Fallopian Tube Cancer, Ovarian Cancer, Peritoneal Cancer
Conditions
Keywords
ARIEL3, ARIEL 3, platinum sensitive, PARP Inhibitor, rucaparib, homologous recombination, homologous recombination deficiency, CO-338, PF 01367338, AG 14699, platinum sensitive ovarian cancer, platinum sensitive fallopian tube cancer, platinum sensitive primary peritoneal cancer, platinum sensitive peritoneal cancer, gynecological cancer, Clovis, Clovis Oncology
Brief summary
Patients enrolled into this study will be stratified into 3 groups based on gene mutations identified in their tumor tissue. The purpose of this study is to evaluate patient response to maintenance treatment with rucaparib versus placebo. Response to treatment will be analyzed based on homologous recombination (HR) status of tumor samples.
Detailed description
Rucaparib is an orally available, small molecule inhibitor of poly-adenosine diphosphate \[ADP\] ribose polymerase (PARP) being developed for treatment of ovarian cancer associated with homologous recombination (HR) DNA repair deficiency (HRD). Clinical data have shown that ovarian cancer patients with and without evidence of a gBRCA mutation benefit from treatment with a PARP and that maintenance treatment with a PARP inhibitor following a response to platinum-based treatment increases PFS in patients with ovarian cancer. While patients with a BRCA mutation derived the most benefit, patients without evidence of a BRCA mutation also derived significant benefit. Patients enrolled into this study will be stratified into 3 groups based on tumor HRD status. The purpose of this study is to identify which of these groups of patients will most likely benefit from treatment with rucaparib. It is anticipated that rucaparib will provide therapeutic benefit and increase PFS in patients with HRD associated with a BRCA gene mutation or other HR gene alteration.
Interventions
DRUGRucaparib
Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.
DRUGPlacebo
Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.
Sponsors
Foundation Medicine
Myriad Genetics, Inc.
pharmaand GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer. * Received ≥2 prior platinum-based treatment regimens including platinum based regimen that must have been administered immediately prior to maintenance therapy in this trial. * Received no more than 1 non-platinum chemotherapy regimen. Prior hormonal therapy will not be counted as a non-platinum regimen. * Must have had at least a 6-month disease-free period following prior treatment with the penultimate platinum-based chemotherapy and achieved a response. * For the last chemotherapy course prior to study entry, patients must have received a platinum-based doublet chemotherapy regimen and have achieved a CR or PR (as defined by RECIST) and/or a GCIG CA-125 response. * Have sufficient archival tumor tissue for analysis.
Exclusion criteria
* History of prior cancer except for non-melanoma skin cancer, breast cancer curatively \> 3 years ago, curatively treated solid tumor (\>5 years ago without evidence of recurrence), and synchronous endometrial cancer (Stage 1A) with ovarian cancer. * Prior treatment with any PARP inhibitor, including rucaparib. Patients who received prior iniparib are eligible. * Untreated or symptomatic central nervous system metastases. * Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of study drug. * Required drainage of ascites during the final 2 cycles of their last platinum-based regimen and/or during the period between the last dose of chemotherapy of that regimen and randomization to maintenance treatment in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Progression According to RECIST Version 1.1, as Assessed by the Investigator, or Death From Any Cause (Investigator Progression Free Survival as Per invPFS) | Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 3 years. | Progression-free survival by Investigator (invPFS) is defined as the time from randomization to disease progression, according to RECIST v1.1 criteria as assessed by the investigator, or death due to any cause, whichever occurs first. Progressive disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS) | Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 8.2 years. | To evaluate PFS by RECIST v1.1, as assessed by independent radiology review (IRR). |
| Overall Survival (OS) | All patients were followed for survival up to approximately 8.2 years. | Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive. |
| Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18 | Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years. | The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related symptoms and is based on numerical point scoring of symptoms. The DRS-P subscale of the questionnaire is specifically designed to assess physical symptoms of ovarian cancer and evaluate changes in the subscale point score in individual assessments over time. This study looked at the time to a 4-point reduction in subscale score as an indicator of improvement in disease-related physical symptoms on cancer therapy. |
| Time to an 8-point Decrease in the Total Score of the FOSI-18 | Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years. | The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related physical, emotional and treatment-related symptoms, and is based on numerical point scoring of symptoms. The questionnaire is designed to evaluate changes in the total score in individual assessments over time. This study looked at the time to an 8-point reduction in the total score as an indicator of improvement in disease-related symptoms on cancer therapy. |
| Individual Model Parameter Estimates of Rucaparib and Covariates Identification | Study data collection occurred over approximately 7 months. | Concentration summary statistics |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, New Zealand, Spain, United Kingdom, United States
Participant flow
Recruitment details
564 subjects were recruited from 87 sites across 11 countries and randomized (2:1) to treatment with rucaparib or placebo
Participants by arm
| Arm | Count |
|---|---|
| Rucaparib 600 mg Tablets Taken orally twice daily (continuous 28 day treatment cycles) | 375 |
| Placebo Tablets Taken orally twice daily (continuous 28 day treatment cycles) | 189 |
| Total | 564 |
Baseline characteristics
| Characteristic | Rucaparib 600 mg Tablets | Total | Placebo Tablets |
|---|---|---|---|
| Age, Continuous | 61 Years | 61 Years | 62 Years |
| Best Response from Previous Platinum Therapy RECIST / CA-125 PR | 249 Participants | 374 Participants | 125 Participants |
| Best Response from Previous Platinum Therapy RECIST CR | 126 Participants | 190 Participants | 64 Participants |
| Bulky Lesions (lesion >20 mm) at Baseline No | 304 Participants | 464 Participants | 160 Participants |
| Bulky Lesions (lesion >20 mm) at Baseline Yes | 71 Participants | 100 Participants | 29 Participants |
| Penultimate Progression-free (PF) Interval >12 Months | 224 Participants | 337 Participants | 113 Participants |
| Penultimate Progression-free (PF) Interval 6-12 Months | 151 Participants | 227 Participants | 76 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 21 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 20 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 48 Participants | 75 Participants | 27 Participants |
| Race (NIH/OMB) White | 292 Participants | 436 Participants | 144 Participants |
| Sex: Female, Male Female | 375 Participants | 564 Participants | 189 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 372 | 2 / 189 |
| other Total, other adverse events | 372 / 372 | 182 / 189 |
| serious Total, serious adverse events | 91 / 372 | 20 / 189 |
Outcome results
Primary
Disease Progression According to RECIST Version 1.1, as Assessed by the Investigator, or Death From Any Cause (Investigator Progression Free Survival as Per invPFS)
Progression-free survival by Investigator (invPFS) is defined as the time from randomization to disease progression, according to RECIST v1.1 criteria as assessed by the investigator, or death due to any cause, whichever occurs first. Progressive disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s).
Time frame: Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 3 years.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib 600 mg Tablets | Disease Progression According to RECIST Version 1.1, as Assessed by the Investigator, or Death From Any Cause (Investigator Progression Free Survival as Per invPFS) | 10.8 Months |
| Placebo Tablets | Disease Progression According to RECIST Version 1.1, as Assessed by the Investigator, or Death From Any Cause (Investigator Progression Free Survival as Per invPFS) | 5.4 Months |
p-value: <0.000195% CI: [0.295, 0.451]Regression, Cox
Secondary
Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS)
To evaluate PFS by RECIST v1.1, as assessed by independent radiology review (IRR).
Time frame: Every 12 calendar weeks (within 7 days prior is permitted) after start of treatment until treatment discontinuation due to disease progression. Total follow-up was up to approximately 8.2 years.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib 600 mg Tablets | Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS) | 13.7 months |
| Placebo Tablets | Disease Progression According to RECIST v1.1, as Assessed by Independent Radiology Review (IRR), or Death From Any Cause (irrPFS) | 5.4 months |
p-value: <0.000195% CI: [0.278, 0.45]Regression, Cox
Secondary
Individual Model Parameter Estimates of Rucaparib and Covariates Identification
Concentration summary statistics
Time frame: Study data collection occurred over approximately 7 months.
Population: All patients who are treated with rucaparib with at least one pharmacokinetic (PK) measurement
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Rucaparib 600 mg Tablets | Individual Model Parameter Estimates of Rucaparib and Covariates Identification | Cycle 2 Day 1 | 1128 ng/mL | Geometric Coefficient of Variation 95.42 |
| Rucaparib 600 mg Tablets | Individual Model Parameter Estimates of Rucaparib and Covariates Identification | Cycle 4 Day 1 | 1136 ng/mL | Geometric Coefficient of Variation 86.19 |
| Rucaparib 600 mg Tablets | Individual Model Parameter Estimates of Rucaparib and Covariates Identification | Cycle 7 Day 1 | 1165 ng/mL | Geometric Coefficient of Variation 78.53 |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive.
Time frame: All patients were followed for survival up to approximately 8.2 years.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib 600 mg Tablets | Overall Survival (OS) | 36.0 Months |
| Placebo Tablets | Overall Survival (OS) | 43.2 Months |
Secondary
Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18
The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related symptoms and is based on numerical point scoring of symptoms. The DRS-P subscale of the questionnaire is specifically designed to assess physical symptoms of ovarian cancer and evaluate changes in the subscale point score in individual assessments over time. This study looked at the time to a 4-point reduction in subscale score as an indicator of improvement in disease-related physical symptoms on cancer therapy.
Time frame: Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib 600 mg Tablets | Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18 | 1.9 Months |
| Placebo Tablets | Time to a 4-point Decrease in the Disease-related Symptoms - Physical (DRS-P) Subscale of the FOSI-18 | 6.4 Months |
Secondary
Time to an 8-point Decrease in the Total Score of the FOSI-18
The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index (FOSI-18) is a questionnaire, for completion by patients, designed to assess the impact of cancer therapy on ovarian cancer-related physical, emotional and treatment-related symptoms, and is based on numerical point scoring of symptoms. The questionnaire is designed to evaluate changes in the total score in individual assessments over time. This study looked at the time to an 8-point reduction in the total score as an indicator of improvement in disease-related symptoms on cancer therapy.
Time frame: Screening, Day 1 of each treatment cycle, Treatment Discontinuation visit, and 28-day Follow-up visit. Total follow-up was up to approximately 6.4 years.
Population: Intent-to-treat: All patients randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib 600 mg Tablets | Time to an 8-point Decrease in the Total Score of the FOSI-18 | 2.9 Months |
| Placebo Tablets | Time to an 8-point Decrease in the Total Score of the FOSI-18 | 10.8 Months |