A Study Of Avelumab Alone Or In Combination With Pegylated Liposomal Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients With Platinum Resistant/Refractory Ovarian Cancer (JAVELIN Ovarian 200)

Phase 3

Completed

Conditions: Ovarian Cancer

Interventions: Drug: PLD
Biological: avelumab

Registration Number: NCT02580058

Lead Sponsor: Pfizer

Brief Summary: A Phase 3 global study comparing avelumab alone to avelumab plus PLD and to PLD alone to demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging Overall Survival in patients with platinum resistant/platinum refractory ovarian cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 566

Inclusion Criteria

Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, including malignant mixed Müllerian tumors with high grade serous component.
Platinum resistant/refractory disease, defined as disease progression within 180 days following the last administered dose of platinum therapy (resistant), or lack of response or disease progression while receiving the most recent platinum based therapy (refractory), respectively.
Received up to 3 lines of systemic anticancer therapy for platinum sensitive disease, most recently platinum containing, and no prior systemic therapy for platinum resistant disease
Measurable disease by investigator assessment with at least 1 unidimensional measurable lesion by RECIST v.1.1 that has not previously been irradiated
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

Mandatory tumor biopsy must be performed prior to enrollment for all patients (unless there is a documented clinical contraindication). In addition, availability of archived FFPE tumor tissue should be confirmed. If a patient underwent tumor tissue collection within 3 months prior to enrollment with no intervening treatment, and the sample is provided, then a new de novo tumor biopsy is not required.

Exclusion Criteria

Non epithelial tumor or ovarian tumors with low malignant potential (ie, borderline tumors).
Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways).
Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry and are neurologically stable.
Diagnosis of any other malignancy within 5 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix.
Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4 weeks prior to enrollment, or history of inflammatory bowel disease.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PLD	PLD	Arm C: PLD alone
avelumab	avelumab	Arm A: avelumab alone
avelumab plus pegylated liposomal doxorubicin (PLD)	avelumab	Arm B: avelumab plus PLD
avelumab plus pegylated liposomal doxorubicin (PLD)	PLD	Arm B: avelumab plus PLD

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.	PFS is defined as the time from date of randomization to the date of the first documentation of progression of disease (PD) or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method. PFS based on BICR assessment was evaluated for this endpoint.
Overall Survival (OS)	From randomization until the date of first documented progression or date of deaths from any cause, whichever came first, assessed up to 30 months (based on cutoff date: 19 September 2018).	OS is defined as the time from the date of randomization to the date of death due to any cause. OS time was summarized by treatment arm using the Kaplan-Meier method.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) Based on BICR Assessment	Tumor assessments as assessed by BICR were conducted at every 8 weeks from screening until documented disease progression (approximately up to 30 months); based on cutoff date: 19 September 2018.	Percentage of participants achieved objective response (OR) based on BICR assessment is presented for this endpoint. OR is defined as a complete response (CR, disappearance of all target lesions) or partial response (PR, \>=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the 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 and before the first documentation of disease progression. Only tumor assessments performed on or before the start date of any further anti-cancer therapies are considered in the assessment of best overall response.
PFS Based on Investigator Assessment According to RECIST Version 1.1	From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.	PFS is defined as the time from date of randomization to the date of the first documentation of PD or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method.
ORR Based on Investigator Assessment	Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.	Percentage of participants achieved OR based on investigator assessment is presented for this endpoint. OR is defined as a CR (disappearance of all target lesions) or PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the RECIST (version 1.1) recorded from randomization until disease progression or death due to any cause. The ORR on each randomized treatment arm were estimated by dividing the number of participants with OR (CR or PR) by number of participants randomized to the respective treatment arm.
Disease Control (DC) Rate Based on BICR Assessment	Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.	Percentage of participants achieving DC based on BICR assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or stable disease (SD) according to the RECIST version 1.1.
DC Rate Based on Investigator Assessment	Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.	Percentage of participants achieving DC based on investigator assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or SD according to the RECIST version 1.1.
Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28	From Day 1 of Cycle 1 to prior to end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 28 (EORTC QLQ-OV28) is a 28 item instrument with 7 functional domain subscales. Time to deterioration was defined as the time from randomization to the first time the participant's score showed a 15-point or higher increase in the score of the abdominal/GI symptom subscale of the EORTC QLQ-OV28.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From the time of the first dose of study treatment through a minimum of 30 days + last dose of study treatment, start day of new anti-cancer therapy -1 day (up to 70 months); based on cutoff date: 13 July 2022.	An adverse event (AE) is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; progression of the malignancy under study. Treatment emergent AEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period.
Number of Participants With Laboratory Abnormalities	From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.	The number of participants with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 4.03 were summarized: hematology (anemia, lymphocyte count decreased, neutrophil count decreased; and platelet count decreased) and chemistry laboratory tests (creatinine increased; serum amylase increased and lipase increased).
Number of Participants With Electrocardiogram (ECG) Abnormalities	From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.	Categorical summarization ECG criteria were as follows: 1) QT interval, QTcB, QTcF and QTcP: increase from baseline \>30 ms or 60 ms; absolute value \> 450 ms, \>480 ms and \> 500 ms; 2) heart rate (HR): change from baseline \>=20 bpm and absolute value \<=50 bpm or \>=120 bpm; 3) PR interval: absolute value \>=220 ms and increase from baseline \>=20 ms; 4) QRS: \>= 120 ms.
Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose	At predose (0 H) on Cycle 2 Day 1	Ctrough was defined as predose concentration during multiple dosing, and can be observed directly from data.
Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose	From 0 through 24 hours postdose	AUC24 was defined as area under the concentration time profile from time zero to 24 hours.
Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose	From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose	AUC336 was defined as area under the concentration time profile from time zero to 336 hours.
Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose	From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose	AUClast was defined as area under the concentration time profile from time zero to the time of the last quantifiable concentration (Clast).
Number of Participants With Treatment-Induced Neutralizing Antibody (nAb)	At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab	Treatment-induced nAb was defined as participant who was not nAb positive at baseline and had at least one positive post-baseline nAb result; or if participant did not have a baseline sample, the participant had at least one positive past-baseline ADA result.
Duration of Response (DR) Based on BICR Assessment	Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.	DR is defined, for participants with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR \[disappearance of all target lesions\] or PR \[\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions\]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline	Screening, Cycle 3 Day 1 (repeated every 2 cycles) to the end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.	LVEF decrease was summarized by multiple-gated acquisition (MUGA)/ echocardiogram (ECHO) parameter. Participants with a LVEF% \>=10 points and \>= 15 points decrease from baseline during the on-treatment period were summarized.
Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS	Biomarkers are measured only at screening.	PD-L1 expression was assessed by immunohistochemistry. Participants were considered positive for PD-L1 if their baseline tissue sample demonstrated PD-L1 expression on \>=1% of tumor cells or \>=5% of immune cells.
Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS	Biomarkers are measured only at screening.	Tumor infiltrating CD8 positive (CD8+) T lymphocytes was assessed by immunohistochemistry. Participants were considered positive for CD8 T cells if their baseline tissue sample demonstrated presence of \>=1% CD8+ cells across the area of the tumor.
Change From Baseline in EQ-VAS Score at End of Treatment	Baseline and end of treatment/withdrawal visit	The EuroQol- 5 Dimensions- 5 Levels (EQ-5D-5L) questionnaire consists of the EQ-5D-5L descriptive system and a visual analogue scale (the EuroQol-visual analogue scale \[EQ-VAS\]). The respondent's self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS.
DR Based on Investigator Assessment	Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.	DR is defined, for participants with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR \[disappearance of all target lesions\] or PR \[\>=30% decrease under the baseline of the sum of diameters of all target measurable lesions\]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
Change From Baseline in Vital Signs - Blood Pressure	From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.	Vital signs included blood pressure and pulse rate. Changes from baseline in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were summarized.
Change From Baseline in Vital Signs - Pulse Rate	From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.	Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL	Day 1 of Cycle 1, Day 1 of each subsequent cycle, end of treatment/withdrawal visit and the 30, 60 and 90 days safety follow up visits, based on cutoff date: 19 September 2018.	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) is a 30 question survey and includes 5 functional domain subscales, global health status/quality of life, disease/treatment related symptoms, and the perceived financial impact of disease. Higher scores are reflective of a greater presence of symptoms.
Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose	At postdose (end of infusion, 1H) on Cycle 2 Day 1	Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose	From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose	Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA)	At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab	Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab.
Number of Participants With Treatment-Induced ADA	At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab	Treatment-induced ADA was defined as participant who was ADA-negative at baseline and has at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive past-baseline ADA result.

Trial Locations

Locations (256): Arizona Oncology Associates, PC - HAL
🇺🇸
Scottsdale, Arizona, United States
Arizona Oncology Associates, PC-HAL
🇺🇸
Tempe, Arizona, United States
Arizona Oncology Associates, PC - HOPE
🇺🇸
Tucson, Arizona, United States
Highlands Oncology Group
🇺🇸
Rogers, Arkansas, United States
University of California, Irvine/UC Irvine Health
🇺🇸
Orange, California, United States
Sansum Clinic
🇺🇸
Solvang, California, United States
Rocky Mountain Cancer Centers
🇺🇸
Lakewood, Colorado, United States
Florida Cancer Specialists
🇺🇸
West Palm Beach, Florida, United States
Atlanta Gynecologic Oncology
🇺🇸
Atlanta, Georgia, United States
Northside Hospital - Pharmacy
🇺🇸
Atlanta, Georgia, United States
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Arizona Oncology Associates, PC - HAL
🇺🇸Scottsdale, Arizona, United States