Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant Ovarian Cancer
Study Details
Study Description
Brief Summary
The study was to evaluate the efficacy and safety of avelumab in combination with M6620 + carboplatin in participants with PARPi-resistant, recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
The study was intended to be a phase Ib/II trial, but after completing Phase 1b and confirming the safe combination dose, the sponsor decided not to conduct Phase II.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A: Carboplatin + M6620 + Avelumab
|
Drug: M6620
Participants received 90 milligrams per square meter (mg/m^2) of M6620, intravenously (IV) on Day 2 of every 3 weeks (Q3W) cycle for a maximum of 6 cycles in combination treatment with carboplatin and avelumab on Day 1. The M6620 dose may be de-escalated to 60 mg/m^2, or 40 mg/m^2.
Drug: Avelumab
Participants received IV infusion of avelumab 1600 mg on Day 1 of each Q3W cycle for maximum of 6 cycles in combination treatment with carboplatin and M6620. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Drug: Carboplatin
Participants received carboplatin area under the concentration-time curve 5 on Day 1 of each Q3W cycle for a maximum of 6 cycles in combination treatment with avelumab and M6620.
|
Outcome Measures
Primary Outcome Measures
- Part A: Number of Participants With Dose Limiting Toxicities (DLTs) [Up to 3 weeks]
DLT: any death not clearly due to underlying disease/extraneous causes/Grade(Gr) >=3 nonhematologic/Gr>=4 hematologic toxicity that was probably/definitely related to any of study interventions, individually/combination that occurred during DLT observation period, except for any of following: Gr3 infusion-related reaction; Transient (<=6hr) Gr3 flu-like symptoms/fever, controlled with medical management; Transient (<=72hr) Gr3 fatigue, local reactions, headache, nausea/emesis; Gr3 diarrhea, skin toxicity, liver function test increase; Single laboratory values out of normal range and controlled with medical management; Tumor flare phenomenon: local pain, irritation/rash, localized at sites of known/suspected tumor; Neutropenia (Gr3/4) for <7 days not associated with any infection; Gr3 thrombocytopenia for <7 days without clinically significant bleeding and not requiring platelet transfusion; Symptomatic thyroid dysfunction manageable with treatment.
Secondary Outcome Measures
- Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs [Time from first dose of study treatment up to 230 days]
An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious AEs. Treatment-related TEAE: reasonably related to the study intervention. The AE could medically (pharmacologically/clinically) be attributed to the study intervention under study in this clinical study protocol.
- Part A: Number of Participants With Confirmed Best Overall Response (BOR) [Time from first dose of study treatment up to 230 days]
Confirmed BOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression/ recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category (CR, PR, SD, PD) were reported.
- Part A: Progression-Free Survival (PFS) [Time from first dose of study treatment up to 230 days]
PFS according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.
- Part A: Duration of Response (DoR) [Time from first dose of study treatment up to 230 days]
DoR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. If a participant has not an event (PD or death), DoR was censored at the date of last adequate tumor assessment.
- Part A: Time to Progression (TTP) [Time from first dose of study treatment up to 230 days]
TTP according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and assessed by an Investigator was defined as the time from first dose of study intervention until progression disease (PD). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.
- Part A: Time to First Subsequent Therapy (TFST) [From date of randomization to the earliest date of first subsequent therapy or death, assessed up to 230 days]
The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death.
- Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
- Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
- Part A: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
- Part A: Terminal Rate Constant (Lambda z) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
- Part A: Maximum Observed Plasma Concentration (Cmax) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
Cmax was obtained directly from the concentration versus time curve.
- Part A: Minimum Observed Plasma Concentration (Cmin) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
Cmin was minimum observed plasma concentration obtained directly from the concentration versus time curve.
- Part A: Time to Reach the Maximum Plasma Concentration (Tmax) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
Tmax was obtained directly from the concentration versus time curve.
- Part A: Apparent Terminal Half-life (t1/2) of M6620 and Avelumab [Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)]
t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Female participants with recurrent epithelial ovarian cancer who have disease progression following maintenance treatment with a PARPi as defined below:
-
Participant must have histologically diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer, with nonmucinous histology
-
Participants must have completed at least 2 previous courses of platinum containing therapy (for example, carboplatin or cisplatin) and had documented response (complete response [CR] or partial response [PR]) to the last platinum-based treatment prior to treatment with a PARPi
-
Participant has received the last dose of platinum-containing treatment at least 6 months prior to study enrollment
-
Participant has documented disease progression (radiological) after at least 4 months of maintenance treatment with PARPi following a response to platinum-based chemotherapy.
-
Confirmed breast cancer gene (BRCA) 1/2 mutation status or agree to its testing on samples collected in the study.
-
Available formalin-fixed, paraffin-embedded (FFPE) tumor biopsies.
-
Part A: Optional 2 paired on-treatment biopsies on Day 2 of Cycle 1 (first biopsy) and Day 2 of Cycle 1 or Cycle 2 (second biopsy) respectively, before and after M6620 administration, if assessed as feasible at low risk by the interventional radiologist.
-
Part B: Histological tissue specimen (tissue block or 8 to 10 unstained slides) must be available. An archival tumor biopsy is acceptable if obtained after the last progression on PARPi treatment and is less than 4 months old. Otherwise, participants must be willing to undergo mandatory biopsy during the Screening Period to obtain sufficient tissue for histological assessment. Participants need to have an attempted biopsy. However, participants who have measurable disease documented by a radiologist as not feasible or safe to be biopsied are eligible to enter the study
-
Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
-
Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- Treatment with a nonpermitted drug/intervention as listed below:
-
Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, or targeted small molecule therapy) or any study intervention within 4 weeks prior to start of study intervention, or not recovered from AEs related to such therapies
-
History of prior dose reductions or dose interruptions while receiving cisplatin or carboplatin due to toxicity from the platinum or intolerance to either agent, unless discussed with and approved by the Sponsor Medical Monitor
-
Prior treatment with a PD-1/PD-L1 targeting agent
- Current use of the following medications at the time of enrollment:
-
Immunotherapy or immunosuppressive drugs at the time of enrollment (for example (e.g.,) chemotherapy or systemic corticosteroids) EXCEPT for (a) intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra articular injection), (b) systemic corticosteroids at physiologic doses less than or equals to (≤) 10 milligram per day (mg/day) of prednisone or equivalent, (c) steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
-
Growth factors EXCEPT where indicated for treatment of study intervention related myelosuppression and for prophylaxis of repeat myelosuppression after initial occurrence
-
Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to potentially interfere with major organ function (e.g., hypericin)
-
Other DNA damage repair inhibitors (except PARPi) (e.g., inhibitors of ATR, ataxia telangiectasia mutated [ATM] kinase, DNA-dependent protein kinase [DNA-PK], or Wee kinases).
- Other protocol defined exclusion criteria could apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Marin Cancer Care, Inc. | Greenbrae | California | United States | 94904 |
| 2 | The Stamford Hospital | Stamford | Connecticut | United States | 06904 |
| 3 | Covenant Health Care | Saginaw | Michigan | United States | 48604 |
| 4 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065-6007 |
| 5 | Mount Sinai - PRIME | New York | New York | United States | 11041 |
| 6 | Peggy & Charles Stephenson Oklahoma Cancer Ctr | Oklahoma City | Oklahoma | United States | 73104 |
| 7 | Mary Crowley Cancer Research Centers | Dallas | Texas | United States | 75251 |
| 8 | UZ Leuven | Leuven | Belgium | ||
| 9 | CHU Sart Tilman | Liège | Belgium | ||
| 10 | GZA Ziekenhuizen - Campus Sint-Augustinus | Wilrijk | Belgium | ||
| 11 | Royal Cornwall Hospital | Truro | Cornwall | United Kingdom | |
| 12 | Royal Marsden Hospital | Sutton | Surrey | United Kingdom | |
| 13 | Royal Marsden Hospital | London | United Kingdom |
Sponsors and Collaborators
- EMD Serono Research & Development Institute, Inc.
- Merck KGaA, Darmstadt, Germany
Investigators
- Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- MS201943_0029
- 2018-001534-17
Study Results
Participant Flow
| Recruitment Details | First participant signed informed consent: 04 Mar 2019, Last participant last visit: 06 Nov 2019. |
|---|---|
| Pre-assignment Detail | This study was planned to be conducted in 2 parts; Part A was the safety run-in part and Part 2 was the randomized controlled part. However, after completing Part A and confirming the safe combination dose, the sponsor decided not to conduct Part B. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Period Title: Overall Study | |
| STARTED | 3 |
| COMPLETED | 3 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Overall Participants | 3 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
2
66.7%
|
| >=65 years |
1
33.3%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
3
100%
|
| Male |
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
0
0%
|
| Not Hispanic or Latino |
3
100%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
3
100%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Part A: Number of Participants With Dose Limiting Toxicities (DLTs) |
|---|---|
| Description | DLT: any death not clearly due to underlying disease/extraneous causes/Grade(Gr) >=3 nonhematologic/Gr>=4 hematologic toxicity that was probably/definitely related to any of study interventions, individually/combination that occurred during DLT observation period, except for any of following: Gr3 infusion-related reaction; Transient (<=6hr) Gr3 flu-like symptoms/fever, controlled with medical management; Transient (<=72hr) Gr3 fatigue, local reactions, headache, nausea/emesis; Gr3 diarrhea, skin toxicity, liver function test increase; Single laboratory values out of normal range and controlled with medical management; Tumor flare phenomenon: local pain, irritation/rash, localized at sites of known/suspected tumor; Neutropenia (Gr3/4) for <7 days not associated with any infection; Gr3 thrombocytopenia for <7 days without clinically significant bleeding and not requiring platelet transfusion; Symptomatic thyroid dysfunction manageable with treatment. |
| Time Frame | Up to 3 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| DLT analysis set included all evaluable participants with data used for implementing the dose-escalation schedule. These participants received at least 1 study intervention administration of each avelumab, M6620, and/or chemotherapy in the DLT evaluation period or should have stopped treatment because of DLTs in the DLT evaluation period. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 3 |
| Count of Participants [Participants] |
0
0%
|
| Title | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs |
|---|---|
| Description | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious AEs. Treatment-related TEAE: reasonably related to the study intervention. The AE could medically (pharmacologically/clinically) be attributed to the study intervention under study in this clinical study protocol. |
| Time Frame | Time from first dose of study treatment up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any study intervention. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 3 |
| TEAEs |
3
100%
|
| Treatment-Related TEAEs |
3
100%
|
| Title | Part A: Number of Participants With Confirmed Best Overall Response (BOR) |
|---|---|
| Description | Confirmed BOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression/ recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category (CR, PR, SD, PD) were reported. |
| Time Frame | Time from first dose of study treatment up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set included all participants who received at least 1 dose of any study intervention. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 3 |
| Complete Response |
0
0%
|
| Partial Response |
0
0%
|
| Stable Disease |
1
33.3%
|
| Progressive Disease |
2
66.7%
|
| Title | Part A: Progression-Free Survival (PFS) |
|---|---|
| Description | PFS according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure. |
| Time Frame | Time from first dose of study treatment up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set was used. No summary analysis was done as study was early discontinued as per Sponsor's decision and participant wise data was reported. Here, "Number Analyzed" signifies specific participant evaluated in the arm of this outcome measure. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 3 |
| Participant 1 |
1.9
|
| Participant 2 |
2.1
|
| Participant 3 |
6.1
|
| Title | Part A: Duration of Response (DoR) |
|---|---|
| Description | DoR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. If a participant has not an event (PD or death), DoR was censored at the date of last adequate tumor assessment. |
| Time Frame | Time from first dose of study treatment up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data could not be calculated as none of the participants showed objective response. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Time to Progression (TTP) |
|---|---|
| Description | TTP according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and assessed by an Investigator was defined as the time from first dose of study intervention until progression disease (PD). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure. |
| Time Frame | Time from first dose of study treatment up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set was used. No summary analysis was done as study was early discontinued as per Sponsor's decision and participant wise data was reported. Here, "Overall Number of Participants Analyzed" = participants who were evaluable for this outcome measure and "number analyzed" = specific participants evaluated in the arm. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 2 |
| Participant 1 |
1.9
|
| Participant 2 |
2.1
|
| Title | Part A: Time to First Subsequent Therapy (TFST) |
|---|---|
| Description | The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death. |
| Time Frame | From date of randomization to the earliest date of first subsequent therapy or death, assessed up to 230 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data could not be calculated since the date of first subsequent treatment was not recorded in the electronic case report form (eCRF) as per changes in planned analysis. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab |
|---|---|
| Description | Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M6620 and Avelumab |
|---|---|
| Description | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) |
|---|---|
| Description | AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Terminal Rate Constant (Lambda z) of M6620 and Avelumab |
|---|---|
| Description | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Maximum Observed Plasma Concentration (Cmax) of M6620 and Avelumab |
|---|---|
| Description | Cmax was obtained directly from the concentration versus time curve. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Minimum Observed Plasma Concentration (Cmin) of M6620 and Avelumab |
|---|---|
| Description | Cmin was minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Time to Reach the Maximum Plasma Concentration (Tmax) of M6620 and Avelumab |
|---|---|
| Description | Tmax was obtained directly from the concentration versus time curve. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
| Title | Part A: Apparent Terminal Half-life (t1/2) of M6620 and Avelumab |
|---|---|
| Description | t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z. |
| Time Frame | Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. |
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab |
|---|---|
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Measure Participants | 0 |
Adverse Events
| Time Frame | Time from first dose of study treatment up to 230 days | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Part A: Carboplatin + M6620 + Avelumab | |
| Arm/Group Description | Participants received intravenous infusion of Carboplatin area under the concentration-time curve 5 on Day 1 in combination with 90 milligrams per square meter (mg/m^2) of M6620 on Day 2 and avelumab at an established dose of 1600 mg over 60 minutes on Day 1 for every 3 weeks cycle for a maximum of 6 cycles. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. | |
All Cause Mortality |
||
| Part A: Carboplatin + M6620 + Avelumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | |
Serious Adverse Events |
||
| Part A: Carboplatin + M6620 + Avelumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 1/3 (33.3%) | |
| Infections and infestations | ||
| Pyelonephritis | 1/3 (33.3%) | |
Other (Not Including Serious) Adverse Events |
||
| Part A: Carboplatin + M6620 + Avelumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 1/3 (33.3%) | |
| Neutropenia | 1/3 (33.3%) | |
| Thrombocytopenia | 1/3 (33.3%) | |
| Ear and labyrinth disorders | ||
| Vertigo | 1/3 (33.3%) | |
| Endocrine disorders | ||
| Hypothyroidism | 1/3 (33.3%) | |
| Eye disorders | ||
| Vision blurred | 1/3 (33.3%) | |
| Gastrointestinal disorders | ||
| Abdominal pain | 2/3 (66.7%) | |
| Constipation | 1/3 (33.3%) | |
| Diarrhoea | 2/3 (66.7%) | |
| Gastrooesophageal reflux disease | 1/3 (33.3%) | |
| Nausea | 3/3 (100%) | |
| Toothache | 1/3 (33.3%) | |
| Vomiting | 1/3 (33.3%) | |
| General disorders | ||
| Chest discomfort | 1/3 (33.3%) | |
| Fatigue | 2/3 (66.7%) | |
| Peripheral swelling | 1/3 (33.3%) | |
| Immune system disorders | ||
| Drug hypersensitivity | 1/3 (33.3%) | |
| Infections and infestations | ||
| Tooth infection | 1/3 (33.3%) | |
| Injury, poisoning and procedural complications | ||
| Infusion related reaction | 2/3 (66.7%) | |
| Tooth fracture | 1/3 (33.3%) | |
| Investigations | ||
| Blood urine present | 1/3 (33.3%) | |
| Lymphocyte count decreased | 1/3 (33.3%) | |
| Platelet count decreased | 1/3 (33.3%) | |
| White blood cell count decreased | 1/3 (33.3%) | |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 1/3 (33.3%) | |
| Back pain | 2/3 (66.7%) | |
| Flank pain | 1/3 (33.3%) | |
| Myalgia | 1/3 (33.3%) | |
| Nervous system disorders | ||
| Dizziness | 1/3 (33.3%) | |
| Headache | 1/3 (33.3%) | |
| Neuropathy peripheral | 1/3 (33.3%) | |
| Psychiatric disorders | ||
| Anxiety | 1/3 (33.3%) | |
| Depressed mood | 1/3 (33.3%) | |
| Insomnia | 2/3 (66.7%) | |
| Renal and urinary disorders | ||
| Bladder pain | 1/3 (33.3%) | |
| Hydronephrosis | 1/3 (33.3%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/3 (33.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Night sweats | 1/3 (33.3%) | |
| Pruritus | 1/3 (33.3%) | |
| Pruritus generalised | 1/3 (33.3%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Communication Center |
|---|---|
| Organization | Merck KGaA, Darmstadt, Germany |
| Phone | +49-6151-72-5200 |
| service@emdgroup.com |
- MS201943_0029
- 2018-001534-17