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Nivolumab

Ipilimumab

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Immunoglobulins, Intravenous

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Immune Checkpoint Inhibitors

Patients receive ipilimumab IV over 90 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 5 (day 85), patients receive nivolumab IV over 30 minutes. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive ipilimumab IV over 90 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 2, patients then undergo SBRT on days 29-32 for 4 fractions or on days 29-40 for 10 fractions. Beginning day 1 of cycle 5 (day 85), patents receive nivolumab IV over 30 minutes. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive nivolumab IV over 30 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 over 60 minutes on day 1. Patients also undergo SBRT over 30-45 minutes on days 1-4 for 4 fractions or on days 1-12 for 10 fractions. Treatment repeats every 28 days for up to 26 cycles of nivolumab and for up to 4 cycles of anti-GITR agonistic monoclonal antibody BMS-986156 in the absence of disease progression or unacceptable toxicity.

Anti-GITR Agonistic Monoclonal Antibody BMS-986156

Stereotactic Body Radiation Therapy

Joe Chang

This phase I/II trial studies the side effects and best dose of anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) agonistic monoclonal antibody BMS-986156 (BMS-986156) when given together with ipilimumab and nivolumab with or without stereotactic body radiation therapy and to see how well they work in treating patients with lung/chest or liver cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as BMS-986156, ipilimumab, and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. It is not yet known whether giving BMS-986156, ipilimumab, and nivolumab with or without stereotactic body radiation therapy will work better in treating patients with lung/chest or liver cancers.

PRIMARY OBJECTIVES:

I. To determine the safe dose of BMS-986156 and dose limiting toxicities (DLT) (30 mg versus \[vs\] 100 mg) when combined with ipilimumab (3 mg/kg) for patients with metastatic cancer.

II. To evaluate the safety and toxicity profile of ipilimumab (3mg/kg) with BMS-986156 (30 or 100 mg) administered in combination with stereotactic body radiation therapy (SBRT) targeting 1-4 LIVER lesion(s) for patients with metastatic cancers.

III. To evaluate the safety and toxicity profile of ipilimumab (3mg/kg) with BMS-986156 (30 or 100 mg) administered in combination with SBRT targeting 1-4 LUNG lesion(s) for patients with metastatic cancer.

IV. To determine safety and toxicity profile of nivolumab (480 mg) with BMS-986156 (30 mg) administered in combination with SBRT targeting 1-4 LIVER lesion(s) for patients with metastatic cancers.

V. To determine safety and toxicity profile of nivolumab (480 mg) with BMS-986156 (30 mg) administered in combination with SBRT targeting 1-4 LUNG lesion(s) for patients with metastatic cancers.

SECONDARY OBJECTIVES:

I. To determine antitumor activity of ipilimumab therapy with BMS-986156 (30 or 100 mg) as well as nivolumab with BMS-986156 (30 mg) with SBRT treatment for 1-4 lung lesions in both the SBRT treated lesion and non-irradiate tumors.

II. To determine antitumor activity of ipilimumab therapy with or without BMS-986156 (30 or 100 mg) as well as nivolumab with BMS-986156 (30 mg) with SBRT treatment for 1-4 liver lesions in both the SBRT treated lesion and non-irradiate tumors.

III. To compare response and progression of the non-irradiated tumors between BMS-986156 with ipilimumab vs BMS-986156 with nivolumab, using both immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors (RECIST) version (V) 1.1.

IV. To evaluate the predictive potential value of tumor-associated and systemic immune biomarkers for therapy effectiveness and toxicity prediction.

V. To evaluate whether skeletal mass, neutrophil, neutrophil to lymphocyte ratio, and tumor bulk are correlated with clinical outcomes and adverse events.

VI. To evaluate whether tumor kinetics in combination with clinical correlates can help determine treatment response.

VII. To evaluate whether tumor mutational burden correlates with improved clinical outcomes and response criteria.

OUTLINE: This is a phase I, dose-escalation study of anti-GITR agonistic monoclonal antibody BMS-986156, followed by a phase II study. Patients are assigned to 1 of 3 groups.

GROUP I: Patients receive ipilimumab intravenously (IV) over 90 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 5 (day 85), patients receive nivolumab IV over 30 minutes. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive ipilimumab IV over 90 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 2, patients then undergo SBRT on days 29-32 for 4 fractions or on days 29-40 for 10 fractions. Beginning day 1 of cycle 5 (day 85), patents receive nivolumab IV over 30 minutes. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

GROUP III: Patients receive nivolumab IV over 30 minutes and anti-GITR agonistic monoclonal antibody BMS-986156 over 60 minutes on day 1. Patients also undergo SBRT over 30-45 minutes on days 1-4 for 4 fractions or on days 1-12 for 10 fractions. Treatment repeats every 28 days for up to 26 cycles of nivolumab and for up to 4 cycles of anti-GITR agonistic monoclonal antibody BMS-986156 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 2-4 months for up to 1 year.

BMS-986156, Ipilimumab, and Nivolumab With or Without Stereotactic Body Radiation Therapy in Treating Patients With Advanced or Metastatic Lung/Chest or Liver Cancers

Phase I/II Trial of Ipilimumab or Nivolumab With BMS-986156 and Hypofractionated Stereotactic Radiation Therapy in Patients With Advanced Solid Malignancies

Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Descriptive statistics will be computed. Safety will be compared in two separate analyses among different treatment regimens: treatment group 1 versus (vs.) treatment group 2, treatment group 2 vs. treatment group 3, and among different SBRT targets liver vs lung: treatment group 2 vs. treatment group 3.

Will be assessed using CTCAE version 4.0. Descriptive statistics will be computed. Safety will be compared in two separate analyses among different treatment regimens: treatment group 1 vs. treatment group 2, treatment group 2 vs. treatment group 3, and among different SBRT targets liver vs lung: treatment group 2 vs. treatment group 3.

Assessment of antitumor activity of ipilimumab \& nivolumab with BMS-986156 \& SBRT for 1-4 lung lesions in both SBRT treated lesion and non-irradiate tumors where treatment success defined as immune-related complete response (irCR) or immune-related partial response (irPR) or immune-related stable disease (irSD), assessed using immune-related response criteria (irRC) (e.g. the best response obtained by a patient).irCR, complete disappearance all lesions (whether measurable or not, no new lesions) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; irPR, decrease in tumor burden ≥50% relative to baseline confirmed by consecutive assessment at least 4 week after first documentation; irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; irSD, not irCR or irPR, in absence of irPD, does not require repeat confirmation.

Assessment of antitumor activity of ipilimumab with or without BMS-986156 as well as nivolumab with BMS-986156 with SBRT treatment for 1-4 liver lesions in both the SBRT treated lesion and non irradiate tumors where treatment success defined as irCR or irPR or irSD, assessed using irRC (e.g. the best response obtained by a patient).irCR, complete disappearance all lesions (whether measurable or not, no new lesions) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; irPR, decrease in tumor burden ≥50% relative to baseline confirmed by consecutive assessment at least 4 week after first documentation; irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; irSD, not irCR or irPR, in absence of irPD, does not require repeat confirmation. Clinical benefit established as having irSD for up to 6 months for irSD.

Comparison of response of non-irradiated tumors between BMS-986156 with ipilimumab vs BMS-986156 with nivolumab done using irRc (e.g. the best response obtained by a patient).irRc efined as irCR, complete disappearance all lesions (whether measurable or not, no new lesions) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; irPR, decrease in tumor burden ≥50% relative to baseline confirmed by consecutive assessment at least 4 week after first documentation; irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) confirmation by repeat, consecutive assessment no less than 4 weeks from date first documented; ; irSD, not irCR or irPR, in absence of irPD, does not require repeat confirmation. Clinical benefit established as having irSD for up to 6 months for irSD.Comparisons between groups will be assessed with regard to the irRC outcomes.

For the predictive potential value of tumor-associated and systemic immune biomarkers, comparisons will be performed between group 2 (Ipilimumab plus BMS-986156 with SBRT) and group 3 (Nivolumab plus BMS-986156 with SBRT) per treatment site (liver or lung). Potential values may be summarized as qualitative or descriptive lists.

It will be evaluated whether skeletal mass, neutrophil, neutrophil to lymphocyte ratio, and tumor bulk are correlated with clinical outcomes and adverse events.Correlation may be summarized as qualitative or descriptive list of item's possible association to clinical outcome and/or adverse event.

It will be evaluated whether tumor kinetics in combination with clinical correlates can help determine treatment response. The radiological response and clinical data will be analyzed using mathematical and statistical models to identify prognostic groups.

Will be correlated with improved clinical outcomes and response criteria.

Comparison of progression of non-irradiated tumors between BMS-986156 with ipilimumab vs BMS-986156 with nivolumab done using irRc where treatment success defined as Response Evaluation Criteria in solid Tumors (RECIST) version 1.1: Complete Response (CR): Disappearance all target lesions; Partial Response (PR): At least 30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease (PD): At least 20% increase in sum LD target lesions, reference smallest sum LD recorded since treatment started or appearance 1/\> new lesions; Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD, reference smallest sum LD since treatment started

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BMS-986156, Ipilimumab, and Nivolumab With or Without Stereotactic Body Radiation Therapy in Treating Patients With Advanced or Metastatic Lung/Chest or Liver Cancers	NCT04021043	Advanced Malign... Metastatic Carc... Metastatic Carc... Metastatic Mali... Metastatic Mali...	Anti-GITR Agoni... Ipilimumab Nivolumab Stereotactic Bo...	18 Years -	M.D. Anderson Cancer Center
BMS-986156, Ipilimumab, and Nivolumab With or Without Stereotactic Body Radiation Therapy in Treating Patients With Advanced or Metastatic Lung/Chest or Liver Cancers	NCT04021043	Advanced Malign... Metastatic Carc... Metastatic Carc... Metastatic Mali... Metastatic Mali...	Anti-GITR Agoni... Ipilimumab Nivolumab Stereotactic Bo...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for metastatic carcinoma in the lung