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
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Gastroesophageal Cancer
- Sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Enrollment
- 21
- Locations
- 3
- Primary Endpoint
- Change in the infiltrating CD8+ T cell density units after systemic treatment with radiation plus nivolumab +/- Relatlimib
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
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).
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 21 patients will be enrolled on study with 6 enrolled on Arm A, and 15 enrolled on Arm B.
Investigators
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
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
Arms & Interventions
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.
Intervention: Nivolumab
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.
Intervention: Nivolumab
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.
Intervention: Relatlimab
Outcomes
Primary Outcomes
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 Outcomes
- Safety profile of nivolumab +/- Relatlimib plus systemic radiation as determined by number of drug-related adverse events(5 years)
- Efficacy of PD-1 inhibition +/- Relatlimib as determined by number of participants without evidence of disease progression(3 months post targeted radiation)