This phase I trial studies the side effects and best dose of nivolumab when given with ipilimumab in treating patients with human immunodeficiency virus (HIV) associated classical Hodgkin lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory), or solid tumors that have spread from where it first started to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as 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. Ipilimumab is an antibody that acts against a molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 controls a part of the immune system by shutting it down. Nivolumab is a type of antibody that is specific for human programmed cell death 1 (PD-1), a protein that is responsible for destruction of immune cells. Giving ipilimumab with nivolumab may work better in treating patients with HIV associated classical Hodgkin lymphoma or solid tumors compared to ipilimumab with nivolumab alone.
PRIMARY OBJECTIVE: I. To demonstrate safety and feasibility of ipilimumab and nivolumab at the standard doses of drug in solid tumor and relapsed refractory HIV-classical Hodgkin lymphoma (cHL) participants with human immunodeficiency virus (HIV) infection given the possibility of increased toxicity based on immune activation, co-morbidity, or interference with highly active antiretroviral therapy (HAART) therapy. (Dose De-escalation and Dose Expansion Cohorts) SECONDARY OBJECTIVES: I. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (HIV viral load in plasma using conventional assay, CD4+ and CD8+ cells). (Dose De-escalation Cohort) II. To preliminarily assess objective response rates associated with treatment for commonly represented solid tumors (Kaposi sarcoma, anal cancer, and lung cancer) and relapsed refractory HIV-cHL. (Solid Tumor Dose Expansion and cHL Cohorts) III. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (HIV viral load in plasma using conventional HIV assay, CD4+, and CD8+ cells). (Solid Tumor Dose Expansion and cHL Cohorts) EXPLORATORY OBJECTIVES: I. Understand the immune response to agent in the context of antiretroviral therapy (ART), of altered immune function, and repertoire due to prior HIV infection. Ia. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on intratumor immune cells by immunohistochemistry (IHC) such as PD1, programmed cell death 1 ligand 1 (PDL-1), and others. Ib. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on circulating cytokine markers by multiplex assay, such as: interleukin (IL)-2, IL-4, IL-6, IL-10, IL-8, interferon gamma-induced protein 10 (IP10), chemokine (C-X-C motif) ligand 13 (CXCL13), interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, soluble IL-2 receptor (sIL2R)-alpha, sCD27, soluble TNF receptor (sTNFR)1, and sTNFR2. II. To understand the response of human tumor viruses (human papillomavirus \[HPV\], Epstein-Barr virus \[EBV\], Kaposi's sarcoma-associated herpesvirus \[KSHV\]) to agent. IIa. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on herpesvirus loads (EBV, KSHV, cytomegalovirus \[CMV\]) in plasma. IIb. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on latent herpesvirus (EBV, KSHV, CMV) in peripheral blood mononuclear cells (PBMC). IIc. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on herpesvirus specific CD8 and CD4 T cells in PBMC. IId. In cases of Kaposi sarcoma, to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on viral transcription in tumor biopsies. IIe. In cases of anal cancer, to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on HPV types in anal swabs, when feasible. III. Understand the response of HIV to agent. IIIa. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on latent HIV loads in PBMC using outgrowth assay. IIIb. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab on HIV reactive T cells. OUTLINE: This is a dose-escalation study of nivolumab. Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Patients in dose level 2 also receive ipilimumab IV over 90 minutes on day 1 of every third cycle of nivolumab, and patients in dose level -2 also receive ipilimumab IV over 90 minutes on day 1 of every sixth cycle of nivolumab. Treatment repeats every 14 days for up to 46 cycles of nivolumab (with ipilimumab if receiving dose level 2 or -2) in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients undergo positron emission tomography (PET) and computed tomography (CT) during screening and on study. Patients undergo bone marrow biopsy on screening and may undergo it during follow up. After completion of study treatment, patients are followed up for 16 weeks or 112 days (based on 5 half lives).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
79
Undergo blood sample collection
Undergo bone marrow biopsy
Undergo CT scan
Given IV
Given IV
Undergo PET scan
UC San Diego Moores Cancer Center
La Jolla, California, United States
UCLA Center for Clinical AIDS Research and Education
Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
UC San Diego Medical Center - Hillcrest
San Diego, California, United States
Zuckerberg San Francisco General Hospital
San Francisco, California, United States
Maximum Tolerated Dose of Nivolumab
Will be defined as the starting dose level at which 1/6 subjects experience dose limiting toxicity (DLT) with the next higher dose having at least \>= 2 participants encountering DLT. Toxicity data will be presented by type and severity for each dose group and overall; the incidence of toxicity related dose reductions and treatment discontinuations will be summarized.
Time frame: Each patient will be evaluated for DLT for the safety evaluation period of 6 weeks
Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts
Incidence of DLTs during the safety evaluation period of 6 weeks at a given dose from the first dose of treatment.
Time frame: 6 weeks from the first dose of Nivolumab
Incidence of Adverse Events According to NCI CTCAE v5.0
Number of adverse events that are either possibly, probably or definitely attributed to study intervention. In case an adverse event as per the CTCAE v5.0 occurs within a same patient, an instance with the highest severity of the adverse event is counted. Separate event-instances are reported otherwise.
Time frame: Participants will be followed for 16 weeks or 112 days after removal from study treatment, or until death, whichever occurs first.
Objective Response Rate
The proportion of patients achieving objective responses (by Response Evaluation Criteria In Solid Tumors 1.1 or Kaposi's sarcoma response criteria, which includes RECIST for visceral disease, or by Response Evaluation Criteria in Lymphoma for classical Hodgkin lymphoma \[cHL\]) and their corresponding 95% confidence intervals (calculated using exact binomial) will be reported separately for solid tumor and cHL according to treatment (combination therapy and single agent) using designated response criteria. Descriptive statistics will also be compiled for duration of response.
Time frame: Up to 3 years
Immune Function, Defined as CD4 and CD8 Cell Counts at Baseline and at End of 46 Cycles of Treatment+ 6 Weeks
Descriptive statistics will be generated to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (CD4 and CD8 cells). Changes in CD4+ T-cell counts, CD8+ T-cell from baseline to end of 46 cycles of treatment+ 6 weeks visit were evaluated by Wilcoxon signed-rank test for paired data.
Time frame: end of 46 cycles of treatment+ 6 weeks
Immune Function, Defined as CD4 and CD8 Cell Counts at Baseline and at End of 46 Cycles of Treatment+ 16 Weeks
Descriptive statistics will be generated to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (CD4 and CD8 cells). Changes in CD4+ T-cell counts, CD8+ T-cell from baseline to end of 46 cycles of treatment+ 16 weeks visit were evaluated by Wilcoxon signed-rank test for paired data.
Time frame: end of 46 cycles of treatment+ 16 weeks
HIV Viral Load at Baseline and at End of 46 Cycles of Treatment+ 6 Weeks
Descriptive statistics will be generated to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on HIV viral load. Changes in HIV viral load from baseline to end of 46 cycles of treatment+ 6 weeks visit were evaluated by Wilcoxon signed-rank test for paired data.
Time frame: end of 46 cycles of treatment+ 6 weeks
HIV Viral Load at Baseline and at End of 46 Cycles of Treatment+ 16 Weeks
Descriptive statistics will be generated to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on HIV viral load. Changes in HIV viral load from baseline to end of 46 cycles of treatment+ 16 weeks visit were evaluated by Wilcoxon signed-rank test for paired data.
Time frame: end of 46 cycles of treatment+16 weeks
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