Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors (Cohorts A, B and C)

• ClinicalTrials.gov Identifier: NCT01876511
• Recruitment Status: Completed
• First Posted: June 12, 2013
• Results First Posted: January 7, 2020
• Last Update Posted: February 6, 2020
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief Summary:

This study will be looking at whether MK-3475 (an antibody that blocks negative signals to T cells) is effective (anti-tumor activity) and safe in three different patient populations. These include: 1. patients with MSI positive colon cancer, 2. patients with MSI negative colon cancer and 3. patients with other MSI positive cancers.

Condition or disease	Intervention/treatment	Phase
MSI Positive Colorectal Cancer; MSI Negative Colorectal Cancer; MSI Positive Non-Colorectal Cancers	Drug: MK-3475	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 113 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors
• Actual Study Start Date: September 2013
• Actual Primary Completion Date: August 2019
• Actual Study Completion Date: August 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A: MSI Positive Colorectal Cancer	Drug: MK-3475; MK-3475 10 mg/kg every 14 days
Experimental: Cohort B: MSI Negative Colorectal Cancer	Drug: MK-3475; MK-3475 10 mg/kg every 14 days
Experimental: Cohort C: MSI Positive Non-Colorectal Cancer	Drug: MK-3475; MK-3475 10 mg/kg every 14 days

Outcome Measures

Primary Outcome Measures :

1. Immune-related Progression Free Survival (irPFS) at 20 Weeks in MSI Positive and Negative Colorectal Adenocarcinoma Participants Using Immune Related Response Criteria (irRC) During Stages 1 and 2 [ Time Frame: 20 weeks ]
   For Cohorts A and B: irPFS rate is defined as the percentage of patients with disease progression (irPD or relapse from irCR as assessed using irRC criteria) or death due to any cause at 20 weeks. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater by a consecutive assessment at least 4 weeks after first documentation, Stable Disease (irSD) is the failure to meet criteria for irCR or irPR (in absence of irPD), Progressive Disease (irPD) is at least 25% increase in tumor burden relative to nadir. Estimation based on the Kaplan-Meier curve.
2. Immune-related Objective Response Rate in MSI Positive and Negative Colorectal Adenocarcinoma Participants Using Immune Related Response Criteria (irRC) During Stages 1 and 2 [ Time Frame: 28 months ]
   For Cohorts A and B: Immune-related Objective Response Rate (irORR) is defined as the percentage of patients achieving a complete response (irCR) or partial response (irPR) based on irRC criteria. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater by a consecutive assessment at least 4 weeks after first documentation.
3. Immune-related Progression Free Survival (irPFS) at 20 Weeks in MSI Positive Non-colorectal Adenocarcinoma Participants Using Immune Related Response Criteria (irRC) During Stages 1 and 2 [ Time Frame: 20 weeks ]
   For Cohort C: irPFS rate is defined as the percentage of patients with disease progression (irPD or relapse from irCR as assessed using irRC criteria) or death due to any cause at 20 weeks. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater by a consecutive assessment at least 4 weeks after first documentation, Stable Disease (irSD) is the failure to meet criteria for irCR or irPR (in absence of irPD), Progressive Disease (irPD) is at least 25% increase in tumor burden relative to nadir. Estimation based on the Kaplan-Meier curve.
4. Objective Response Rate in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: 28 months ]
   For Cohorts A and C: Objective Response Rate (ORR) is defined as the percentage 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.
5. Progression Free Survival (PFS) at 20 Weeks in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: 20 weeks ]
   For Cohorts A and C: PFS is defined as the percentage of patients with disease progression (PD or relapse from CR as assessed using RECIST 1.1 criteria) or death due to any cause at 20 weeks. 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.

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: 4 years ]
   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.
2. Immune-related Progression Free Survival (irPFS) at 28 Weeks in MSI Positive and Negative Solid Tumor Malignancies Using Immune Related Response Criteria (irRC) [ Time Frame: 28 weeks ]
   irPFS rate is defined as the percentage of patients with disease progression (irPD or relapse from irCR as assessed using irRC criteria) or death due to any cause at 28 weeks. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater by a consecutive assessment at least 4 weeks after first documentation, Stable Disease (irSD) is the failure to meet criteria for irCR or irPR (in absence of irPD), Progressive Disease (irPD) is at least 25% increase in tumor burden relative to nadir. Estimation based on the Kaplan-Meier curve.
3. Objective Response Rate (ORR) in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: 28 months ]
   ORR is defined as the percentage 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.
4. Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity [ Time Frame: 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.
5. Progression Free Survival (PFS) at 28 Weeks in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: 28 weeks ]
   PFS is defined as the percentage of patients with disease progression (PD or relapse from CR as assessed using RECIST 1.1 criteria) or death due to any cause at 28 weeks. 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.
6. Disease Control Rate in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: 28 months ]
   Disease Control Rate (DCR) is defined as the percentage 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.
7. Does MSI as a Marker Predict Treatment Response [ Time Frame: 28 months ]
   ORR was used to determine whether MSI is a marker that predicts treatment response. This is the same data presented in outcome measure number 8 (ORR, to test against null of 5%).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Cohort A only: Patients with microsatellite instability (MSI) positive colorectal cancer
• Cohort B only: Patients with MSI negative colorectal cancer
• Cohort C only: Patients with MSI positive non-colorectal cancer -
• 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 participants' 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

Contacts and Locations

Locations

United States, California

Stanford University

Stanford, California, United States, 94305

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21231

Investigator Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NIH

Bethesda, Maryland, United States, 20892

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, Oregon

Providence Portland Medical Center

Portland, Oregon, United States, 97213

United States, Pennsylvania

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States, 15232

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Dung Le, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  Study Documents (Full-Text)

Documents provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

Study Protocol and Statistical Analysis Plan  [PDF] December 1, 2017

More Information

Publications:

Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01876511
• Other Study ID Numbers: J1365 (Cohort A, B and C); MK-3475-016 ( Other Identifier: Merck ); NA_00085756 ( Other Identifier: JHMIRB )
• First Posted: June 12, 2013
• Results First Posted: January 7, 2020
• Last Update Posted: February 6, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

microsatellite unstable (MSI); microsatellite stable (MSS); MLH 1; MSH 2; MSH 6; PMS2

Additional relevant MeSH terms:

Colorectal Neoplasms; Microsatellite Instability; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Genomic Instability; Pathologic Processes; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action