Nivolumab with or without Relatlimab in Treating Advanced Esophageal or Gastric Cancer

Status: Active

Description

This phase IB trial studies how well nivolumab with or without relatlimab works in treating patients with esophageal or gastric cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab and relatlimab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Histologically proven (squamous cell or adenocarcinoma) esophageal or gastro-esophageal junction cancer or gastric cancer (core biopsy required).
  • Either a formalin fixed paraffin block or a minimum of ten 5-micron tissue section’s (slides) of tumor biopsy sample must be available for biomarker evaluation.
  • Recurrent disease or stage IV disease as per American Joint Committee on Cancer (AJCC) staging 8.0 – patients who declines systemic chemotherapy or trastuzumab plus chemotherapy (if HER2 positive) in the first line metastatic or recurrent disease setting are eligible.
  • Left ventricular ejection fraction (LVEF) assessment with documented LVEF >= 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) (TTE preferred test) after prior anti-cancer therapy received (if patient received any therapy prior to enrolling) or within 6 months of first study drug administration, whichever is most recent. (Relatlimab arm only)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
  • Leukocytes >= 2,000/mm^3.
  • Absolute neutrophil count (ANC) >= 1000/mm^3.
  • Platelet count >= 100,000/mm^3.
  • Hemoglobin >= 9 g/dL.
  • Creatinine =< 2.0 mg/dL.
  • Bilirubin (total) within normal institutional limits (except subjects with Gilbert syndrome who must have total bilirubin < 3.0 mg/dL).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]), and alkaline phosphatase =< 2.5 times the institutional upper limit of normal.
  • Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) =< institutional upper limit of normal.
  • Adequate cardiac function as defined by: no evidence of PR prolongation or AV block on baseline electrocardiogram (ECG).
  • The effects of nivolumab or relatlimab on the developing human fetus are unknown. For this reason women of child bearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 24 weeks after the last dose of study treatment (ie, 30 days [duration of ovulatory cycle] plus the time required for the nivolumab and relatlimab to undergo approximately 5 half-lives).
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) plus 33 weeks after the last dose of the study treatment (ie, 90 days [duration of sperm turnover] plus the time required for nivolumab and relatlimab to undergo approximately 5 half-lives). In addition, male participants must be willing to refrain from sperm donation during this time.
  • Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form. Voluntary signed and dated institutional review board/independent ethics committee (IRB/IEC) approved written 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.

Exclusion Criteria

  • Any active or history of autoimmune disease (including any history of inflammatory bowel disease), or history of syndrome that required systemic steroids or immune-suppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy.
  • Troponin T (TnT) or I (TnI) > 2 x institutional 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 subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the Bristol-Myers Squibb (BMS) Medical Monitor or designee. 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 a cardiac evaluation and be considered for treatment, following a discussion with the BMS Medical Monitor or designee. (Relatlimab arm only)
  • Participants must not have a history of myocarditis. (Relatlimab arm only)
  • Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following (Relatlimab arm only): * Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) 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, poorly controlled atrial fibrillation, ventricular fibrillation, or torsades de pointes). * Corrected QT interval (QTc) prolongation > 480 msec. * History of other clinically 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, , poorly controlled venous thrombosis etc.). * Cardiovascular disease-related requirement for daily supplemental oxygen. * History of two or more MIs OR two or more coronary revascularization procedures.
  • LVEF assessment with documented LVEF >= 50% by either TTE or MUGA (TTE preferred test) within 6 months from first study drug administration. (Relatlimab arm only)
  • Ongoing requirement for systemic corticosteroids. However, inhalational steroids are allowed.
  • Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder, gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
  • Subjects with known brain metastasis are excluded from this study. Patients with suspected brain metastasis must have brain imaging (either magnetic resonance imaging [MRI] brain or computed tomography [CT] brain with contrast) prior to enrollment.
  • Subjects with a history of interstitial lung disease. Patients requiring continuous supplemental oxygen are excluded.
  • Use of any vaccines against infectious diseases (e.g., influenza, varicella. etc.) within 4 weeks (28 days) of initiation of study therapy.
  • Active systemic infection requiring therapy, positive tests for hepatitis B surface antigen or hepatitis C ribonucleic acid (RNA).
  • Known positive history or positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).
  • History of allergy to study drug components.
  • Women who are pregnant or nursing.
  • Men with female partners (WOCBP) that are not willing to use contraception.
  • Underlying medical conditions that, in the investigator’s opinion, will make the administration of study drug or radiation hazardous or obscure the interpretation of toxicity or adverse events.
  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or any other antibody targeting T cell co-regulatory pathways).
  • Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
  • Patients with more than 5 metastatic lesions.

Locations & Contacts

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Josephine Louella Feliciano
Phone: 410-550-2174
Email: jfelici4@jhmi.edu

Pennsylvania

Pittsburgh
Allegheny General Hospital
Status: Approved
Contact: Blair Anderson Jobe
Email: bjobe1@wpahs.org

Texas

Dallas
Texas Oncology at Baylor Charles A Sammons Cancer Center
Status: Approved
Contact: Ronan Joseph Kelly
Email: Ronan.Kelly@BSWHealth.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evalaute changes in the infiltrating CD8+ T cell density pre and post systemic treatment with radiation plus nivolumab +/- relatlimib in the non-irradiated metastatic lesion.

SECONDARY OBJECTIVES:

I. To describe the safety profile of nivolumab +/- relatlimab plus systemic radiation as assessed according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

II. To assess changes in recognition of mutation associated neoantigens (MANAs) in the non-irradiated metastatic lesion before and after systemic irradiation plus immuno-oncology (IO) therapy.

III. To assess the peripheral T cell dynamics of MANA-specific T cells pre and post systemic irradiation plus IO therapy.

IV. To compare the intra tumoral T cell repertoire in the non-irradiated lesion before and after systemic irradiation plus nivolumab +/- relatlimab).

V. To investigate the efficacy of PD-1 inhibition +/- relatlimab plus systemic irradiation by assessing the rate of stable disease at 3 months post targeted radiation, progression free survival (PFS) and overall survival (OS) will also be measured.

VI. To measure changes in expression of selected immune markers including changes in the quality and quantity of tumor infiltrating lymphocytes and the T effector to regulatory T cell (T-Reg) ratio compared to baseline, in the blood, primary tumor tissue and draining lymph nodes post radiation and how this impacts response to novel IO combinations.

VII. Assess the prognostic value of peripheral blood mononuclear cell (PBMC) T cell subset status (% CD4+ T-cells, % CD8+ T-cells, % Treg T-cells, % myeloid derived suppressor cells, % natural killer cells, etc.) and change in status, as assessed by flow cytometry analysis post systemic radiation plus IO therapy.

VIII. To assess the prognostic value of serum cytokine markers of interest (i.e. IFN-alpha, TGF-beta, IL-10, IL-4, IL-5, IL-13, IFN-gamma) and changes in these markers pre and post systemic radiation plus nivolumab + IO therapy.

IX. To assess the prognostic value of multiple checkpoints of interest (i.e. PD-L1, CTLA-4, IDO, LAG-3, TIM-3, KIR, GITR) and changes in these checkpoints pre and post systemic radiation plus nivolumab +/- relatlimab.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab IV over 30 minutes every 2 weeks and relatlimab IV over 60 minutes every 2 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 weeks, every 2 months of 1 year, and then every 3 months for up to 5 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Josephine Louella Feliciano

Trial IDs

Primary ID J1884
Secondary IDs NCI-2019-02384, CRMS-69461, IRB00166032
Clinicaltrials.gov ID NCT03610711