Ovarian Cancer
Conditions
Keywords
platinum resistant, platinum refractory
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.
Interventions
BIOLOGICALavelumab
10 mg/kg will be given as a 1 hour intravenous infusion (IV) every 2 weeks (Q2W) in 4 week cycles
DRUGPLD
PLD (Arm B, Arm C) 40 mg/m2 will be given as a 1 hour IV infusion every 4 weeks (Q4W) in 4 week cycles
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 - 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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-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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, France, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Netherlands, Norway, Poland, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Data reported based on last participant last visit (LPLV) date (12 July 2022).
Participants by arm
| Arm | Count |
|---|---|
| Avelumab Avelumab 10 milligram (mg)/kilogram (kg) given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles. | 188 |
| Avelumab + PLD Avelumab 10 mg/kg given as a 1-hour IV Q2W in 4-week cycles + pegylated liposomal doxorubicin (PLD) 40 mg/square meter given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles. | 188 |
| Pegylated Liposomal Doxorubicin (PLD) PLD 40 mg/square meter given as a 1-hour IV infusion Q4W in 4-week cycles. | 190 |
| Total | 566 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 16 | 30 | 20 |
| Overall Study | Death | 4 | 4 | 5 |
| Overall Study | Global Deterioration of Health Status | 19 | 18 | 24 |
| Overall Study | No Longer Meets Eligibility Criteria | 1 | 0 | 2 |
| Overall Study | Non-Compliance With Study Drug | 1 | 0 | 0 |
| Overall Study | Other | 5 | 1 | 3 |
| Overall Study | Physician Decision | 1 | 3 | 11 |
| Overall Study | Progressive Disease | 137 | 125 | 94 |
| Overall Study | Withdrawal by Subject | 4 | 7 | 31 |
Baseline characteristics
| Characteristic | Avelumab | Avelumab + PLD | Pegylated Liposomal Doxorubicin (PLD) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 77 Participants | 64 Participants | 76 Participants | 217 Participants |
| Age, Categorical Between 18 and 65 years | 111 Participants | 124 Participants | 114 Participants | 349 Participants |
| Age, Continuous | 61.0 years STANDARD_DEVIATION 10.26 | 59.5 years STANDARD_DEVIATION 10.05 | 60.4 years STANDARD_DEVIATION 10.64 | 60.3 years STANDARD_DEVIATION 10.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 176 Participants | 176 Participants | 183 Participants | 535 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 9 Participants | 6 Participants | 25 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 34 Participants | 53 Participants | 46 Participants | 133 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 2 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Unknown | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 148 Participants | 133 Participants | 135 Participants | 416 Participants |
| Sex: Female, Male Female | 188 Participants | 188 Participants | 190 Participants | 566 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 122 / 187 | 107 / 182 | 116 / 177 |
| other Total, other adverse events | 173 / 187 | 176 / 182 | 167 / 177 |
| serious Total, serious adverse events | 72 / 187 | 74 / 182 | 51 / 177 |
Outcome results
Primary
Overall Survival (OS)
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.
Time frame: 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).
Population: The primary analyses of OS were performed based on the Full Analysis Set (FAS). The FAS included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | Overall Survival (OS) | 11.8 months |
| Avelumab + PLD | Overall Survival (OS) | 15.7 months |
| Pegylated Liposomal Doxorubicin (PLD) | Overall Survival (OS) | 13.1 months |
p-value: 0.825395% CI: [0.867, 1.497]Log Rank
p-value: 0.208295% CI: [0.672, 1.179]Log Rank
Primary
Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
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.
Time frame: 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.
Population: The primary analyses of PFS based on BICR assessment were performed using FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 1.9 months |
| Avelumab + PLD | Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 3.7 months |
| Pegylated Liposomal Doxorubicin (PLD) | Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | 3.5 months |
p-value: >0.999995% CI: [1.31, 2.16]Log Rank
p-value: 0.030195% CI: [0.607, 1.011]Log Rank
Secondary
Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUC24 was defined as area under the concentration time profile from time zero to 24 hours.
Time frame: From 0 through 24 hours postdose
Population: The PK parameter analysis set was defined as a subset of the safety analysis set and included patients who had at least one of the PK parameters of interest for doxorubicin.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 567600 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 11 |
| Avelumab + PLD | Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 541700 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 14 |
Comparison: PLD was the Reference treatment and Avelumab + PLD was the Test treatment.90% CI: [88, 104]
Secondary
Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUC336 was defined as area under the concentration time profile from time zero to 336 hours.
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Population: The PK parameter analysis set was defined as a subset of the safety analysis set and included patients who had at least one of the PK parameters of interest for doxorubicin.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 2848000 ng*hr/mL | Geometric Coefficient of Variation 20 |
| Avelumab + PLD | Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 2571000 ng*hr/mL | Geometric Coefficient of Variation 30 |
Comparison: PLD was the Reference treatment and Avelumab + PLD was the Test treatment.90% CI: [76, 107]
Secondary
Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose
AUClast was defined as area under the concentration time profile from time zero to the time of the last quantifiable concentration (Clast).
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Population: The PK parameter analysis set was defined as a subset of the safety analysis set and included patients who had at least one of the PK parameters of interest for doxorubicin.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 2043000 ng*hr/mL | Geometric Coefficient of Variation 119 |
| Avelumab + PLD | Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 2052000 ng*hr/mL | Geometric Coefficient of Variation 71 |
Comparison: PLD was the Reference treatment and Avelumab + PLD was the Test treatment.90% CI: [60, 168]
Secondary
Change From Baseline in EQ-VAS Score at End of Treatment
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.
Time frame: Baseline and end of treatment/withdrawal visit
Population: The analysis is based on the FAS. The FAS included all participants who were randomized. 'Number Analyzed' represents number of participants in the FAS with an assessment at the visit or with at least a baseline and post-baseline assessment at visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Change From Baseline in EQ-VAS Score at End of Treatment | -13.6 scores on a scale | Standard Deviation 20.56 |
| Avelumab + PLD | Change From Baseline in EQ-VAS Score at End of Treatment | -11.2 scores on a scale | Standard Deviation 19.79 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in EQ-VAS Score at End of Treatment | -7.7 scores on a scale | Standard Deviation 22.26 |
Secondary
Change From Baseline in Vital Signs - Blood Pressure
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were summarized.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Population: 'Number of Participants Analyzed' is based on the safety analysis set, which included all participants who received at least 1 dose of study treatment. 'Number Analyzed' included the number of participants in the safety analysis set with at least a baseline and post-baseline assessment at the visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 1 Day 15 | 0.1 mm Hg | Standard Deviation 9.79 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 1 | -1.1 mm Hg | Standard Deviation 9.61 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 15 | 0.1 mm Hg | Standard Deviation 10.05 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 1 | 0 mm Hg | Standard Deviation 10.81 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 15 | -0.6 mm Hg | Standard Deviation 9.25 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | DBP End of Treatment | 1.1 mm Hg | Standard Deviation 10.87 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 1 Day 15 | -0.9 mm Hg | Standard Deviation 14.35 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 1 | -2.2 mm Hg | Standard Deviation 14.44 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 15 | -0.6 mm Hg | Standard Deviation 14.11 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 1 | -0.2 mm Hg | Standard Deviation 15.59 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 15 | -0.2 mm Hg | Standard Deviation 13.78 |
| Avelumab | Change From Baseline in Vital Signs - Blood Pressure | SBP End of Treatment | -0.9 mm Hg | Standard Deviation 17.21 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP End of Treatment | -1.0 mm Hg | Standard Deviation 16.83 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 1 Day 15 | -2.2 mm Hg | Standard Deviation 9.12 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 1 Day 15 | -2.3 mm Hg | Standard Deviation 13.12 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 15 | -3.7 mm Hg | Standard Deviation 14.78 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 1 | -2.8 mm Hg | Standard Deviation 8.01 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP End of Treatment | -0.3 mm Hg | Standard Deviation 11.08 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 15 | -2.1 mm Hg | Standard Deviation 15.3 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 15 | -2.8 mm Hg | Standard Deviation 9.19 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 1 | -3.4 mm Hg | Standard Deviation 13.7 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 15 | -2.3 mm Hg | Standard Deviation 8.56 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 1 | -2.7 mm Hg | Standard Deviation 8.95 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 1 | -2.7 mm Hg | Standard Deviation 14.36 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 1 | -0.2 mm Hg | Standard Deviation 8.96 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 3 Day 15 | -0.5 mm Hg | Standard Deviation 8.67 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 1 | -1.5 mm Hg | Standard Deviation 14.14 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP End of Treatment | 0.8 mm Hg | Standard Deviation 10.4 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 1 Day 15 | -1.0 mm Hg | Standard Deviation 13.94 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 1 | -2.8 mm Hg | Standard Deviation 13.39 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 3 Day 15 | -2.2 mm Hg | Standard Deviation 13.96 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 1 Day 15 | 0.7 mm Hg | Standard Deviation 8.89 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 1 | -0.1 mm Hg | Standard Deviation 9.34 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP Cycle 2 Day 15 | -1.8 mm Hg | Standard Deviation 14.98 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | DBP Cycle 2 Day 15 | -0.1 mm Hg | Standard Deviation 8.83 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Blood Pressure | SBP End of Treatment | -3.2 mm Hg | Standard Deviation 15.92 |
Secondary
Change From Baseline in Vital Signs - Pulse Rate
Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Population: 'Number of Participants Analyzed' is based on the safety analysis set, which included all participants who received at least 1 dose of study treatment. 'Number Analyzed' included the number of participants in the safety analysis set with at least a baseline and post-baseline assessment at the visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | Cycle 1 Day 15 | 2.9 bpm | Standard Deviation 9.95 |
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 1 | 2.6 bpm | Standard Deviation 10.92 |
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 15 | 2.9 bpm | Standard Deviation 11.19 |
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 15 | 3.0 bpm | Standard Deviation 12.23 |
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | End of Treatment | 7.7 bpm | Standard Deviation 14.27 |
| Avelumab | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 1 | 2.4 bpm | Standard Deviation 10 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 15 | 1.4 bpm | Standard Deviation 11.44 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | Cycle 1 Day 15 | 1.8 bpm | Standard Deviation 12.1 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 1 | 2.1 bpm | Standard Deviation 11.78 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 15 | 3.5 bpm | Standard Deviation 11.79 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 1 | 2.9 bpm | Standard Deviation 11.18 |
| Avelumab + PLD | Change From Baseline in Vital Signs - Pulse Rate | End of Treatment | 7.4 bpm | Standard Deviation 13.7 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 1 | 1.7 bpm | Standard Deviation 9.71 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | Cycle 2 Day 15 | 3.2 bpm | Standard Deviation 11.54 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 1 | 1.4 bpm | Standard Deviation 11.14 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | Cycle 1 Day 15 | 3.5 bpm | Standard Deviation 10.7 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | Cycle 3 Day 15 | 2.4 bpm | Standard Deviation 10.41 |
| Pegylated Liposomal Doxorubicin (PLD) | Change From Baseline in Vital Signs - Pulse Rate | End of Treatment | 5.7 bpm | Standard Deviation 14.1 |
Secondary
Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose
Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Time frame: From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose
Population: The PK parameter analysis set was defined as a subset of the safety analysis set and included patients who had at least one of the PK parameters of interest for doxorubicin.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 26810 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 14 |
| Avelumab + PLD | Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose | 25850 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 17 |
Comparison: PLD was the Reference treatment and Avelumab + PLD was the Test treatment.90% CI: [87, 106]
Secondary
DC Rate Based on Investigator Assessment
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 frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab | DC Rate Based on Investigator Assessment | 34.0 percentage of participants |
| Avelumab + PLD | DC Rate Based on Investigator Assessment | 61.7 percentage of participants |
| Pegylated Liposomal Doxorubicin (PLD) | DC Rate Based on Investigator Assessment | 54.7 percentage of participants |
Secondary
Disease Control (DC) Rate Based on BICR Assessment
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab | Disease Control (DC) Rate Based on BICR Assessment | 33.0 percentage of participants |
| Avelumab + PLD | Disease Control (DC) Rate Based on BICR Assessment | 57.4 percentage of participants |
| Pegylated Liposomal Doxorubicin (PLD) | Disease Control (DC) Rate Based on BICR Assessment | 48.9 percentage of participants |
Secondary
DR Based on Investigator Assessment
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized. Number analyzed are participants with confirmed CR or PR in the FAS within each treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | DR Based on Investigator Assessment | 10.4 months |
| Avelumab + PLD | DR Based on Investigator Assessment | 7.6 months |
| Pegylated Liposomal Doxorubicin (PLD) | DR Based on Investigator Assessment | 7.4 months |
Secondary
Duration of Response (DR) Based on BICR Assessment
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized. Number analyzed are participants with confirmed CR or PR in the FAS within each treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | Duration of Response (DR) Based on BICR Assessment | 9.2 months |
| Avelumab + PLD | Duration of Response (DR) Based on BICR Assessment | 8.5 months |
| Pegylated Liposomal Doxorubicin (PLD) | Duration of Response (DR) Based on BICR Assessment | 13.1 months |
Secondary
Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS
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.
Time frame: Biomarkers are measured only at screening.
Population: The biomarker analysis set included participants who had at least 1 screening biomarker assessment. 'Number of Participants Analyzed' is based on number of participants in the biomarker analysis set within each treatment group with reported CD8 status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab | Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS | 76 Participants |
| Avelumab + PLD | Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS | 80 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With CD8 Expression for PFS (Based on BICR Assessment) and for OS | 72 Participants |
Secondary
Number of Participants With Electrocardiogram (ECG) Abnormalities
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.
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Population: 'Number of Participants Analyzed' is based on the safety analysis set, which included all participants who received at least 1 dose of study treatment. 'Number Analyzed' included the number of participants in the safety analysis set who had a at least 1 post-baseline ECG assessment performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >60 ms | 9 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >60 ms | 5 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >450 ms | 6 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >480 ms | 1 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >500 ms | 1 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >30 ms | 33 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >30 ms | 26 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >450 ms | 56 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >480 ms | 9 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >500 ms | 5 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >30 ms | 19 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >60 ms | 6 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >450 ms | 18 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >480 ms | 4 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >500 ms | 3 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >30 ms | 17 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >60 ms | 6 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >450 ms | 19 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >480 ms | 2 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >500 ms | 1 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate <=50 bpm and decrease >= 20 bpm | 0 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate >=120 bpm and increase >= 20 bpm | 5 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR >=220 ms and increase from baseline >=20 ms | 3 Participants |
| Avelumab | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS >=120 ms | 7 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate >=120 bpm and increase >= 20 bpm | 5 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >30 ms | 40 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >450 ms | 27 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >60 ms | 5 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >60 ms | 9 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >30 ms | 24 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate <=50 bpm and decrease >= 20 bpm | 1 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >450 ms | 10 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >480 ms | 8 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR >=220 ms and increase from baseline >=20 ms | 4 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >480 ms | 2 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >500 ms | 9 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >450 ms | 29 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >500 ms | 1 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >500 ms | 2 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >60 ms | 5 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >30 ms | 36 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >480 ms | 19 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS >=120 ms | 9 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >60 ms | 7 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >30 ms | 23 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >480 ms | 7 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >450 ms | 63 Participants |
| Avelumab + PLD | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >500 ms | 2 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >450 ms | 45 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >480 ms | 9 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB >500 ms | 5 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >30 ms | 13 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >500 ms | 2 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF increase from baseline >60 ms | 5 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR >=220 ms and increase from baseline >=20 ms | 2 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >450 ms | 14 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >480 ms | 5 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate <=50 bpm and decrease >= 20 bpm | 0 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF >500 ms | 4 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS >=120 ms | 9 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >30 ms | 12 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >30 ms | 47 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT increase from baseline >60 ms | 4 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP increase from baseline >60 ms | 4 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >450 ms | 5 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | Heart rate >=120 bpm and increase >= 20 bpm | 3 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >480 ms | 2 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT >500 ms | 1 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >450 ms | 17 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >30 ms | 22 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB increase from baseline >60 ms | 8 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcP >480 ms | 2 Participants |
Secondary
Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL
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.
Time frame: 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.
Population: The analysis is based on the FAS. The FAS included all participants who were randomized. 'Number Analyzed' in represents number of participants in the FAS with a score at baseline and post-baseline.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Improved | 23 Participants |
| Avelumab | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Deterioration | 46 Participants |
| Avelumab | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Stable | 83 Participants |
| Avelumab + PLD | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Improved | 20 Participants |
| Avelumab + PLD | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Deterioration | 65 Participants |
| Avelumab + PLD | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Stable | 81 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Deterioration | 46 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Stable | 76 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL | Improved | 26 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
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).
Time frame: From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
Population: 'Number of Participants Analyzed' is based on the safety analysis set, which included all participants who received at least 1 dose of study treatment. 'Number Analyzed' included the number of participants in the safety analysis set who can be evaluated for CTCAE criteria for each parameter in each treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab | Number of Participants With Laboratory Abnormalities | Lymphocyte count decreased | 89 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Creatinine increased | 154 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Platelet count decreased | 33 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Anemia | 135 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Lipase increased | 27 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Serum amylase increased | 43 Participants |
| Avelumab | Number of Participants With Laboratory Abnormalities | Neutrophil count decreased | 26 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Platelet count decreased | 48 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Anemia | 155 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Lymphocyte count decreased | 148 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Neutrophil count decreased | 80 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Creatinine increased | 151 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Serum amylase increased | 35 Participants |
| Avelumab + PLD | Number of Participants With Laboratory Abnormalities | Lipase increased | 33 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Creatinine increased | 120 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Lymphocyte count decreased | 107 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Lipase increased | 21 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Serum amylase increased | 27 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Platelet count decreased | 50 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Neutrophil count decreased | 62 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Laboratory Abnormalities | Anemia | 144 Participants |
Secondary
Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline
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.
Time frame: Screening, Cycle 3 Day 1 (repeated every 2 cycles) to the end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
Population: 'Number of Participants Analyzed' is based on number of participants in the safety analysis set with a baseline and a post-baseline assessment within each treatment group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 10 point decrease from baseline | 8 Participants |
| Avelumab | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 15 point decrease from baseline | 3 Participants |
| Avelumab + PLD | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 10 point decrease from baseline | 22 Participants |
| Avelumab + PLD | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 15 point decrease from baseline | 8 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 10 point decrease from baseline | 13 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With % Left Ventricular Ejection Fraction (LVEF) Decrease From Baseline | >= 15 point decrease from baseline | 3 Participants |
Secondary
Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS
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.
Time frame: Biomarkers are measured only at screening.
Population: The biomarker analysis set included participants who had at least 1 screening biomarker assessment. 'Number of Participants Analyzed' is based on number of participants in the biomarker analysis set within each treatment group with reported PD-L1 status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab | Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS | 100 Participants |
| Avelumab + PLD | Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS | 100 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With PD-L1 Expression for PFS (Based on BICR Assessment) and for OS | 88 Participants |
Secondary
Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA)
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.
Time frame: 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
Population: The analysis set was defined as participants with valid baseline ADA results and at least one valid post-baseline ADA result in the immunogenicity analysis set. The immunogenicity analysis set was a subset of the safety analysis set and included patients who had at least one ADA/nAb sample collected for avelumab in the avelumab containing arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab | Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA) | 1 Participants |
| Avelumab + PLD | Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA) | 0 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Treatment-Boosted Anti-Drug Antibody (ADA) | 1 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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.
Population: Analysis is based on the safety analysis set. The safety analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 180 Participants |
| Avelumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment emergent SAEs | 72 Participants |
| Avelumab + PLD | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 180 Participants |
| Avelumab + PLD | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment emergent SAEs | 74 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment emergent SAEs | 51 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE | 173 Participants |
Secondary
Number of Participants With Treatment-Induced ADA
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.
Time frame: 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
Population: The analysis set was defined as participants with at least 1 valid post-baseline ADA results and without positive baseline ADA result in the immunogenicity analysis set. The immunogenicity analysis set was a subset of the safety analysis set and included patients who had at least one ADA/nAb sample collected for avelumab in the avelumab containing arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab | Number of Participants With Treatment-Induced ADA | 27 Participants |
| Avelumab + PLD | Number of Participants With Treatment-Induced ADA | 2 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Treatment-Induced ADA | 29 Participants |
Secondary
Number of Participants With Treatment-Induced Neutralizing Antibody (nAb)
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.
Time frame: 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
Population: The analysis set was defined as participants with at least 1 valid post-baseline ADA result and without positive baseline nAb result in the immunogenicity analysis set. The immunogenicity analysis set was a subset of the safety analysis set and included patients who had at least one ADA/nAb sample collected for avelumab in the avelumab containing arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab | Number of Participants With Treatment-Induced Neutralizing Antibody (nAb) | 5 Participants |
| Avelumab + PLD | Number of Participants With Treatment-Induced Neutralizing Antibody (nAb) | 1 Participants |
| Pegylated Liposomal Doxorubicin (PLD) | Number of Participants With Treatment-Induced Neutralizing Antibody (nAb) | 6 Participants |
Secondary
Objective Response Rate (ORR) Based on BICR Assessment
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab | Objective Response Rate (ORR) Based on BICR Assessment | 3.7 percentage of participants |
| Avelumab + PLD | Objective Response Rate (ORR) Based on BICR Assessment | 13.3 percentage of participants |
| Pegylated Liposomal Doxorubicin (PLD) | Objective Response Rate (ORR) Based on BICR Assessment | 4.2 percentage of participants |
Secondary
ORR Based on Investigator Assessment
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab | ORR Based on Investigator Assessment | 5.3 percentage of participants |
| Avelumab + PLD | ORR Based on Investigator Assessment | 18.6 percentage of participants |
| Pegylated Liposomal Doxorubicin (PLD) | ORR Based on Investigator Assessment | 9.5 percentage of participants |
Secondary
PFS Based on Investigator Assessment According to RECIST Version 1.1
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.
Time frame: 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.
Population: The secondary efficacy endpoint was analyzed in FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | PFS Based on Investigator Assessment According to RECIST Version 1.1 | 1.9 month |
| Avelumab + PLD | PFS Based on Investigator Assessment According to RECIST Version 1.1 | 4.7 month |
| Pegylated Liposomal Doxorubicin (PLD) | PFS Based on Investigator Assessment According to RECIST Version 1.1 | 3.7 month |
Secondary
Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose
Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
Time frame: At postdose (end of infusion, 1H) on Cycle 2 Day 1
Population: The PK parameter analysis set was defined as participants in the safety analysis set who had at least 1 post-dose concentration measurement above the LLQ for avelumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose | 231.6 mcg/mL | Geometric Coefficient of Variation 43 |
| Avelumab + PLD | Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose | 207.9 mcg/mL | Geometric Coefficient of Variation 71 |
Comparison: Avelumab was the Reference treatment and Avelumab + PLD was the Test treatment90% CI: [79.5, 101.5]
Secondary
Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose
Ctrough was defined as predose concentration during multiple dosing, and can be observed directly from data.
Time frame: At predose (0 H) on Cycle 2 Day 1
Population: The PK parameter analysis set was defined as participants in the safety analysis set who had at least 1 post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Avelumab | Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose | 21.1 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 89 |
| Avelumab + PLD | Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose | 23.19 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 74 |
Comparison: Avelumab was the Reference treatment and Avelumab + PLD was the Test treatment90% CI: [95.4, 126.7]
Secondary
Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28
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.
Time frame: From Day 1 of Cycle 1 to prior to end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
Population: The analysis is based on the FAS. The FAS included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab | Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28 | NA months |
| Avelumab + PLD | Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28 | 11.1 months |
| Pegylated Liposomal Doxorubicin (PLD) | Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28 | 10.6 months |