Clinical trial NCT01876511: Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors (Cohorts A, B and C)
Official title: Phase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-06-12
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: 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
timeFrame: 20 weeks
measure: Immune-related Objective Response Rate in MSI Positive and Negative Colorectal Adenocarcinoma Participants Using Immune Related Response Criteria (irRC) During Stages 1 and 2
timeFrame: 28 months
measure: 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
timeFrame: 20 weeks
measure: Objective Response Rate in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
timeFrame: 28 months
measure: Progression Free Survival (PFS) at 20 Weeks in MSI Positive Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
timeFrame: 20 weeks
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 4 years
measure: Immune-related Progression Free Survival (irPFS) at 28 Weeks in MSI Positive and Negative Solid Tumor Malignancies Using Immune Related Response Criteria (irRC)
timeFrame: 28 weeks
measure: Objective Response Rate (ORR) in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
timeFrame: 28 months
measure: Number of Patients Experiencing a Grade 3 or Above Treatment-related Toxicity
timeFrame: 28 months
measure: 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)
timeFrame: 28 weeks
measure: Disease Control Rate in MSI Positive and Negative Solid Tumor Malignancies Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
timeFrame: 28 months
measure: Does MSI as a Marker Predict Treatment Response
timeFrame: 28 months
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: Investigator Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NIH
state: Maryland
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Dung Le, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.