Solid Tumor
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
This study will assess the efficacy and safety of pembrolizumab (MK-3475) administered to participants with incurable advanced biomarker-positive solid tumors that have not responded to current therapy or for which current therapy is not appropriate. The study hypothesis is that administration of pembrolizumab to participants with some types of solid tumors will result in a clinically meaningful response rate.
Detailed description
Qualified participants who complete up to \ 2 years of pembrolizumab treatment but progress after discontinuation may be eligible for a second course of pembrolizumab for up to \ 1 additional year, at the Investigator's discretion. Per protocol, response or progression during this second course will not count towards efficacy outcome measures and adverse events during this second course will not count towards safety outcome measures.
Interventions
BIOLOGICALPembrolizumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically documented locally-advanced and/or metastatic solid malignancy that is incurable, and has failed prior standard therapy or for which standard therapy is not appropriate * Have biomarker-positive solid tumor * Have measurable disease based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) * Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 * Adequate organ function * Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study medication
Exclusion criteria
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment * Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Prior anti-cancer therapy with a monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from adverse events due to mAbs administered more than 4 weeks earlier * Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks (12 weeks for measurable sites of central nervous system \[CNS\] disease) prior to study Day 1 or not recovered from adverse events due to a previously administered agent * Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer * Known active CNS metastases and/or carcinomatous meningitis * Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment * Has evidence of interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Active infection requiring systemic therapy * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial * Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Known history of human immunodeficiency virus (HIV) * Known active Hepatitis B or Hepatitis C * Has received a live vaccine within 30 days of planned start of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to approximately 86 months | Overall response rate (ORR) was defined as the percentage of participants who experienced a complete response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 28 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE was assessed. |
| Number of Participants Who Discontinued From Study Treatment Due to an AE | Up to approximately 25 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed. |
| Progression Free Survival (PFS) | Up to approximately 86 months | PFS was defined as the time from the date of allocation to the date of the first documentation of disease progression, as determined by investigator per modified RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. |
| Overall Survival (OS) | Up to approximately 86 months | OS was defined as the time from the date of allocation to the date of death due to any cause. Participants who were lost to follow-up and those who were alive at the end of the trial were censored at the date of last assessment. |
| Duration of Response (DOR) | Up to approximately 86 months | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per modified RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per modified RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on investigator with confirmation. The DOR according to modified RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported. Per protocol, participants were analyzed according to disease type. |
Participant flow
Recruitment details
Participants with a histologically- or cytologically-confirmed diagnosis of 20 advanced (unresectable and/or metastatic) solid tumors, were recruited into a single arm.
Pre-assignment details
Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures respectively. Per protocol, analyses of disease type cohort was planned and conducted for efficacy outcome measures only.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab (MK-3475) 10 mg/kg Participants received pembrolizumab 10 mg/kg IV over 30 minutes once every 2 weeks (Q2W) for up to \
2 years. Qualified participants who completed the first course of pembrolizumab treatment but progressed after discontinuation were eligible for a second course of pembrolizumab at 10 mg/kg IV Q2W for up to \
1 additional year, at the Investigator's discretion. Per protocol participants were presented by treatment received in the single arm study. | 475 |
| Total | 475 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 391 |
| Overall Study | Lost to Follow-up | 10 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Sponsor Decision | 31 |
| Overall Study | Withdrawal by Subject | 43 |
Baseline characteristics
| Characteristic | Pembrolizumab (MK-3475) 10 mg/kg |
|---|---|
| Age, Continuous | 58.7 Years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 380 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 77 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 99 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 73 Participants |
| Race (NIH/OMB) White | 280 Participants |
| Sex: Female, Male Female | 281 Participants |
| Sex: Female, Male Male | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 426 / 477 | 6 / 11 |
| other Total, other adverse events | 429 / 475 | 10 / 11 |
| serious Total, serious adverse events | 160 / 475 | 3 / 11 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall response rate (ORR) was defined as the percentage of participants who experienced a complete response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by the investigator.
Time frame: Up to approximately 86 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, had a baseline scan with measurable disease per modified RECIST 1.1 and had the intended indication. Per protocol, participants were analyzed according to disease type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Overall Response Rate (ORR) | 4.3 Percentage of Participants |
| Cohort A2: Anal Canal Squamous Cell Carcinoma | Overall Response Rate (ORR) | 20.0 Percentage of Participants |
| Cohort A3: Pancreas Adenocarcinoma | Overall Response Rate (ORR) | 0.0 Percentage of Participants |
| Cohort A4: Esophageal Squamous Cell Carcinoma or Adenocarcinoma | Overall Response Rate (ORR) | 30.4 Percentage of Participants |
| Cohort A5: Biliary Tract Adenocarcinoma | Overall Response Rate (ORR) | 17.4 Percentage of Participants |
| Cohort A6: Carcinoid Tumors | Overall Response Rate (ORR) | 16.0 Percentage of Participants |
| Cohort A7: Neuroendocrine Carcinomas | Overall Response Rate (ORR) | 6.3 Percentage of Participants |
| Cohort B1: ER Positive HER2 Negative Breast Cancer | Overall Response Rate (ORR) | 12.0 Percentage of Participants |
| Cohort B2: Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma | Overall Response Rate (ORR) | 11.5 Percentage of Participants |
| Cohort B3: Endometrial Carcinoma | Overall Response Rate (ORR) | 13.0 Percentage of Participants |
| Cohort B4: Cervical Squamous Cell Cancer | Overall Response Rate (ORR) | 16.7 Percentage of Participants |
| Cohort B5: Vulvar Squamous Cell Carcinoma | Overall Response Rate (ORR) | 5.6 Percentage of Participants |
| Cohort C1: Small Cell Lung Cancer | Overall Response Rate (ORR) | 34.8 Percentage of Participants |
| Cohort C2: Mesothelioma | Overall Response Rate (ORR) | 20.0 Percentage of Participants |
| Cohort D1: Thyroid Cancer | Overall Response Rate (ORR) | 13.6 Percentage of Participants |
| Cohort D2: Salivary Gland Carcinoma | Overall Response Rate (ORR) | 11.5 Percentage of Participants |
| Cohort D3: Nasopharyngeal Carcinoma | Overall Response Rate (ORR) | 25.9 Percentage of Participants |
| Cohort E1: Glioblastoma Multiforme | Overall Response Rate (ORR) | 8.0 Percentage of Participants |
| Cohort E2: Leiomyosarcoma | Overall Response Rate (ORR) | 4.2 Percentage of Participants |
| Cohort E3: Prostate Adenocarcinoma | Overall Response Rate (ORR) | 13.0 Percentage of Participants |
Secondary
Duration of Response (DOR)
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per modified RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per modified RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on investigator with confirmation. The DOR according to modified RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported. Per protocol, participants were analyzed according to disease type.
Time frame: Up to approximately 86 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, had a baseline scan with measurable disease per modified RECIST 1.1, had the intended indication, and experienced a response. Per protocol-specified definition, DOR could not be analyzed in arms which did not have a confirmed response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Duration of Response (DOR) | NA Months |
| Cohort A2: Anal Canal Squamous Cell Carcinoma | Duration of Response (DOR) | 28.9 Months |
| Cohort A4: Esophageal Squamous Cell Carcinoma or Adenocarcinoma | Duration of Response (DOR) | 14.5 Months |
| Cohort A5: Biliary Tract Adenocarcinoma | Duration of Response (DOR) | NA Months |
| Cohort A6: Carcinoid Tumors | Duration of Response (DOR) | 10.1 Months |
| Cohort A7: Neuroendocrine Carcinomas | Duration of Response (DOR) | 25.1 Months |
| Cohort B1: ER Positive HER2 Negative Breast Cancer | Duration of Response (DOR) | 12.0 Months |
| Cohort B2: Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma | Duration of Response (DOR) | 37.0 Months |
| Cohort B3: Endometrial Carcinoma | Duration of Response (DOR) | 68.5 Months |
| Cohort B4: Cervical Squamous Cell Cancer | Duration of Response (DOR) | 5.4 Months |
| Cohort B5: Vulvar Squamous Cell Carcinoma | Duration of Response (DOR) | 3.9 Months |
| Cohort C1: Small Cell Lung Cancer | Duration of Response (DOR) | NA Months |
| Cohort C2: Mesothelioma | Duration of Response (DOR) | 12.0 Months |
| Cohort D1: Thyroid Cancer | Duration of Response (DOR) | 8.4 Months |
| Cohort D2: Salivary Gland Carcinoma | Duration of Response (DOR) | 3.9 Months |
| Cohort D3: Nasopharyngeal Carcinoma | Duration of Response (DOR) | 15.0 Months |
| Cohort E1: Glioblastoma Multiforme | Duration of Response (DOR) | 15.6 Months |
| Cohort E2: Leiomyosarcoma | Duration of Response (DOR) | 12.4 Months |
| Cohort E3: Prostate Adenocarcinoma | Duration of Response (DOR) | 14.2 Months |
Secondary
Number of Participants Who Discontinued From Study Treatment Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.
Time frame: Up to approximately 25 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Number of Participants Who Discontinued From Study Treatment Due to an AE | 30 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE was assessed.
Time frame: Up to approximately 28 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Number of Participants Who Experienced an Adverse Event (AE) | 456 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of allocation to the date of death due to any cause. Participants who were lost to follow-up and those who were alive at the end of the trial were censored at the date of last assessment.
Time frame: Up to approximately 86 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, had a baseline scan with measurable disease per modified RECIST 1.1 and had the intended indication. Per protocol, participants were analyzed according to disease type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Overall Survival (OS) | 5.3 Months |
| Cohort A2: Anal Canal Squamous Cell Carcinoma | Overall Survival (OS) | 8.3 Months |
| Cohort A3: Pancreas Adenocarcinoma | Overall Survival (OS) | 3.9 Months |
| Cohort A4: Esophageal Squamous Cell Carcinoma or Adenocarcinoma | Overall Survival (OS) | 7.1 Months |
| Cohort A5: Biliary Tract Adenocarcinoma | Overall Survival (OS) | 5.7 Months |
| Cohort A6: Carcinoid Tumors | Overall Survival (OS) | 16.2 Months |
| Cohort A7: Neuroendocrine Carcinomas | Overall Survival (OS) | 37.8 Months |
| Cohort B1: ER Positive HER2 Negative Breast Cancer | Overall Survival (OS) | 8.0 Months |
| Cohort B2: Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma | Overall Survival (OS) | 13.1 Months |
| Cohort B3: Endometrial Carcinoma | Overall Survival (OS) | 13.6 Months |
| Cohort B4: Cervical Squamous Cell Cancer | Overall Survival (OS) | 10.8 Months |
| Cohort B5: Vulvar Squamous Cell Carcinoma | Overall Survival (OS) | 3.7 Months |
| Cohort C1: Small Cell Lung Cancer | Overall Survival (OS) | 9.3 Months |
| Cohort C2: Mesothelioma | Overall Survival (OS) | 18.0 Months |
| Cohort D1: Thyroid Cancer | Overall Survival (OS) | 39.7 Months |
| Cohort D2: Salivary Gland Carcinoma | Overall Survival (OS) | 12.3 Months |
| Cohort D3: Nasopharyngeal Carcinoma | Overall Survival (OS) | 16.5 Months |
| Cohort E1: Glioblastoma Multiforme | Overall Survival (OS) | 13.1 Months |
| Cohort E2: Leiomyosarcoma | Overall Survival (OS) | 12.0 Months |
| Cohort E3: Prostate Adenocarcinoma | Overall Survival (OS) | 7.9 Months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from the date of allocation to the date of the first documentation of disease progression, as determined by investigator per modified RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
Time frame: Up to approximately 86 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, had a baseline scan with measurable disease per modified RECIST 1.1 and had the intended indication. Per protocol, participants were analyzed according to disease type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A1: Colon or Rectal Adenocarcinoma | Progression Free Survival (PFS) | 1.7 Months |
| Cohort A2: Anal Canal Squamous Cell Carcinoma | Progression Free Survival (PFS) | 3.1 Months |
| Cohort A3: Pancreas Adenocarcinoma | Progression Free Survival (PFS) | 1.7 Months |
| Cohort A4: Esophageal Squamous Cell Carcinoma or Adenocarcinoma | Progression Free Survival (PFS) | 1.8 Months |
| Cohort A5: Biliary Tract Adenocarcinoma | Progression Free Survival (PFS) | 1.8 Months |
| Cohort A6: Carcinoid Tumors | Progression Free Survival (PFS) | 5.5 Months |
| Cohort A7: Neuroendocrine Carcinomas | Progression Free Survival (PFS) | 4.5 Months |
| Cohort B1: ER Positive HER2 Negative Breast Cancer | Progression Free Survival (PFS) | 1.8 Months |
| Cohort B2: Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma | Progression Free Survival (PFS) | 1.9 Months |
| Cohort B3: Endometrial Carcinoma | Progression Free Survival (PFS) | 1.8 Months |
| Cohort B4: Cervical Squamous Cell Cancer | Progression Free Survival (PFS) | 1.8 Months |
| Cohort B5: Vulvar Squamous Cell Carcinoma | Progression Free Survival (PFS) | 2.5 Months |
| Cohort C1: Small Cell Lung Cancer | Progression Free Survival (PFS) | 1.8 Months |
| Cohort C2: Mesothelioma | Progression Free Survival (PFS) | 5.5 Months |
| Cohort D1: Thyroid Cancer | Progression Free Survival (PFS) | 8.2 Months |
| Cohort D2: Salivary Gland Carcinoma | Progression Free Survival (PFS) | 3.6 Months |
| Cohort D3: Nasopharyngeal Carcinoma | Progression Free Survival (PFS) | 6.4 Months |
| Cohort E1: Glioblastoma Multiforme | Progression Free Survival (PFS) | 2.8 Months |
| Cohort E2: Leiomyosarcoma | Progression Free Survival (PFS) | 2.0 Months |
| Cohort E3: Prostate Adenocarcinoma | Progression Free Survival (PFS) | 3.5 Months |