Pembrolizumab in Treating Patients with Metastatic or Locally Advanced Microsatellite Unstable Solid Tumors
Basic Trial Information
|Phase II||Biomarker/Laboratory analysis, Treatment||Active||18 and over||J1365|
NCI-2013-02436, CIR00001187, MK-3475-016, NA_00085756, NCT01876511
This phase II trial studies how well pembrolizumab works in treating patients with genomic instability associated with defective deoxyribonucleic acid (DNA) mismatch repair in tumors (microsatellite unstable) solid tumors that have spread to other places in the body or have spread to nearby tissue or lymph nodes. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.
Further Study Information
I. To determine the immune-related progression free survival (irPFS) rate at 20 weeks and objective response rate (irORR) in patients with microsatellite instability (MSI) positive and negative colorectal adenocarcinoma treated with MK-3475 (pembrolizumab) using immune related response criteria (irRC) during stages 1 and 2.
II. To determine the immune-related progression free survival (irPFS) rate in patients with MSI positive non-colorectal solid tumor malignancies treated with MK-3475 using immune related response criteria (irRC) at 20 weeks during stages 1 and 2.
III. To determine the progression free survival (PFS) rate at 20 weeks and the objective response rate (ORR) in patients with MSI positive solid tumor malignancies treated with MK-3475 using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria during the second expansion.
I. To determine the overall survival of patients with MSI positive and negative tumors treated with MK-3475.
II. To estimate irPFS and progression free survival (PFS) in patients with MSI positive and negative tumors treated with MK-3475 at 28 weeks using irRC and RECIST 1.1.
III. To estimate best overall response rate and disease control rate in patients with MSI positive and negative tumors treated with MK-3475.
IV. To assess safety and characterize toxicities of MK-3475 in patients with MSI positive and negative tumors.
V. To evaluate MSI as a marker to predict treatment response.
I. To explore the association of MSI positive, programmed death cell ligand 1 (PD-L1) positivity, and tumor infiltrating lymphocyte characteristics with clinical responses.
II. To assess tumor tissue for molecular determinants of response, progression and disease stability using next generation sequencing technology.
III. To assess tumor burden dynamics using both standard protein biomarkers such as CEA, CA19-9, and other exploratory circulating biomarkers in serial collections of sera and plasma at baseline and throughout treatment.
IV. To assess the baseline characteristic of the subjects enrolled and to correlate these molecular and clinicopathologic criteria with treatment response and toxicity.
V. To collect peripheral blood lymphocytes to explore the association of MSI positive, PD-1 positivity, and lymphocyte activation markers with clinical responses.
VI. To determine alternative markers of MSI status.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 14 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then every 3 months for 24 months.
Cohort A: patients with histologically proven metastatic or locally advanced MSI colorectal adenocarcinoma
Cohort B: patients with histologically proven metastatic or locally advanced microsatellite stable (MSS) colorectal adenocarcinoma
Cohort C: patients with histologically proven metastatic or locally advanced non-colorectal MSI solid tumor malignancies
Patients with the presence of at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node by RECIST 1.1 and irRC criteria for response assessment
Patients must agree to have a biopsy at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
Patients with colon cancer must have received at least 2 prior cancer therapy regimens; patients with other cancer types must have received at least 1 prior cancer therapy regimen; patients must have progressive disease on study entry
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Life expectancy of greater than 3 months
Absolute neutrophil count >= 1,000/mcL
Platelets >= 90 x 10^3/uL
Hemoglobin >= 9.0 g/dL
Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with diagnosed Gilbert’s syndrome will not be excluded if their direct bilirubin is within normal institutional limits)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
Creatinine =< 1.5 x ULN
Female patient of childbearing potential has a negative urine or serum pregnancy test; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; the serum pregnancy test must be negative for the patient to be eligible
Female patients enrolled in the study, who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with visit 1 through 120 days after the last dose of study therapy; approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives; spermicides alone are not an acceptable method of contraception
Male patients must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study therapy
Ability to understand and the willingness to sign a written informed consent document
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 1 week prior to trial treatment; this is not applicable to patients with primary brain tumors
Patient who has had chemotherapy, or biological cancer therapy within 2 weeks prior to the first dose of study drug; patient who has had radiation within 2 weeks prior to the first dose of study drug
Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study drug
Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
Patients who have had surgery within 4 weeks of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc), celiac plexus block, and biliary stent placement
Patients with a history of prior treatment with anti-programmed cell death (PD-1), anti-PD-L1, anti-programmed cell death 1 ligand 2 (PD-L2), anti-tumor necrosis factor receptor superfamily, member 9 (CD137), anti-tumor necrosis factor receptor superfamily, member 4 (OX-40), anti- TNF receptor superfamily member 5 (CD40), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies
Patients who have received any of the following concomitant therapy: interleukin (IL)-2, interferon or other non-study immunotherapy regimens; immunosuppressive agents; other investigational therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses) within 1 week prior to first dose; Note: systemic steroid therapy allowed for subjects with primary brain tumors as long as =< dexamethasone 4 mg or its steroid equivalent
Patients who have received a live vaccine within 4 weeks prior to or after any dose of MK-3475
Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Patients receiving 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; use of such agents while on study is also prohibited; prior use of growth factors should be documented in the patient’s medical history
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Has a 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
Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
Patients with a known active hepatitis B (e.g., hepatitis B surface antigen[HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
Patients with evidence of interstitial lung disease
Patients with a pulse oximetry of < 92% on room air
Patients on supplemental home oxygen
Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
Women who are pregnant or breastfeeding
Women with a positive pregnancy test on enrollment or prior to investigational product administration
Sexually active fertile men not using effective birth control if their partners are women of childbearing potential (WOCBP)
Trial Contact Information
Trial Lead Organizations / Sponsors / Collaborators
Johns Hopkins University/Sidney Kimmel Cancer Center
- National Cancer Institute
Stanford Cancer Institute
Providence Medical Center
Todd S. Crocenzi
Todd S. Crocenzi
Johns Hopkins University/Sidney Kimmel Cancer Center
Dung Thi Le
Dung Thi Le
National Institutes of Health Clinical Center
Tim F. Greten
Tim F. Greten
Ohio State University Comprehensive Cancer Center
Kristen Keon Ciombor
Kristen Keon Ciombor
Link to the current ClinicalTrials.gov record.
NLM Identifier NCT01876511
Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.