Colorectal Carcinoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), MSI-H, MSI
Brief summary
In this study, participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) will be treated with pembrolizumab (MK-3475, KEYTRUDA®) monotherapy. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, participants are required to have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment into Cohort A has been completed. For Cohort B, participants are required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. The primary hypothesis is that Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST 1.1) assessed by central imaging vendor in participants with locally advanced unresectable or metastatic MMR deficient or MSI high CRC is greater than 15%.
Detailed description
With protocol amendment 08 (13-Nov-2019), once study participants have achieved the study objective or the study has ended, participants will be discontinued from this study and may be enrolled in a pembrolizumab extension study (NCT03486873) to continue protocol-defined assessments and treatment.
Interventions
BIOLOGICALPembrolizumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
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-proven locally advanced unresectable or metastatic colorectal carcinoma * Locally confirmed MMR deficient or MSI-H status * Has been previously treated with standard therapies, which must include, for Cohort A, fluoropyrimidine, oxaliplatin, and irinotecan, and for Cohort B, at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-VEGF/EGFR monoclonal antibody (mAb). * Eastern Cooperative Oncology Group performance status of 0 or 1 * Life expectancy of greater than 3 months * Provides an archival or newly obtained (≤60 days prior to first dose of study treatment) tumor tissue sample (Cohort B) * At least one measurable lesion * Female participants of childbearing potential should be willing to use acceptable methods of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment * Male participants should agree to use an adequate method of contraception starting with the first dose of study treatment through 120 days after the last dose of study treatment * Adequate organ function
Exclusion criteria
* Currently participating in another study and receiving trial treatment, participated in a study of an investigational agent and received trial treatment within 4 weeks of the first dose of treatment in this study, or used an investigational device within 4 weeks of the first dose of treatment in this study * Active autoimmune disease that has required systemic treatment in past 2 years * Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Known active central nervous system metastases and/or carcinomatous meningitis * Prior monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events (AEs) due to a previously administered agent * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. * Received a live vaccine within 30 days of planned start of study treatment * Known history of human immunodeficiency virus (HIV) * Known active Hepatitis B or C * Has known history of, or any evidence of interstitial lung disease or active, noninfectious pneumonitis * Active infection requiring systemic therapy * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor | Up to approximately 48 months | Objective response rate was defined as the percentage of the participants in the analysis population who had a complete response (CR) or partial response (PR). Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. The point estimate and 95% confidence interval for the ORR, were provided using an exact binomial distribution (Clopper and Pearson method). Participants without response data were counted as nonresponders. The data cutoff date was 09-SEPT-2019. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor. | Up to approximately 66 months | PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression). PFS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 19-FEB-2021. |
| Overall Survival (OS) | Up to approximately 66 months | OS is defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of analysis are censored at the date of the last follow-up. OS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 19-FEB-2021. |
| Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor. | Up to approximately 66 months | Disease Control Rate was defined as the percentage of participants who achieved confirmed CR or PR or had demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. or the appearance of new lesion(s). Participants in the analysis population with missing DCR were considered as disease not under control. The data cutoff date was 19-Feb-2021. |
| Number of Participants Who Discontinued Study Treatment Due to an AE. | Up to approximately 36 months | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor | Up to approximately 66 months | For participants who demonstrated a CR or PR, duration of response was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. Duration of Response was based on Independent radiologist review (IRC) using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR. |
| Number of Participants Who Experienced an Adverse Event (AE). | Up to approximately 66 months | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. |
Participant flow
Recruitment details
This study was conducted at 34 clinical sites in 10 countries.
Pre-assignment details
Participant flow as per the database cutoff date of 19FEB2021.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A - Pembrolizumab 200 mg Participants were previously treated with standard therapies, which included fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment. | 61 |
| Cohort B - Pembrolizumab 200 mg Participants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants received pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment. | 63 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Death | 36 | 28 |
| Overall Study | Did Not Continue on Extension Study | 6 | 11 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Site Terminated By Sponsor | 0 | 1 |
| Overall Study | Transferred to Extension Study | 15 | 15 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Cohort B - Pembrolizumab 200 mg | Total | Cohort A - Pembrolizumab 200 mg |
|---|---|---|---|
| Age, Continuous | 57.8 Years STANDARD_DEVIATION 15.2 | 56.1 Years STANDARD_DEVIATION 14.9 | 54.3 Years STANDARD_DEVIATION 14.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 119 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 33 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 7 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 84 Participants | 42 Participants |
| Sex: Female, Male Female | 30 Participants | 55 Participants | 25 Participants |
| Sex: Female, Male Male | 33 Participants | 69 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 38 / 61 | 31 / 63 | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 56 / 61 | 58 / 63 | 5 / 6 | 3 / 3 |
| serious Total, serious adverse events | 31 / 61 | 25 / 63 | 1 / 6 | 1 / 3 |
Outcome results
Primary
Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor
Objective response rate was defined as the percentage of the participants in the analysis population who had a complete response (CR) or partial response (PR). Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. The point estimate and 95% confidence interval for the ORR, were provided using an exact binomial distribution (Clopper and Pearson method). Participants without response data were counted as nonresponders. The data cutoff date was 09-SEPT-2019.
Time frame: Up to approximately 48 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor | 32.8 Percentage of participants |
| Cohort B - Pembrolizumab 200 mg | Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor | 34.9 Percentage of participants |
Secondary
Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor.
Disease Control Rate was defined as the percentage of participants who achieved confirmed CR or PR or had demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. or the appearance of new lesion(s). Participants in the analysis population with missing DCR were considered as disease not under control. The data cutoff date was 19-Feb-2021.
Time frame: Up to approximately 66 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor. | 50.8 Percentage of participants |
| Cohort B - Pembrolizumab 200 mg | Disease Control Rate (DCR) Per RECIST 1.1 Assessed by Central Imaging Vendor. | 55.6 Percentage of participants |
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor
For participants who demonstrated a CR or PR, duration of response was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. Duration of Response was based on Independent radiologist review (IRC) using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR.
Time frame: Up to approximately 66 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment and demonstrated a CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor | NA Months |
| Cohort B - Pembrolizumab 200 mg | Duration of Response (DOR) Per RECIST 1.1 as Assessed by the Central Imaging Vendor | NA Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE.
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Time frame: Up to approximately 36 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Number of Participants Who Discontinued Study Treatment Due to an AE. | 5 Participants |
| Cohort B - Pembrolizumab 200 mg | Number of Participants Who Discontinued Study Treatment Due to an AE. | 5 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE).
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Time frame: Up to approximately 66 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Number of Participants Who Experienced an Adverse Event (AE). | 60 Participants |
| Cohort B - Pembrolizumab 200 mg | Number of Participants Who Experienced an Adverse Event (AE). | 63 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of analysis are censored at the date of the last follow-up. OS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 19-FEB-2021.
Time frame: Up to approximately 66 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Overall Survival (OS) | 31.4 Months |
| Cohort B - Pembrolizumab 200 mg | Overall Survival (OS) | 47 Months |
Secondary
Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor.
PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression). PFS was summarized by Kaplan-Meier (KM) methods. The data cutoff date was 19-FEB-2021.
Time frame: Up to approximately 66 months
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - Pembrolizumab 200 mg | Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor. | 2.3 Months |
| Cohort B - Pembrolizumab 200 mg | Progression-Free Survival (PFS) Per RECIST 1.1 Assessed by Central Imaging Vendor. | 4.1 Months |