randomisation to First Subsequent Therapy or Death (TFST) | Up to 4 years | To determine the efficacy by assessment of TFST of olaparib maintenance monotherapy compared to placebo. The TFST was defined as time to first subsequent therapy or death. |
| Time From Randomisation to Study Treatment Discontinuation or Death (TDT) | Up to 4 years | To determine the efficacy by assessment of TDT compared to placebo. compared to placebo. The TDT was defined as time to study treatment discontinuation or death. |
| Overall Survival (OS) | Upto 4 years | To determine the efficacy by assessment of OS of olaparib maintenance monotherapy compared to placebo. The OS was defined as the time from the date of randomization until death due to any cause. |
| Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | At 16 weeks | Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. |
| Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire | From baseline up to 6 months | To assess the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale. The EORTC-QLQ-C30 is defined as EORTC QLQ-C30: a questionnaire (30 questions) used to evaluate disease symptoms, functional impacts (eg, physical functioning), and HRQoL and to characterize clinical benefit from the patient perspective. The HRQoL score ranges from 0 to 100. A higher score indicates better QoL. A score change of 10 points was pre-defined as clinically meaningful. bd twice daily. |
| Number of Participants With Adverse Events (AEs) | Up to 4 years | To assess the safety and tolerability of olaparib maintenance monotherapy. SAE: serious adverse events CTCAE: Common Terminology Criteria for Adverse Events |
| Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1 | Up to 4 years | To determine efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. The ORR is defined as the number of with a BoR of CR and PR according to the BICR data divided by the number of patients in the treatment group with measurable disease at baseline. |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study randomised patients at a total of 59 study centres in 12 countries: United States of America (13), Germany (8), France (7), Israel (7), Spain (7), United Kingdom (6), Italy (4), Belgium (2), Republic of Korea (2), Australia (1), Canada (1) and Netherlands (1).
Pre-assignment details
Screening Part 1 was only required if a patient's gBRCAm status was unknown and Screening Part 2 was for patients with known local germline BRCA (gBRCA) test. All other screening parameters were done as per the Study Schedule.
Participants by arm
| Arm | Count |
|---|---|
| Olaparib 300 mg Twice Daily (bd) Randomised participants received orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions. | 92 |
| Placebo Randomised participants received placebo tablets orally 300 mg bd which were made up of 2 x 150 mg tablets bd with 100 mg tablets used to manage dose reductions. | 62 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 67 | 44 |
| Overall Study | Eligibility criteria not fulfilled | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Other | 0 | 3 |
| Overall Study | Patient decision | 5 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Olaparib 300 mg Twice Daily (bd) |
|---|---|---|---|
| Age, Continuous | 56.4 Years STANDARD_DEVIATION 9.07 | 57.5 Years STANDARD_DEVIATION 9.81 | 58.2 Years STANDARD_DEVIATION 10.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 148 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 59 Participants | 141 Participants | 82 Participants |
| Sex: Female, Male Female | 31 Participants | 70 Participants | 39 Participants |
| Sex: Female, Male Male | 31 Participants | 84 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 68 / 92 | 52 / 62 |
| other Total, other adverse events | 89 / 90 | 56 / 61 |
| serious Total, serious adverse events | 28 / 90 | 10 / 61 |
Outcome results
Primary
Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1)
To determine the efficacy of olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression.
Time frame: Up to 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1) | 7.4 Months |
| Placebo | Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Using Modified Response Evaluation Criteria in Solid Tumours. This Study Used Modified RECIST Version (v) 1.1 (RECIST v1.1) | 3.8 Months |
p-value: 0.003895% CI: [0.346, 0.815]Log-rank test
Secondary
Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire
To assess the effect of olaparib on health-related quality of life (QoL) as measured by the EORTC-QLQ-C30 global QoL scale. The EORTC-QLQ-C30 is defined as EORTC QLQ-C30: a questionnaire (30 questions) used to evaluate disease symptoms, functional impacts (eg, physical functioning), and HRQoL and to characterize clinical benefit from the patient perspective. The HRQoL score ranges from 0 to 100. A higher score indicates better QoL. A score change of 10 points was pre-defined as clinically meaningful. bd twice daily.
Time frame: From baseline up to 6 months
Population: Patient reported outcome (PRO) analysis set was defined as the analysis population for PRO data were a subset of the FAS (ITT) population who had evaluable baseline EORTC QLQ-C30 or QLQ-PAN26 forms where evaluable meant that at least 1 sub-scale baseline score could be determined from at least 1 of the 2 forms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire | -1.03 Unit on scale |
| Placebo | Adjusted Mean Change From Baseline up to 6 Months in Global Quality of Life (QoL) Score From the EORTC-QLQ-C30 Questionnaire | 1.18 Unit on scale |
p-value: 0.35595% CI: [-6.917, 2.496]Mixed Models Analysis
Secondary
Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1
Efficacy by assessment of disease control rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo.
Time frame: At 16 weeks
Population: Intention to treat (ITT): All randomised patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | Yes | 51 Participants |
| Olaparib 300 mg Twice Daily (bd) | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | No | 34 Participants |
| Olaparib 300 mg Twice Daily (bd) | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | Not evaluable/missing | 7 Participants |
| Placebo | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | Yes | 24 Participants |
| Placebo | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | No | 34 Participants |
| Placebo | Disease Control Rate (DCR) by BICR Using Modified RECIST 1.1 | Not evaluable/missing | 4 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
To assess the safety and tolerability of olaparib maintenance monotherapy. SAE: serious adverse events CTCAE: Common Terminology Criteria for Adverse Events
Time frame: Up to 4 years
Population: Safety Analysis Set consisted of all patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any AE with outcome = death | 1 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | AnyAE leading to withdrawal of olaparib/placebo | 8 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any AE of CTCAE Grade 3 or higher | 44 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 38 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 28 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any AE leading to dose reduction | 16 Participants |
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Adverse Events (AEs) | Any AE | 89 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE leading to dose reduction | 3 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE | 56 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE of CTCAE Grade 3 or higher | 15 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE with outcome = death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any SAE (including events with outcome = death) | 10 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AnyAE leading to withdrawal of olaparib/placebo | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 4 Participants |
Secondary
Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1
To determine efficacy by assessment of objective response rate according to modified RECIST 1.1 of olaparib maintenance monotherapy compared to placebo. The ORR is defined as the number of with a BoR of CR and PR according to the BICR data divided by the number of patients in the treatment group with measurable disease at baseline.
Time frame: Up to 4 years
Population: All randomised patients with measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1 | 22 Participants |
| Placebo | Number of Participants With Objective Response Rate (ORR) by BICR Using Modified RECIST 1.1 | 11 Participants |
p-value: 0.327395% CI: [0.668, 3.61]Regression, Logistic
Secondary
Overall Survival (OS)
To determine the efficacy by assessment of OS of olaparib maintenance monotherapy compared to placebo. The OS was defined as the time from the date of randomization until death due to any cause.
Time frame: Upto 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Overall Survival (OS) | 19.0 Months |
| Placebo | Overall Survival (OS) | 19.2 Months |
p-value: 0.348795% CI: [0.564, 1.224]Log-rank test
Secondary
Time From Randomisation to First Subsequent Therapy or Death (TFST)
To determine the efficacy by assessment of TFST of olaparib maintenance monotherapy compared to placebo. The TFST was defined as time to first subsequent therapy or death.
Time frame: Up to 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Time From Randomisation to First Subsequent Therapy or Death (TFST) | 9.0 Months |
| Placebo | Time From Randomisation to First Subsequent Therapy or Death (TFST) | 5.4 Months |
p-value: <0.000195% CI: [0.297, 0.658]Log-rank test
Secondary
Time From Randomisation to Second Progression (PFS2)
To determine efficacy by assessment of PFS2 of olaparib maintenance monotherapy compared to placebo. The PFS2 was defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or death.
Time frame: Up to 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Time From Randomisation to Second Progression (PFS2) | 16.9 Months |
| Placebo | Time From Randomisation to Second Progression (PFS2) | 9.3 Months |
p-value: 0.061395% CI: [0.426, 1.02]Log-rank test
Secondary
Time From Randomisation to Second Subsequent Therapy or Death (TSST)
To determine the efficacy by assessment of TSST of olaparib maintenance monotherapy compared to placebo. The TSST was defined as time to second subsequent therapy or death.
Time frame: Up to 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Time From Randomisation to Second Subsequent Therapy or Death (TSST) | 14.9 Months |
| Placebo | Time From Randomisation to Second Subsequent Therapy or Death (TSST) | 9.6 Months |
p-value: 0.011195% CI: [0.418, 0.894]Log-rank test
Secondary
Time From Randomisation to Study Treatment Discontinuation or Death (TDT)
To determine the efficacy by assessment of TDT compared to placebo. compared to placebo. The TDT was defined as time to study treatment discontinuation or death.
Time frame: Up to 4 years
Population: Intention to treat (ITT): All randomised patients, Myriad confirmed Breast cancer susceptibility gene mutation (gBRCAm) subgroup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300 mg Twice Daily (bd) | Time From Randomisation to Study Treatment Discontinuation or Death (TDT) | 7.5 Months |
| Placebo | Time From Randomisation to Study Treatment Discontinuation or Death (TDT) | 3.8 Months |
p-value: <0.000195% CI: [0.289, 0.627]Log-rank test