Avelumab in Previously Untreated Patients With Epithelial Ovarian Cancer (JAVELIN OVARIAN 100)

• ClinicalTrials.gov Identifier: NCT02718417
• Recruitment Status: Terminated
• First Posted: March 24, 2016
• Results First Posted: December 18, 2019
• Last Update Posted: July 14, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: March 15, 2016
• First Posted Date: March 24, 2016
• Results First Submitted Date: September 6, 2019
• Results First Posted Date: December 18, 2019
• Last Update Posted Date: July 14, 2020
• Actual Study Start Date: May 19, 2016
• Actual Primary Completion Date: September 7, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 5, 2019)

Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]

BICR assessed PFS: Duration from randomization until disease progression or death. PFS data was censored on the date of the last adequate tumor assessment for participants who did not have an event (progression of disease or death), who started a new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. Progression as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1: as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method.

Original Primary Outcome Measures (submitted: March 18, 2016)

Progression-Free Survival (PFS) [ Time Frame: Baseline to measured progressive disease (up to 36 months) ]

The period from study entry until disease progression, death or date of last contact. Assessments to be completed by third-party blinded independent committee review.

Current Secondary Outcome Measures (submitted: June 19, 2020)

• Overall Survival [ Time Frame: Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
• Progression-Free Survival (PFS) as Assessed by Investigator [ Time Frame: Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  Investigator assessed PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression as per RECIST 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using a Cox's Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.
• Percentage of Participants With Objective Response as Assessed by Investigator [ Time Frame: Baseline to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of 27 months) ]
  Investigator assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions.
• Percentage of Participants With Objective Response as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Baseline to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of 27 months) ]
  BICR assessed objective response according to RECIST version 1.1, was defined as participants with confirmed best overall response of CR or PR. CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions.
• Duration of Response (DOR) as Assessed by Investigator [ Time Frame: First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  Investigator assessed DOR: time (in months) from the first documentation of objective response (confirmed CR or PR) to the date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 mm. PR: at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method.
• Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  BICR assessed DOR: time (in months) from the first documentation of objective response (confirmed CR or PR) to the date of first documentation of PD or death due to any cause. As per RECIST version 1.1, CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 mm. PR: at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method.
• Maintenance Progression-Free Survival as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: From Day 1 of Cycle 1 (42 days) of maintenance phase to progression of disease or death, whichever occurred first (maximum duration of 27 months) ]
  BICR assessed maintenance PFS was defined as the time from Cycle 1 Day 1 of the maintenance phase to the date of the first documentation of PD or death due to any cause, whichever occurs first. It was defined, for participants who proceeded to maintenance phase and who did not have disease progression by BICR during the chemotherapy phase. As per RECIST version 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method.
• Maintenance Progression-Free Survival (PFS) as Assessed by Investigator [ Time Frame: From Day 1 of Cycle 1 (42 days) of maintenance phase to progression of disease or death, whichever occurred first (maximum duration of 27 months) ]
  Investigator assessed maintenance PFS was defined as the time from Cycle 1 Day 1 of the maintenance phase to the date of the first documentation of PD or death due to any cause, whichever occurs first. It was defined, for participants who proceeded to maintenance phase and who did not have disease progression by investigator during the chemotherapy phase. As per RECIST version 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method
• Percentage of Participants With Pathological Complete Response (pCR) [ Time Frame: Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  pCR was defined (for neoadjuvant participants who underwent interval debulking surgery [IDS]), as the chemotherapy response score 3 (CSR3), based on a study by Bohm et al, 2015. CSR3 was defined as complete or near-complete response with no residual tumor or minimal irregularly scattered tumor foci seen as individual cells, cell groups, or nodules up to 2 mm. Complete or near-complete response was defined as complete or near-complete microscopic disappearance of invasive tumor/ residual disease.
• Progression-Free Survival 2 (PFS2) [ Time Frame: Baseline up to start of second subsequent treatment after first PD or discontinuation from study or death, which ever occured first (maximum duration of 27 months) ]
  PFS2 was defined as time (in months) from the date of randomization to the start of second subsequent treatment after first documentation of PD, or death from any cause, whichever occurred first. Progression as per RECIST version 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method.
• Progression-Free Survival (PFS) as Assessed by Gynecological Cancer Intergroup (GCIG) Criteria [ Time Frame: Baseline until disease progression by GCIG criteria or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  PFS by GCIG was assessed by both RECIST 1.1 and cancer antigen 125 (CA-125). It was defined as time from randomization to first documentation of disease progression (PD) or death, whichever occurred first. As per RECIST 1.1, PD: greater than or equal to (>=) 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study with absolute increase >= 5 millimeters. PD based on serum CA-125 was defined as (i) participants with elevated CA-125 pretreatment and normalization of CA-125, (ii) participants with CA-125 in the reference range before treatment; (i) and (ii) must have showed CA-125 >= 2 times the upper limit of the reference range on 2 occasions >= 1 week apart, or (iii) participants with elevated CA-125 before treatment, which never normalized, showed CA-125 >= 2 times the nadir value on 2 occasions >= 1 week apart. Censoring date for PFS by GCIG was the latest of the censoring dates for PFS by RECIST 1.1 and PFS by CA-125.
• Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [ Time Frame: Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 36 months) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Treatment-emergent events are events between first dose of study drug and up to 36 months that were absent before treatment or that worsened relative to pretreatment state.
• Number of Participants With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [ Time Frame: Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  As per NCI-CTCAE v 4.03, Grade 3 and above criteria were; Hematology [Anemia - Grade 3: hemoglobin <8.0 grams per deciliter (g/dL), <4.9 millimoles per liter (mmol/L), <80 grams per liter (g/L), transfusion indicated, Grade 4: life-threatening consequences, urgent intervention indicated, Grade 5: death; platelet count decreased- Grade 3:<50.0 to 25.0*10^9/Liters(L), Grade 4: <25.0*10^9/L; lymphocyte count decreased-Grade 3: <0.5-0.2*10^9/L, Grade 4: <0.2*10^9/L; neutrophil count decreased-Grade 3: <1.0 to 0.5*10^9 /L, Grade 4: <0.5*10^9/L]. Chemistry [creatinine increased-Grade 3: >3.0 to 6.0*upper limit of normal (ULN), Grade 4: >6.0*ULN; serum amylase increased, lipase increased-Grade 3: >2.0 - 5.0*ULN, Grade 4: >5.0*ULN]. Liver function [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)-Grade 3: >5.0 to 20.0*ULN, Grade 4: >20.0*ULN].
• Change From Baseline in Vital Signs - Blood Pressure at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance/ Observation Phase and at End of Treatment [ Time Frame: Baseline, first 3 months of Chemotherapy Phase (CP): Day 1 of Cycles 2, 3 and 4 (each cycle 21 days); Maintenance/Observation Phase (MP/OP): Days 1, 15 and 29 of Cycles 1 and 2 (each cycle 42 days) and at end of treatment (up to 27 months) ]
  Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). MP is applicable only for two arms 'Chemotherapy followed by Avelumab' and 'Chemotherapy + Avelumab followed by Avelumab'. OP is applicable only for third arm 'Chemotherapy followed by Observation'. Category titles 'MP/OP' imply which ever phase was applicable for the respective reporting arms.
• Change From Baseline in Vital Signs - Pulse Rate at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance/ Observation Phase and at End of Treatment [ Time Frame: Baseline, first 3 months of Chemotherapy Phase (CP): Day 1 of Cycles 2, 3 and 4 (each cycle 21 days); Maintenance/Observation Phase (MP/OP): Days 1, 15 and 29 of Cycles 1 and 2 (each cycle 42 days) and at end of treatment (up to 27 months) ]
  Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized. MP is applicable only for two arms 'Chemotherapy followed by Avelumab' and 'Chemotherapy + Avelumab followed by Avelumab'. OP is applicable only for third arm 'Chemotherapy followed by Observation'. Category titles 'MP/OP' imply which ever phase was applicable for the respective reporting arms.
• Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months) ]
  ECG abnormalities included: 1) QT interval, QT interval corrected using Bazett's formula (QTcB) and QT interval corrected using Fridericia's formula (QTcF): increase from baseline greater than (>) 30 millisecond (ms) or 60 ms; absolute value > 450 ms, >480 ms and > 500 ms; 2) heart rate (HR) : absolute value <=50 bpm and decrease from baseline >=20 bpm; absolute value >=120 beats per minute (bpm) and increase from baseline >=20 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS interval: absolute value >= 120 ms.
• Functional Assessment of Ovarian Symptom Index- 18 (FOSI-18) Score [ Time Frame: CP: Pre-dose on Day 1 of Cycles 2 to 6 (1 cycle= 21 days); MP/OP: Day 1 of Cycles 1 to 12 (1 cycle= 42 days), End of treatment (any time up to Month 27) ]
  National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) Ovarian Symptom Index-18 (FOSI-18) is an 18-itemed participant completed questionnaire, designed to assess impact of cancer therapy on ovarian cancer-related symptoms. Based on numerical point scoring of symptoms. Includes three subscales: disease-related symptoms (10 items), treatment-related side effects (5) and general function/well-being (3). Participants rated their level of symptoms for each items using 5-point scale from 0=not at all to 4=very much. Items that were negatively framed, scores were reversed for analysis so that higher scores= good quality of life. Total symptom index: total of 18 scores, ranging from 0=severely symptomatic to 72=asymptomatic. Higher FOSI-18 scores= better functioning or lower symptom burden. MP applicable only for arms 'Chemotherapy followed by Avelumab' and 'Chemotherapy + Avelumab followed by Avelumab' and OP for 'Chemotherapy followed by Observation'.
• European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Score [ Time Frame: Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 36 months) ]
  EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). In VAS, participants rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Published weights are available that allow for the creation of a single summary score. 57 overall scores ranged from 0 to 1, with low scores representing a higher level of dysfunction.
• Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once a Week [QW] Regimen) [ Time Frame: Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  Cmax is maximum plasma concentration of paclitaxel. The LLQ of paclitaxel was 10.0 ng/mL.
• Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once Every Three Weeks [Q3W] Regimen) [ Time Frame: Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  Cmax is maximum plasma concentration of paclitaxel. The LLQ of paclitaxel was 10.0 ng/mL.
• Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Carboplatin (Total and Free) [ Time Frame: Pre-dose and at 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2 ]
  Cmax is maximum plasma concentration of carboplatin. The LLQ of carboplatin was 100.0 ng/mL.
• Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (QW Regimen) [ Time Frame: Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
• Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (Q3W Regimen) [ Time Frame: Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
• Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Carboplatin (Total and Free) [ Time Frame: Pre-dose and at 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2 ]
  AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
• Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (QW Regimen) [ Time Frame: Pre-dose (0 hour), 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24).
• Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (Q3W Regimen) [ Time Frame: Pre-dose (0 hour), 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2 ]
  AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24).
• Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Carboplatin (Total and Free) [ Time Frame: Pre-dose (0 hour), 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2 ]
  AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose.
• Maintenance Phase: Predose Plasma Concentration (Ctrough) of Avelumab [ Time Frame: Pre-dose (0 hour) on Day 1 of Cycle 2 ]
  Ctrough is the concentration at the end of the dosing interval when avelumab was given as a Q2W regimen in the absence of carboplatin and paclitaxel following 1 cycle of avelumab dosing, i.e. before administration of drug on Day 1 of cycle 2. Ctrough of Avelumab in the absence of chemotherapy (i.e. in the maintenance phase) has been reported. The LLQ of avelumab was 0.20 micro-gram per milliliter (mcg/mL). Data for this outcome measure was not reported for reporting arms "PK: Chemotherapy + Avelumab followed by Avelumab" (since data was not planned to be collected 1 cycle after the initiation of avelumab dosing ) and "PK: Chemotherapy followed by Observation" (since avelumab was not administered in this arm and therefore data collection was not planned).
• Maintenance Phase: Maximum Plasma Concentration (Cmax) of Avelumab [ Time Frame: End of avelumab infusion on Day 1 of Cycle 2 ]
  Cmax is the concentration at the end of a 1 hour infusion, corresponding to the maximum plasma concentration of avelumab. The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not reported for reporting arms "PK: Chemotherapy + Avelumab followed by Avelumab"(since data was not planned to be collected 1 cycle after the initiation of avelumab dosing ) and "PK: Chemotherapy followed by Observation" (since avelumab was not administered in this arm and therefore data collection was not planned).
• Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Avelumab When Given With Paclitaxel and Carboplatin [ Time Frame: End of infusion on Day 1 of Cycle 2 ]
  Cmax is the concentration at the end of a 1 hour infusion, corresponding to the maximum plasma concentration of avelumab. The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not reported for reporting arms "PK: Chemotherapy followed by Avelumab" (data not available for this OM as avelumab was not given along with paclitaxel and carboplatin in this arm) and "PK: Chemotherapy followed by Observation" (since avelumab was not administered in this arm and therefore data collection was not planned).
• Chemotherapy Phase: Predose Plasma Concentration (Ctrough) of Avelumab When Given With Paclitaxel and Carboplatin [ Time Frame: Pre-dose (0 hour) on Day 1 of Cycle 2 ]
  Ctrough is the concentration at the end of the dosing interval when avelumab was given as a Q2W regimen in the absence of carboplatin and paclitaxel following 1 cycle of avelumab dosing, i.e. before administration of drug on Day 1 of cycle 2. The LLQ of avelumab was 0.20 mcg/mL. Data for this outcome measure was not reported for reporting arms "PK: Chemotherapy followed by Avelumab" (data not available for this OM as avelumab was not given along with paclitaxel and carboplatin in this arm) and "PK: Chemotherapy followed by Observation" (since avelumab was not administered in this arm and therefore data collection was not planned).
• Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status [ Time Frame: Up to 36 months ]
  ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive participants. Participants were considered ADA ever-positive if they had at least one positive (ADA titer greater than or equal to 60 with assay cut point of 1.12) ADA result at any time point during 36 months and were otherwise considered negative. Data for this outcome measure was not planned to be collected and analyzed for reporting arm "Chemotherapy followed by Observation", since, avelumab was not administered in this arm.
• Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status [ Time Frame: Up to 36 months ]
  nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive participants. Participants were considered nAb ever-positive if they had at least one positive nAb results (less than or equal to cut point of 0.710 in qualitative competitive ligand binding assay) at any time point during 36 months. nAb never-positive participants were those who had at least one negative nAb results (greater than cut point of 0.710 in qualitative competitive ligand binding assay) at any time point. Data for this outcome measure was not planned to be collected and analyzed for reporting arm "Chemotherapy followed by Observation", since, avelumab was not administered in this arm.
• Number of Participants With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) [ Time Frame: Up to 36 months ]
  PD-L1 assessment was performed using immunohistochemistry. Participants were considered positive if their pretreatment tumor tissue sample demonstrated cell surface PD-L1 expression greater than or equal to (>=) 1 percent (%) tumor cells or >= 5% immune cells and were otherwise considered negative.
• Number of Participants With Positive Tumor-Infiltrating Cluster of Differentiation 8 (CD8+) T Lymphocytes Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) [ Time Frame: Up to 36 months ]
  CD8 assessment was performed using immunohistochemistry. Participants were considered positive if their pre-treatment tumor tissue sample demonstrated >= 1% CD8 positive cells and were otherwise considered negative.

Original Secondary Outcome Measures (submitted: March 18, 2016)

• Overall Survival (OS) [ Time Frame: Baseline to date of death from any cause (up to 112 months) ]
  Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.
• Maintenance Progression-Free Survival (PFS) [ Time Frame: Maintenance baseline to date of measured progressive disease (up to 24 months) ]
  Maintenance PFS is defined, for patients who proceed to maintenance and who do not have PD by BICR during the chemotherapy phase, as the time from Cycle 1 Day 1 of the maintenance phase to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever occurs first
• Duration of Response (DR) [ Time Frame: Baseline up to 36 months ]
  Time in weeks/months from the first documentation of objective tumor response (CR or PR) to objective tumor progression or death due to any cause, whichever occurs first.
• Objective Response Rate - Percentage of Participants With Objective Response [ Time Frame: Baseline up to 36 months ]
  Objective response is defined as a complete response (CR) or partial response (PR) per RECIST version 1.1 recorded from randomization until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. A patient will be considered to have achieved an OR if the patient has a sustained complete response (CR) or partial response (PR) according to RECIST v.1.1 definitions. Otherwise, the patient will be considered as a non responder in the OR rate (ORR) analysis. The ORR on each treatment arm will be estimated by dividing the number of patients with OR (CR or PR) by the number of patients randomized to the respective treatment arm.
• EuroQoL5 Dimension (EQ-5D-5L) [ Time Frame: Baseline, every 6 weeks, through study completion (up to 2 years), and follow-up (up to 3 years) ]
  Participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile which has individuals rate their level of problems (none, slight, moderate, severe, or extreme/unable) in 5 areas (mobility, self care, usual activities, pain/discomfort, and anxiety/depression).
• FOSI-18 [FACT Ovarian Symptom Index-18] [ Time Frame: Baseline, every 6 weeks, through study completion (up to 2 years), and follow-up (up to 3 years) ]
  The FOSI 18 (a revised, more symptom focused version of the FACT O) was developed to be part of the Functional Assessment of Chronic Illness Therapy (FACIT) system and was specifically created with the input from the Food and Drug Administration (FDA) and validated in ovarian cancer patients.designed to be a stand alone instrument to measure disease symptoms, treatment side effects and function/well being in patients with ovarian cancer.
• ADA [Anti-Drug Antibodies] [ Time Frame: Screening, Day 1 of Chemo cycles 1-4, Day 1 and 15 of Maintenance cycles 1 and 2, up to 30 days post follow-up ]
  The percentage of participants with positive ADA and neutralizing antibodies will be summarized for each treatment arm.
• Presence or absence of predictive candidate biomarkers in tumor tissue [ Time Frame: Baseline ]
  To identify predictive biomarkers of sensitivity or resistance in pre-treatment tissue (PD-L1 expression tumor infiltrating CD8+ T cells, etc....)
• Area under the Concentration-Time Curve (AUC) [ Time Frame: 1, 3 4, 5, 6, 10, 24 hr post-paclitaxel on D1 of C2; pre-dose, 0.25, 0.5, 1, 5, 6, 10, 24 hrs post-carboplatin infusion on D1 of C2; 2 hrs prior to and immediately before the end of avelumab infusion on D1 of C1-C4. ]
  AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
• Cmax [ Time Frame: 1, 3 4, 5, 6, 10, 24 hr post-paclitaxel on D1 of C2; pre-dose, 0.25, 0.5, 1, 5, 6, 10, 24 hrs post-carboplatin infusion on D1 of C2; 2 hrs prior to and immediately before the end of avelumab infusion on D1 of C1-C4. ]
  Maximum Observed Plasma Concentration (Cmax)
• Volume of Distribution [ Time Frame: 1, 3 4, 5, 6, 10, 24 hr post-paclitaxel on D1 of C2; pre-dose, 0.25, 0.5, 1, 5, 6, 10, 24 hrs post-carboplatin infusion on D1 of C2; 2 hrs prior to and immediately before the end of avelumab infusion on D1 of C1-C4. ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
• Clearance (CL) [ Time Frame: 1, 3 4, 5, 6, 10, 24 hr post-paclitaxel on D1 of C2; pre-dose, 0.25, 0.5, 1, 5, 6, 10, 24 hrs post-carboplatin infusion on D1 of C2; 2 hrs prior to and immediately before the end of avelumab infusion on D1 of C1-C4. ]
  CL is a quantitative measure of the rate at which a drug substance is removed from the body.
• Progression Free Survival 2 (PFS2) [ Time Frame: Baseline up to second progression up to 3 years ]
  PFS2 is defined as time from randomization to the start of second subsequent treatment after first progression, or death from any cause, whichever occurs first.
• pathological Complete response (pCR) [ Time Frame: Baseline to 9 weeks (after IDS) ]
  pCR is defined for neoadjuvant patients who undergo interval debulking surgery and assessed for pathological response

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Avelumab in Previously Untreated Patients With Epithelial Ovarian Cancer (JAVELIN OVARIAN 100)
• Official Title: A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER JAVELIN OVARIAN 100

Brief Summary

This is a Phase 3, open-label, international, multi-center, efficacy, and safety study of avelumab in combination with and/or following platinum-based chemotherapy. Eligible patients must have previously untreated, histologically confirmed Stage III-IV epithelial ovarian (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) and be candidates for platinum-based chemotherapy.

The primary purpose of the study is to demonstrate if avelumab given as single agent in the maintenance setting following frontline chemotherapy or in combination with carboplatin/paclitaxel is superior to platinum-based chemotherapy alone followed by observation in this population of newly diagnosed ovarian cancer patients.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ovarian Cancer

Intervention

• Drug: carboplatin
  Given Q3W during chemotherapy phase
• Drug: paclitaxel
  Investigator choice of weekly or Q3W during chemotherapy phase
• Drug: Avelumab
  Given Q3W in combination with carboplatin/paclitaxel during chemotherapy portion
• Drug: Avelumab
  Given as single agent in maintenance portion Q2W

Study Arms

• Active Comparator: Arm A
  Chemotherapy followed by observation
  Interventions:

  • Drug: carboplatin
  • Drug: paclitaxel
• Experimental: Arm B
  Chemotherapy followed by avelumab in maintenance
  Interventions:

  • Drug: carboplatin
  • Drug: paclitaxel
  • Drug: Avelumab
• Experimental: Arm C
  Chemotherapy in combination with avelumab followed by avelumab in maintenance
  Interventions:

  • Drug: carboplatin
  • Drug: paclitaxel
  • Drug: Avelumab
  • Drug: Avelumab

• Publications *: Monk BJ, Colombo N, Oza AM, Fujiwara K, Birrer MJ, Randall L, Poddubskaya EV, Scambia G, Shparyk YV, Lim MC, Bhoola SM, Sohn J, Yonemori K, Stewart RA, Zhang X, Perkins Smith J, Linn C, Ledermann JA. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Sep;22(9):1275-1289. doi: 10.1016/S1470-2045(21)00342-9. Epub 2021 Aug 4.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 29, 2019): 998
• Original Estimated Enrollment (submitted: March 18, 2016): 951
• Actual Study Completion Date: May 16, 2019
• Actual Primary Completion Date: September 7, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer, including malignant mixed Müllerian tumors with high grade serous component
• Patients must be candidates for platinum based chemotherapy and previously untreated
• Patients must have completed a surgical debulking procedure, or be candidates for neoadjuvant chemotherapy
• Availability of an archival formalin fixed, paraffin embedded (FFPE) tumor tissue block or a minimum of 15 slides
• ECOG PS 0-1
• Adequate hematological, renal, and liver function

Key Exclusion Criteria:

• Non epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors
• Prior systemic anti-cancer treatment for EOC, FTC, or PPC including prior immunotherapy with IL 2, IFN α, or anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (anti CTLA 4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways
• Patients for whom, in the opinion of the Investigator, there is clinical benefit to administer bevacizumab as a first-line treatment and for whom bevacizumab is approved and available in this setting.
• Cancer for which intraperitoneal cytotoxic chemotherapy is planned
• Active autoimmune disease (some exceptions include diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroidism not requiring immunosuppressive treatment)

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Canada, Croatia, Estonia, Germany, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Republic of, Latvia, Mexico, Netherlands, Poland, Romania, Russian Federation, Singapore, Slovakia, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02718417
• Other Study ID Numbers: B9991010; 2015-003239-36 ( EudraCT Number ); JAVELIN OVARIAN 100 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer
• Study Chair: Bradley Monk, MD; Department of Obstetrics and Gynecology University of Arizona Cancer Center, USA
• Study Chair: Jonathan Ledermann, MD; UCL Cancer Institute, UK

• PRS Account: Pfizer
• Verification Date: June 2020