Nivolumab and Relatlimab in Treating Patients Microsatellite Stable Advanced Colorectal Cancer
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Patients with histologically proven metastatic or locally advanced microsatellite stable (MSS) colorectal adenocarcinoma
- Cohort A: Primary lesion has a composite PD-L1/mucin (CPM) score >= 15%
- Cohort B: Primary lesion has a composite PD-L1/mucin (CPM) score < 15%
- Cohort C: Prior surgical resection of primary tumor. Prospective biomarker evaluation not required
- Patients who have received at least one prior cancer chemotherapy regimen in the locally advanced/metastatic setting. Adjuvant therapy can only be counted if recurrence occurred within 6 months of completing systemic chemotherapy. Radiosensitizing doses of chemotherapy are not considered systemic chemotherapy. Patients should be considered for standard therapies
- 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Patients must have available archival tissue from the surgical resection of their primary tumor for CPM score determination
- Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
- Life expectancy of greater than 3 months
- Leukocytes >= 2,000/mm^3
- Absolute neutrophil count >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin >= 8.5 g/dL
- Total bilirubin =< 1.5 x upper limit of normal (ULN) except subjects with Gilbert’s syndrome, who must have normal direct bilirubin
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN
- Albumin >= 2.8 g/dl
- Lipase and amylase < 1.5 x ULN Subjects with values > 1.5 ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
- Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockroft-Gault formula)
- Left ventricular ejection fraction (LVEF) assessment with documented LVEF >= 50% by either transthoracic echocardiogram (TTE) or multi-gated acquisition scan [MUGA] (TTE preferred) within 6 months prior to start of study treatment
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 3 days prior to start of study drug. In a case of a positive HCG test, a vaginal ultrasound must be used to confirm a lack of pregnancy. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus an additional 165 days (approximately 24 weeks) after the last dose of nivolumab and/or relatlimab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus an additional 225 days (approximately 33 weeks) after the last dose of study drug
- Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report adverse events (AEs), understand the drug dosing schedule and use of medications to control AEs
- 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 initiation of study treatment. This is not applicable to patients with primary brain tumors.
- Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
- Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, or anti-Lag-3 antibodies
- Any of the following procedures or medications: * Within 2 weeks prior to initiation of study treatment: ** Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement steroid doses =< 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease ** Palliative radiation or gamma knife radiosurgery ** Chemotherapy * Within 4 weeks prior to initiation of study treatment: ** Any investigational cytotoxic drug. Exposure to any non-cytotoxic drug within 4 weeks or 5 half-lives (whichever is shorter) is prohibited. If 5 half-lives is shorter than 4 weeks, agreement with investigational new drug (IND) sponsor is mandatory ** Non-oncology vaccines containing live virus ** Allergen hyposensitization therapy ** Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin ** Major surgery
- History of severe hypersensitivity reaction to any monoclonal antibodies or related compounds or to any of their components (e.g., history of severe hypersensitivity reactions to drugs formulated with polysorbate 80)
- Uncontrolled intercurrent acute or chronic medical illness
- Has an active known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Has a diagnosis of immunodeficiency
- Prior tissue or organ allograft or allogeneic bone marrow transplantation. Exceptions can be approved by the IND sponsor if loss of the graft is not a clinical concern
- A known or underlying medical condition that, in the opinion of the investigator, could make the administration of study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate study
- Patients with a history of interstitial lung disease
- Requirement for daily supplemental oxygen
- Uncontrolled or significant cardiovascular disease (i.e. cardiomyopathy, congestive heart failure with New York Heart Association (NYHA) functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion), including, but not limited to any of the following: * Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * Corrected QT (QTc) prolongation > 480 msec * Cardiovascular disease-related requirement for daily supplemental oxygen * History of two or more MIs OR two or more coronary revascularization procedures * Subjects with history of myocarditis, regardless of etiology
- Troponin T (TnT) or I (TnI) > 2 x ULN. Subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subjects may undergo a cardiac evaluation and be considered for treatment, following a discussion with the IND Sponsor. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo cardiac evaluation and be considered for treatment, following discussion with the IND sponsor
- Has a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
- Positive blood screen for human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS)
- Any positive test for hepatitis B or hepatitis C virus indicating presence of virus, e.g. hepatitis B surface antigen or hepatitis C antibody positive (except if hepatitis C virus [HCV]-ribonucleic acid [RNA] negative)
- Has active infection requiring systemic antibacterial, antiviral, or antifungal therapy =< 7 days prior to initiation of study drug
- Subjects unable to undergo venipuncture and/or tolerate venous access
- Any other sound medical, psychiatric, and/or social reason as determined by the investigator
- 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 nursing
- Women with a positive pregnancy test on enrollment or prior to investigational product administration
- WOCBP and men with female partners (WOCBP) who are not willing to use contraception
I. To estimate the objective response rate (ORR) in patients with metastatic or locally advanced microsatellite stable (MSS) colorectal cancer that have a positive and negative composite PDL1/mucin (CPM) score treated with nivolumab and relatlimab. (Cohorts A/B)
II. To estimate the objective response rate (ORR) in patients with metastatic or locally advanced microsatellite stable (MSS) colorectal cancer without prospective biomarker selection treated with nivolumab and relatlimab. (Cohort C)
I. To assess safety and characterize toxicities of nivolumab in combination with relatlimab.
I. To assess the overall survival (OS), progression free survival (PFS), time to-progression (TTP), disease control rate (DCR), best overall response (BOR), duration of response (DOR), duration of clinical benefit (DCB), and time to objective response (TTOR) of patients with metastatic or locally advanced microsatellite stable (MSS) colorectal cancer that have a positive and negative CPM score treated with nivolumab and relatlimab.
II. To assess immune objective response rate (iORR) by immune-related Response Evaluation Criteria in Solid Tumors (RECIST) criteria (iRECIST).
III. To evaluate CPM score and determine the cut-off threshold as a predictive marker for I-O treatment in patients with microsatellite stable (MSS) CRC.
IV. To collect pre- and on-treatment biopsies to explore the association of features of the tumor microenvironment with response to therapy, including assessment of T cell subset markers (CD4, CD8, FoxP3, granzyme A/B, CD69), immune regulation (PD-L1, PD-L2, CTLA4, LAG-3, IDO1, TIM-3), and immune cell population markers (natural killer [NK], dendritic cell [DC], B cell, myeloid-derived suppressor cell [MDSC).
V. To evaluate molecular determinants such as KRAS and BRAF status.
VI. To evaluate molecular determinants of response using next generation sequencing and other sequencing techniques.
VIa. Characterize the tumor mutational landscape through exomic sequencing for mutation analysis and mutation-associated neoantigen (MANA) prediction.
VII. To assess tumor burden dynamics using standard protein biomarkers when available as well as circulating biomarkers (i.e. circulating tumor deoxyribonucleic acid [ctDNA]).
VIII. To collect peripheral blood lymphocytes to explore the association of lymphocyte activation markers with clinical response.
IX. To evaluate clonal T cell populations in the tumor and in the periphery through T cell receptor sequencing, and to functionally assess mutation associated neoantigen-specific T cells.
X. To collect stool and oral wash (and/or buccal mucosal) samples at baseline and throughout treatment to explore the association of changes in the host microbiome and clinical outcome.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A/B: Patients receive nivolumab intravenously (IV) and relatlimab IV co-administered at the same time over 60 minutes on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes sequentially on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 100 days, then every 12 weeks.
Trial Phase Phase II
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Dung Thi Le
- Primary ID J18119
- Secondary IDs NCI-2018-03022, IRB00173537, CRMS-69884
- Clinicaltrials.gov ID NCT03642067