Veliparib With Carboplatin and Paclitaxel and as Continuation Maintenance Therapy in Adults With Newly Diagnosed Stage III or IV, High-grade Serous, Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Phase 3

Terminated

• Conditions: Ovarian Cancer; Ovarian Neoplasm
• Interventions: Drug: Paclitaxel; Drug: Veliparib; Drug: Carboplatin; Other: Placebo to Veliparib

• Registration Number: NCT02470585
• Lead Sponsor: AbbVie

Brief Summary

The primary objective of the study was to evaluate whether progression-free survival (PFS) was prolonged with the addition of veliparib to standard platinum-based chemotherapy (carboplatin/paclitaxel \[C/P\]) and continued as maintenance therapy compared with chemotherapy alone.

Detailed Description

Participants were randomized in a 1:1:1 ratio to one of three arms. Randomization in the entire population was stratified according to the timing of surgery and residual disease status (any residual disease after primary surgery vs. no residual disease after primary surgery vs. interval surgery) and the paclitaxel schedule (weekly vs. every 3 -weeks), stage of disease (III vs. IV), geographic region (Japan vs. North America and rest of world \[ROW\]), and germline breast cancer susceptibility gene (BRCA) mutation status (positive versus negative or Unknown).

Cytoreductive surgery could be performed before randomization and the initiation of study treatment (primary) or after 3 cycles of study treatment (interval). The weekly or every-3-week paclitaxel schedule and the choice of primary or interval cytoreductive surgery were determined at the discretion of the investigator.

The primary objective was evaluated in the BRCA-deficient cohort, participants with homologous recombination deficiency (HRD), and the intention-to-treat (ITT) population. These populations were sequentially inclusive, with the HRD population including the BRCA-deficient population, and the ITT population including the HRD and BRCA-deficient populations. The BRCA-deficient population was defined as participants with either a germline (gBRCA) and/or tissue-based (tBRCA) deleterious or suspected deleterious mutation in BRCA1 or BRCA2 confirmed by centralized testing. The HRD population was defined as participants with HRD tumors based on HRD score or presence of a deleterious or suspected deleterious mutation in BRCA1 or BRCA2 as determined by centralized testing.

Study Timeline

• Study First Submitted: 2015-06-10
• Study First Submitted QC: 2015-06-10
• Study First Posted: 2015-06-12
• Study Start: 2015-07-14
• Primary Completion: 2019-05-03
• Disposition First Submitted: 2020-04-29
• Disposition First Submitted QC: 2020-04-29
• Disposition First Posted: 2020-05-04
• Results First Submitted: 2020-08-04
• Results First Submitted QC: 2020-08-26
• Results First Posted: 2020-09-14
• Study Completion: 2023-10-05
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-02
• Last Update Posted: 2024-10-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 1140

Inclusion Criteria

1. Histologic diagnosis of International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, with the appropriate tissue available for histologic evaluation.
2. High-grade serous adenocarcinoma
3. Willing to undergo testing for gBRCA.
4. Adequate hematologic, renal, and hepatic function.
5. Neuropathy (sensory and motor) less than or equal to Grade 1.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. Participants who undergo primary cytoreductive surgery must be entered between 1 and 12 weeks after surgery. Participants undergoing interval surgery must have a tumor sample confirming the histological diagnosis prior to enrollment.
8. Participants with measurable disease or non-measurable disease are eligible. Participants may or may not have cancer-related symptoms.
9. Participant has one of the following available for pharmacodynamic analyses including somatic BRCA testing: Archived diagnostic formalin-fixed paraffin embedded (FFPE) tumor tissue; or tumor tissue biopsy collected prior to Cycle 1 Day 1.

Exclusion Criteria

1. Endometrioid adenocarcinoma, carcinosarcoma, undifferentiated carcinoma, mixed epithelial adenocarcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, clear cell adenocarcinoma, low-grade serous adenocarcinoma, or malignant Brenner's tumor.
2. Participants with synchronous primary endometrial cancer, or a past history of endometrial cancer unless all of the following conditions are met: endometrial cancer stage not greater than IA, no vascular or lymphatic invasion, no poorly differentiated subtypes including serous, clear cell, or other FIGO grade 3 lesions.
3. Participants with any evidence of other invasive malignancy being present within the last 3 years (with the exception of non-melanoma skin cancer). Participants are also excluded if their previous cancer treatment contraindicates this protocol's therapy.
4. Received prior radiotherapy to any portion of the abdominal cavity or pelvis.
5. Received prior chemotherapy for any abdominal or pelvic tumor.
6. Clinically significant uncontrolled condition(s).
7. Known history of allergic reaction to Cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine (also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C Yellow 6 or E110) or known contraindications to any study supplied drug.
8. History or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months of Cycle 1 Day 1.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + Carboplatin + Paclitaxel -> Placebo	Placebo to Veliparib	Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Placebo	Placebo to Veliparib	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Placebo + Carboplatin + Paclitaxel -> Placebo	Carboplatin	Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Placebo + Carboplatin + Paclitaxel -> Placebo	Paclitaxel	Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Placebo	Veliparib	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Placebo	Paclitaxel	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Placebo	Carboplatin	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Veliparib	Carboplatin	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Veliparib	Veliparib	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
Veliparib + Carboplatin + Paclitaxel -> Veliparib	Paclitaxel	Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) in the BRCA-deficient Population (Arm 3 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death prior to the analysis cut-off date, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The analysis of PFS occurred when the protocol-specified number of PFS events was reached.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
Progression-Free Survival (PFS) in the Homologous Recombination Deficiency Cohort (Arm 3 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached and was performed in 3 sequentially inclusive populations.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.; .
Progression-Free Survival (PFS) in the Intention-to-treat Population (Arm 3 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death (all causes of mortality) if disease progression was not reached. If the participant did not have an event of disease progression according to RECIST criteria (as or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.; The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached.

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) in the BRCA-deficient Population (Arm 2 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death prior to the analysis cut-off date, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The analysis of PFS occurred when the protocol-specified number of PFS events was reached.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
Progression-Free Survival (PFS) in the Homologous Recombination Deficiency Cohort (Arm 2 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached and was performed in 3 sequentially inclusive populations.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.; .
Progression-Free Survival (PFS) in the Intention-to-treat Population (Arm 2 vs Arm 1)	From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.	PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death (all causes of mortality) if disease progression was not reached. If the participant did not have an event of disease progression according to RECIST criteria (as or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method.; Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.; The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached.
Overall Survival (OS) in the BRCA-deficient Population	From the time of randomization to the end of the study, up to 98 months	OS is defined as the time from the day the participant was randomized to the date of death, and was calculated using Kaplan-Meier methods. All events of death will be included, regardless of whether the event occurs while the participant is still taking study drug, or after discontinuation of study drug. If a participant has not died, then the data will be censored at the date the participant is last known to be alive.
Overall Survival (OS) in the Homologous Recombination Deficiency Population	From the time of randomization to the end of the study, up to 98 months	OS is defined as the time from the day the participant was randomized to the date of death, and was calculated using Kaplan-Meier methods. All events of death will be included, regardless of whether the event occurs while the participant is still taking study drug, or after discontinuation of study drug. If a participant has not died, then the data will be censored at the date the participant is last known to be alive.
Overall Survival (OS) in the Whole Population	From the time of randomization to the end of the study, up to 98 months	OS is defined as the time from the day the participant was randomized to the date of death, and was calculated using Kaplan-Meier methods. All events of death will be included, regardless of whether the event occurs while the participant is still taking study drug, or after discontinuation of study drug. If a participant has not died, then the data will be censored at the date the participant is last known to be alive.
Change From Baseline in Disease Related Symptom (DRS) Score in the BRCA-mutation Population	Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35	The Disease Related Symptom score is a subset of the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Ovarian Symptom Index-18 (NFOSI-18), which evaluates nine symptoms related to ovarian cancer. The NFOSI-18 DRS score ranges from 0 to 36, with higher scores indicating a lower burden of symptoms and a score of 0 being severely symptomatic. A 3-point difference was defined as clinically meaningful. A positive change from Baseline indicates improvement.; Change from Baseline was calculated using a used a mixed-model for repeated measures (MMRM) with treatment, stratification factors of residual disease and stage of disease, time point and treatment-by-time point interaction as fixed effect factors, and Baseline DRS score as a covariate.; DRS was not included in the fixed-sequence testing procedure.
Change From Baseline in Disease Related Symptom (DRS) Score in the HRD Population	Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35	The Disease Related Symptom score is a subset of the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Ovarian Symptom Index-18 (NFOSI-18), which evaluates nine symptoms related to ovarian cancer. The NFOSI-18 DRS score ranges from 0 to 36, with higher scores indicating a lower burden of symptoms and a score of 0 being severely symptomatic. A 3-point difference was defined as clinically meaningful. A positive change from Baseline indicates improvement.; Change from Baseline was calculated using a used a mixed-model for repeated measures (MMRM) with treatment, stratification factors of residual disease and stage of disease, time point and treatment-by-time point interaction as fixed effect factors, and Baseline DRS score as a covariate.; DRS was not included in the fixed-sequence testing procedure.
Change From Baseline in Disease Related Symptom (DRS) Score in the Whole Population	Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35	The Disease Related Symptom score is a subset of the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Ovarian Symptom Index-18 (NFOSI-18), which evaluates nine symptoms related to ovarian cancer. The NFOSI-18 DRS score ranges from 0 to 36, with higher scores indicating a lower burden of symptoms and a score of 0 being severely symptomatic. A 3-point difference was defined as clinically meaningful. A positive change from Baseline indicates improvement.; Change from Baseline was calculated using a used a mixed-model for repeated measures (MMRM) with treatment, stratification factors of residual disease, stage of disease, choice of paclitaxel dosing regimen and BRCA-deficient status, time point and treatment-by-time point interaction as fixed effect factors, and Baseline DRS score as a covariate.; DRS was not included in the fixed-sequence testing procedure.

Trial Locations

Locations (210)

University of Alabama at Birmingham - Main /ID# 138087; 🇺🇸 Birmingham, Alabama, United States

Tennessee Valley Gyn-Onc /ID# 139548; 🇺🇸 Huntsville, Alabama, United States

University of South Alabama /ID# 138091; 🇺🇸 Mobile, Alabama, United States

Alaska Womens Cancer Care /ID# 138231; 🇺🇸 Anchorage, Alaska, United States

Arizona Oncology Associates, PC-HOPE /ID# 142002; 🇺🇸 Tucson, Arizona, United States

Arizona Oncology Associates, PC-HOPE /ID# 143805; 🇺🇸 Tucson, Arizona, United States

Arizona Oncology Associates, PC-HOPE /ID# 143806; 🇺🇸 Tucson, Arizona, United States

Arizona Oncology Associates, PC-HOPE /ID# 143808; 🇺🇸 Tucson, Arizona, United States

University of Arizona Cancer Center - North Campus /ID# 138084; 🇺🇸 Tucson, Arizona, United States

University of Arizona Cancer Center - North Campus /ID# 139495; 🇺🇸 Tucson, Arizona, United States

Scroll for more (200 remaining)