Mesothelioma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
This is a multicenter, open-label, non-randomized, study of pembrolizumab in combination with cisplatin and pemetrexed in treatment of naïve participants with a histologically confirmed diagnosis of advanced/unresectable malignant pleural mesothelioma (MPM) in Japanese participants. This study will evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with cisplatin and pemetrexed. The primary objective is to evaluate the safety and tolerability of treatment with pembrolizumab in combination with cisplatin and pemetrexed.
Interventions
DRUGPembrolizumab
Participants will receive Pembrolizumab 200 mg IV every 3 weeks (Q3W) until disease progression, or until participant has received 35 administrations of Pembrolizumab (approximately 2 years).
DRUGPemetrexed
Participants will receive Pemetrexed 500 mg/m\^2 IV on Day 1 of each cycle up to 4-6 cycles where each cycle = 3 weeks
DRUGCisplatin
Participants will receive Cisplatin 75 mg/m\^2 IV on Day 1 of each cycle up to 4-6 cycles where each cycle = 3 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically confirmed diagnosis of advanced/unresectable malignant pleural mesothelioma (MPM) * Have at least one measurable disease, which is systemic therapy naïve, radiologically assessed by the local site investigator per modified Response Evaluation Criteria in Solid Tumors (RECIST) using imaging scanned within 28 days prior to the first dose in this study * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale * Has a life expectancy of at least 3 months * Demonstrate adequate organ function * Male participants are eligible to participate if they agree to remain abstinent or agree to use contraception unless confirmed to be azoospermic * A female participant is eligible to participate if she is not pregnant or breastfeeding, using contraceptives or is not a woman of child bearing potential (WOCBP)
Exclusion criteria
* A WOCBP who has a positive pregnancy test within 72 hours prior to treatment allocation * Has received prior therapy with an anti-programmed cell-death 1 (anti PD-1), anti programmed cell-death ligand 1 (anti-PD-L1), or anti programmed cell-death ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor * Has previously received systemic anti-cancer therapy (including investigational agents) for MPM * Participants who received (neo) adjuvant previously may be eligible, only if the last dose of chemotherapy was completed at least 6 months before registration. Such participants must have recovered from all adverse events (AEs) due to previous (neo) adjuvant therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible * Received radiation therapy to the lung that is \> 30 gray (Gy) within 6 months of the first dose of trial treatment * Completed palliative radiotherapy within 7 days of the first dose of trial treatment * Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis * Had a major surgery within 3 months prior to the first administration in this study * Has received a live vaccine within 30 days prior to the first dose of study drug * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug * Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has had a severe hypersensitivity reaction (≥Grade 3) to treatment a monoclonal antibody/components of the study intervention * Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * Is being treated for pericardial effusion, or has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions is eligible * Has an active infection requiring systemic therapy * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) During Cycle 1, Per Common Terminology Criteria for Adverse Events (AEs), Version 5.0 (CTCAE) | Up to 3 weeks (through Cycle 1 [21 days]) | DLTs were assessed during Cycle 1 (21 days) and defined as any of the following, if considered by investigator to be related to any of the study interventions: Grade 4 hematologic toxicities, except neutropenia and febrile neutropenia; Grade 4 neutropenia lasting \>7 days despite appropriate supportive treatment; Grade 4 febrile neutropenia only if the event considered as clinically significant by investigator and sponsor; any Grade 4 non-hematologic toxicity (except laboratory test abnormal including transient electrolyte abnormalities); any Grade 3 non-hematologic toxicity lasting \>72 hours despite appropriate supportive treatment (not laboratory); and any Grade 4 laboratory test value abnormality; any Grade 3 laboratory test value abnormality lasting \>7 days; delay in start of second course of more than 2 weeks (more than 35 days after the first dose) due to toxicity related to study procedures; any Grade 5 toxicity. |
| Number of Participants With One or More Adverse Events (AEs) | Up to approximately 34 months | An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. |
| Number of Participants Discontinuing Study Treatment Due to an AE | Up to approximately 2 years | An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 31 months | ORR was defined as the percentage of participants who have a Complete Response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions). ORR was based on modified Response Evaluation Criteria In Solid Tumors (RECIST) for Malignant Pleural Mesothelioma (MPM) as assessed by investigator. |
| Disease Control Rate (DCR) | Up to approximately 31 months | DCR was defined as the percentage of participants who had a Complete Response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.\]) DCR was based on modified RECIST for MPM as assessed by investigator. |
| Duration of Response (DOR) | Up to approximately 31 months | For participants who demonstrate a confirmed complete response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or confirmed Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions), DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was based on modified RECIST for MPM as assessed by investigator. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) in combination with pemetrexed 500 mg/m\^2 IV and cisplatin 75 mg/m\^2 IV for 4-6 cycles, followed by pembrolizumab 200 mg/m\^2 IV monotherapy Q3W for up to 35 cycles from the first dose of the study treatment (approximately 2 years). Each cycle was 21 days. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 13 |
Baseline characteristics
| Characteristic | Pembrolizumab + Pemetrexed + Cisplatin |
|---|---|
| Age, Continuous | 67.8 Years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 7 / 19 |
Outcome results
Primary
Number of Participants Discontinuing Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE.
Time frame: Up to approximately 2 years
Population: All participants who received at least 1 dose of study intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Number of Participants Discontinuing Study Treatment Due to an AE | 6 Participants |
Primary
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) During Cycle 1, Per Common Terminology Criteria for Adverse Events (AEs), Version 5.0 (CTCAE)
DLTs were assessed during Cycle 1 (21 days) and defined as any of the following, if considered by investigator to be related to any of the study interventions: Grade 4 hematologic toxicities, except neutropenia and febrile neutropenia; Grade 4 neutropenia lasting \>7 days despite appropriate supportive treatment; Grade 4 febrile neutropenia only if the event considered as clinically significant by investigator and sponsor; any Grade 4 non-hematologic toxicity (except laboratory test abnormal including transient electrolyte abnormalities); any Grade 3 non-hematologic toxicity lasting \>72 hours despite appropriate supportive treatment (not laboratory); and any Grade 4 laboratory test value abnormality; any Grade 3 laboratory test value abnormality lasting \>7 days; delay in start of second course of more than 2 weeks (more than 35 days after the first dose) due to toxicity related to study procedures; any Grade 5 toxicity.
Time frame: Up to 3 weeks (through Cycle 1 [21 days])
Population: All participants who received at least 1 dose of study intervention and who met the criteria for DLT evaluability by finishing Cycle 1 without a DLT or having experienced a DLT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) During Cycle 1, Per Common Terminology Criteria for Adverse Events (AEs), Version 5.0 (CTCAE) | 2 Participants |
Primary
Number of Participants With One or More Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE.
Time frame: Up to approximately 34 months
Population: All participants who received at least 1 dose of study intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Number of Participants With One or More Adverse Events (AEs) | 19 Participants |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants who had a Complete Response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.\]) DCR was based on modified RECIST for MPM as assessed by investigator.
Time frame: Up to approximately 31 months
Population: All participants who received at least 1 dose of study intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Disease Control Rate (DCR) | 94.7 Percentage of participants |
Secondary
Duration of Response (DOR)
For participants who demonstrate a confirmed complete response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or confirmed Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions), DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was based on modified RECIST for MPM as assessed by investigator.
Time frame: Up to approximately 31 months
Population: All participants who received at least 1 dose of study intervention and demonstrated a confirmed response (CR or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Duration of Response (DOR) | 16.8 Months |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants who have a Complete Response (CR: disappearance of target and non-target lesions and normalization of tumor markers) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions). ORR was based on modified Response Evaluation Criteria In Solid Tumors (RECIST) for Malignant Pleural Mesothelioma (MPM) as assessed by investigator.
Time frame: Up to approximately 31 months
Population: All participants who received at least 1 dose of study intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Pemetrexed + Cisplatin | Objective Response Rate (ORR) | 73.7 Percentage of participants |