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

NCT01876511 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: J1365 (Cohort A, B and C)MK-3475-016NA_00085756
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 7

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.

Conditions

MSI Positive Colorectal Cancer; MSI Negative Colorectal Cancer; MSI Positive Non-Colorectal Cancers

Keywords

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

Outcome Measures

Primary Outcomes (5)

• 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

  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.

  20 weeks

• Immune-related Objective Response Rate in MSI Positive and Negative Colorectal Adenocarcinoma Participants Using Immune Related Response Criteria (irRC) During Stages 1 and 2

  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.

  28 months

• 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

  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.

  20 weeks

• Objective Response Rate in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

  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.

  28 months

• Progression Free Survival (PFS) at 20 Weeks in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

  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.

  20 weeks

Secondary Outcomes (7)

• Overall Survival (OS)

  4 years

• Immune-related Progression Free Survival (irPFS) at 28 Weeks in MSI Positive and Negative Solid Tumor Malignancies Using Immune Related Response Criteria (irRC)

  28 weeks

• Objective Response Rate (ORR) in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

  28 months

• Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity

  28 months

• 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)

  28 weeks

Study Arms (3)

Cohort A: MSI Positive Colorectal Cancer

EXPERIMENTAL

Drug: MK-3475

Cohort B: MSI Negative Colorectal Cancer

EXPERIMENTAL

Drug: MK-3475

Cohort C: MSI Positive Non-Colorectal Cancer

EXPERIMENTAL

Drug: MK-3475

Interventions

MK-3475 DRUG

MK-3475 10 mg/kg every 14 days

Cohort A: MSI Positive Colorectal Cancer; Cohort B: MSI Negative Colorectal Cancer; Cohort C: MSI Positive Non-Colorectal Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (7)

Stanford University

Stanford, California, 94305, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

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

Bethesda, Maryland, 20892, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Providence Portland Medical Center

Portland, Oregon, 97213, United States

Location

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (2)

• 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.

  PMID: 28596308 BACKGROUND

• 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.

  PMID: 26028255 BACKGROUND

MeSH Terms

Interventions

pembrolizumab

Results Point of Contact

• Title: Dung Le, MD
• Organization: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

dle@jhmi.edu

443-287-0002

Study Officials

• Dung Le, MD

  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2013
• First Posted: June 12, 2013
• Study Start: September 1, 2013
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: February 6, 2020
• Results First Posted: January 7, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)