High TMB (Tumor Mutation Burden), High Tumor Mutation Burden, MSS (Microsatellite Stable)
Conditions
Keywords
Mutation load, Tumor mutation load, Mutation burden, Tumor mutation burden (TMB), Hypermutation, MSI Negative with Mutator Phenotype (High Tumor Mutation Burden), TMB (Tumor Mutation Burden)
Brief summary
This study will be looking at whether MK-3475 (pembrolizumab) is effective (anti-tumor activity) and safe in patients with MSI (Microsatellite Unstable) negative cancer with a mutator phenotype.
Interventions
DRUGMK-3475
MK-3475 (pembrolizumab) 200 mg flat dose every 21 days
Sponsors
Merck Sharp & Dohme LLC
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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
* Patients with microsatellite stable tumor and a tumor mutation burden (TMB) level measured at \> 20 mutations per megabase pairs (MB) * Have measurable disease * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 * Adequate organ function as defined by study-specified laboratory tests * Must use acceptable form of birth control through the study and for 28 days after final dose of study drug * Signed informed consent form * Willing and able to comply with study procedures * Agree to have a biopsy of their cancer * Patients with colon cancer must have received at least two prior cancer therapy regimens. * Patients with other cancer types must have received at least one prior cancer therapy * Progressive disease
Exclusion criteria
* Patients with uncontrolled intercurrent illness, including but not limited to ongoing or active infection, systematic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric condition that would limit compliance with study requirements. * Patients who have had chemotherapy or biological cancer therapy within 2 weeks prior to the first dose of study drug * Patients who have had radiation within 2 weeks prior to the first dose of study drug * Patients who have undergone major surgery within 4 weeks of dosing of investigational agent * Patients who have received another investigational product or investigational device within 4 weeks prior to receiving study drug * Patients who have received any of the following concomitant therapy: Interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens, immunosuppressive agents, other investigational therapies or chronic use of systemic corticosteroids within one week prior to first dose of study drug * Patients who have received a live vaccine within 4 weeks prior to or after any dose of MK-3475 (exception: inactivated flu vaccines) * Patients who have received growth factors, including but not limited to granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 2 weeks of study drug administration * Patient who have had prior treatment with anti-PD-1 (anti-programmed cell death protein 1), anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies * Patients with history of any autoimmune disease:inflammatory bowel disease, (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus (SLE) autoimmune vasculitis, central nervous system (CNS) or motor neuropathy considered to be of autoimmune origin. * Patients who have known history of infection with HIV, hepatitis B, or hepatitis C * Patients with evidence of interstitial lung disease * Systemically active steroid use * Patients on home oxygen * Patients with oxygen saturation of \<92% on room air by pulse oximetry * Pregnant or lactating * Conditions, including alcohol or drug dependence, or intercurrent illness that would affect the patient's ability to comply with study visits and procedures * Patient with known active central nervous system metastases and/or carcinomatous meningitis. * Patients with primary brain tumors. * Requires any other form of systemic or localized antineoplastic therapy while on study * Has any tissue or organ allograft * Patients with history of allogeneic hematopoeitic stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in Patients With MSI (Microsatellite Unstable)-Negative Solid Tumor Malignancies With a Mutator Phenotype | 2 years | Objective Response Rate (ORR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 80 months | OS will be measured from date of first dose until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve. |
| Progression-Free Survival (PFS) in Patients Using RECIST 1.1(Response Evaluation Criteria In Solid Tumors) | 24 months | PFS is defined as the number of months from the date of first dose to disease progression (progressive disease \[PD\] or relapse from complete response \[CR\] as assessed using RECIST 1.1 criteria) or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =\>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is \>20% increase in sum of diameters of target lesions, Stable Disease (SD) is \<30% decrease or \<20% increase in sum of diameters of target lesions. Estimation based on the Kaplan-Meier curve. |
| Disease Control Rate (DCR) | 2 years | Disease Control Rate (DCR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions, progressive disease (PD) is \>20% increase in sum of diameters of target lesions, stable disease (SD) is \<30% decrease or \<20% increase in sum of diameters of target lesions. |
| Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity | 28 months | When calculating the incidence of AEs, each adverse event (AE) (as defined by NCI CTCAE v4.03) will be counted only once for a given subject. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype MK-3475 (pembrolizumab): MK-3475 200 mg flat dose every 21 days | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease Progression | 7 |
| Overall Study | New Cancer Diagnosis | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | MSI (Microsatellite Unstable) Negative With Mutator Phenotype |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 10 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 12 |
| other Total, other adverse events | 5 / 12 |
| serious Total, serious adverse events | 6 / 12 |
Outcome results
Primary
Objective Response Rate (ORR) in Patients With MSI (Microsatellite Unstable)-Negative Solid Tumor Malignancies With a Mutator Phenotype
Objective Response Rate (ORR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions.
Time frame: 2 years
Population: Only 11/12 were evaluable for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype | Objective Response Rate (ORR) in Patients With MSI (Microsatellite Unstable)-Negative Solid Tumor Malignancies With a Mutator Phenotype | 5 Participants |
Secondary
Disease Control Rate (DCR)
Disease Control Rate (DCR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions, progressive disease (PD) is \>20% increase in sum of diameters of target lesions, stable disease (SD) is \<30% decrease or \<20% increase in sum of diameters of target lesions.
Time frame: 2 years
Population: Only 11/12 were evaluable for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype | Disease Control Rate (DCR) | 7 Participants |
Secondary
Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity
When calculating the incidence of AEs, each adverse event (AE) (as defined by NCI CTCAE v4.03) will be counted only once for a given subject.
Time frame: 28 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype | Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity | 0 Participants |
Secondary
Overall Survival (OS)
OS will be measured from date of first dose until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve.
Time frame: 80 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype | Overall Survival (OS) | 41.9 months |
Secondary
Progression-Free Survival (PFS) in Patients Using RECIST 1.1(Response Evaluation Criteria In Solid Tumors)
PFS is defined as the number of months from the date of first dose to disease progression (progressive disease \[PD\] or relapse from complete response \[CR\] as assessed using RECIST 1.1 criteria) or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =\>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is \>20% increase in sum of diameters of target lesions, Stable Disease (SD) is \<30% decrease or \<20% increase in sum of diameters of target lesions. Estimation based on the Kaplan-Meier curve.
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MSI (Microsatellite Unstable) Negative With Mutator Phenotype | Progression-Free Survival (PFS) in Patients Using RECIST 1.1(Response Evaluation Criteria In Solid Tumors) | 6.8 months |