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REACTION (Radiation Enhanced Assessment of Combination Therapies in Immuno-ONcology) - Nivolumab or Nivolumab in Combination With Other Immuno-oncology (IO) Agents After Targeted Systemic Radiation in Patients With Advanced Esophagogastric Cancer (REACTION)

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ClinicalTrials.gov Identifier: NCT03610711
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : September 30, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
This is a Phase 1B study assessing the safety of immune checkpoint inhibition after SBRT in patients with recurrent or metastatic gastroesophageal cancer (limited metastatic disease).

Condition or disease Intervention/treatment Phase
Gastroesophageal Cancer Immune Checkpoint Inhibition Drug: Nivolumab Drug: Relatlimab Phase 1 Phase 2

Detailed Description:
This is a Phase 1B study assessing the safety of immune checkpoint inhibition after SBRT in patients with recurrent or metastatic gastroesophageal cancer (limited metastatic disease). Arm A explores the safety and efficacy of nivolumab alone, and Arm B explores the safety and efficacy of nivolumab plus Relatlimib. Patients with recurrent or metastatic esophagogastric cancer are eligible for this study which will enroll patients with limited disease burden and who are Programmed death-1(PD-1) therapy naïve. This will allow for us to assess if systemic ablative radiation (SBRT to multiple metastatic sites plus PD-1/ anti-LAG3) is able to enhance the effectiveness of nivolumab +/- anti-LAG3 or to overcome treatment resistance mechanisms. Patients will be treated with targeted high dose radiation (SBRT) to metastatic lesions as outlined below. One of the lesions which is considered the easiest to biopsy and not causing symptoms will not be radiated so as to obtain tissue for correlative analysis. This lesion will then be re-biopsied approx. 4 weeks after the completion of radiation to the other metastatic sites. If a lesion is causing pain or other symptoms this site will not be chosen as the biopsiable site. The chosen metastatic lesion can then be irradiated at a later date if we do not see disease response in that region. Approximately 30 patients will be enrolled on study with 15 enrolled on Arm A, and 15 enrolled on Arm B.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: REACTION (Radiation Enhanced Assessment of Combination Therapies in Immuno-ONcology) - Nivolumab or Nivolumab in Combination With Other Immuno-oncology (IO) Agents After Targeted Systemic Radiation in Patients With Advanced Esophagogastric Cancer
Actual Study Start Date : March 6, 2019
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Arm A Nivolumab Only
stereotactic body radiation (SBRT) 8G x 3 followed by Nivolumab 240mg administered IV over 30 minutes every 2 weeks for one year or until evidence of disease progression or unresolved toxicity.
Drug: Nivolumab
240mg administered IV over 30 minutes every 2 weeks for one year
Other Name: Optivo

Experimental: Arm B Nivolumab + Relatlimab
stereotactic body radiation (SBRT) 8G x 3 followed by Nivolumab 240mg administered IV over 30 minutes every 2 weeks and Relatlimab (anti-LAG3) every 2 weeks for one year or until evidence of disease progression or unresolved toxicity.
Drug: Nivolumab
240mg administered IV over 30 minutes every 2 weeks for one year
Other Name: Optivo

Drug: Relatlimab
every 2 weeks for one year
Other Name: anti-LAG3




Primary Outcome Measures :
  1. Change in the infiltrating CD8+ T cell density units after systemic treatment with radiation plus nivolumab +/- Relatlimib [ Time Frame: 5 years ]
    Change in the infiltrating CD8+ T cell density units pre- and post-systemic treatment with radiation plus nivolumab +/- Relatlimib in the non-irradiated metastatic lesion.


Secondary Outcome Measures :
  1. Safety profile of nivolumab +/- Relatlimib plus systemic radiation as determined by number of drug-related adverse events [ Time Frame: 5 years ]
    Number of drug-related adverse events Grade 3 or higher as defined by CTCAE 5.0 (CTCAE v5.0).

  2. Efficacy of PD-1 inhibition +/- Relatlimib as determined by number of participants without evidence of disease progression [ Time Frame: 3 months post targeted radiation ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women aged ≥ 18 years old.
  • 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 decline systemic chemotherapy in the first line metastatic setting are eligible.
  • (Relatlimab arm only) LVEF assessment with documented left ventricular ejection fraction ( LVEF) >/=50% by either echocardiogram TTE or multigated acquisition scan (MUGA) (TTE preferred test) within 6 months from first study drug administration,whichever is most recent.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Adequate organ function as follows:

    • Leukocytes ≥ 2,000/mm3
    • Absolute neutrophil count (ANC) ≥ 1000/mm3
    • Platelet count ≥ 100,000/mm3
    • 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) (SGOT), Alanine Aminotransferase (ALT) (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 Atrioventricular block (AV block) on baseline electrocardiogram (ECG).
  • The effects of nivolumab, relatlimab or BMS-986178, on the developing human fetus are unknown. For this reason women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 5 months after the last dose of nivolumab +/- IO therapy. 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. Sexually active fertile men must use effective barrier birth control if their partners are WOCBP for 7 months after the last dose of nivolumab +/- IO therapy. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration.
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (see Appendix 4) 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 (IRB) 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.
  • (Relatlimab arm only) Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤1 x ULN. If TnT or TnI levels are > 1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the 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 Bristol Myers Squibb (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:
  • 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
  • (Relatlimab arm only) LVEF (Left Ventricular Ejection Fraction) assessment with documented LVEF ≥ 50% by either TTE or MUGA (TTE preferred test) within 6 months from first study drug administration.
  • 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 MRI brain or 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 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-programmed death-1 (anti-PD-1), anti-programmed death ligand-1 (anti-PD-L1), Anti-programmed cell death 1 ligand 2 (anti-PDL-2), or Anti-Cytotoxic T-lymphocyte antigen 4 (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03610711


Contacts
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Contact: Hanika Rodavia, BSN, MSN 410-550-2751 hreyes3@jhmi.edu
Contact: Peggy Fitzpatrick, MSN, RN 410-550-5848 mfitzpa7@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Hanika Rodavia, BSN, MSN    410-550-2751    hreyes3@jhmi.edu   
Contact: Peggy Fitzpatrick, MSN, RN    410-550-5848    mfitzpa7@jhmi.edu   
Sub-Investigator: Russell Hales, MD         
Sub-Investigator: Rahn Voong, MD         
Sub-Investigator: Richard Battafarano, MD         
Sub-Investigator: Stephen Yang, MD         
Sub-Investigator: Josephine Feliciano, MD         
Principal Investigator: Vincent Lam, MD         
United States, Pennsylvania
Alleghany Health Network Recruiting
Pittsburgh, Pennsylvania, United States, 15212
Contact: Mohammed Islam, MD       MOHAMMED.ISLAM@ahn.org   
Contact: Ali Zaidi, MD       ali.zaidi@ahn.org   
Sub-Investigator: Blaire Job, MD         
Sub-Investigator: G. Scott Long, MD         
Sub-Investigator: Ali Amjad, MD         
Sub-Investigator: Casey Moffa, DO         
Sub-Investigator: Mohammed Islam, MD         
Sub-Investigator: Gene Finley, MD         
Sub-Investigator: Hashem Youned, MD         
Sub-Investigator: Moses Raj, MD         
Sub-Investigator: Ali Zaidi, MD         
Principal Investigator: Mohammed Islam, MD         
United States, Texas
Baylor University Recruiting
Dallas, Texas, United States, 75246
Contact: Ronan Kelly, MD    214-820-2881    Ronan.Kelly@BSWHealth.org   
Sub-Investigator: Andrew S Paulson, MD         
Sub-Investigator: Andrew D McCollum, MD         
Principal Investigator: Ronan Kelly, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Vincent Lam, MD Johns Hopkins University
Publications:

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03610711    
Other Study ID Numbers: J1884
IRB00166032 ( Other Identifier: JHM IRB )
CA224-053 ( Other Identifier: Bristol-Myers Squibb )
First Posted: August 1, 2018    Key Record Dates
Last Update Posted: September 30, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents