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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

NCT03610711

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).

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Carcinoma
  • Gastric Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: J1884
  • SECONDARY ID: IRB00166032
  • SECONDARY ID: CA224-053
  • NCT ID: NCT03610711

Conditions

  • Gastroesophageal Cancer
  • Immune Checkpoint Inhibition

Interventions

DrugSynonymsArms
NivolumabOptivoArm A Nivolumab Only
Relatlimabanti-LAG3Arm B Nivolumab + Relatlimab

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A Nivolumab OnlyExperimentalstereotactic 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. Oligometastatic progression can be treated with additional SBRT if not previously radiated.
  • Nivolumab
Arm B Nivolumab + RelatlimabExperimentalstereotactic 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. Oligometastatic progression can be treated with additional SBRT if not previously radiated.
  • Nivolumab
  • Relatlimab

Eligibility 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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in the infiltrating CD8+ T cell density units after systemic treatment with radiation plus nivolumab +/- Relatlimib
Time Frame:5 years
Safety Issue:
Description: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

Measure:Safety profile of nivolumab +/- Relatlimib plus systemic radiation as determined by number of drug-related adverse events
Time Frame:5 years
Safety Issue:
Description:Number of drug-related adverse events Grade 3 or higher as defined by CTCAE 5.0 (CTCAE v5.0).
Measure:Efficacy of PD-1 inhibition +/- Relatlimib as determined by number of participants without evidence of disease progression
Time Frame:3 months post targeted radiation
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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