A Phase I Study of Ipilimumab and Nivolumab in Advanced HIV Associated Solid Tumors With Expansion Cohort in HIV Associated Solid Tumors and a Cohort of HIV-Associated Classical Hodgkin Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Biospecimen Collection
- Conditions
- Not specified
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 79
- Locations
- 34
- Primary Endpoint
- Maximum Tolerated Dose of Nivolumab
- Status
- Terminated
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Detailed Description
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologically confirmed solid tumor malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; participants with uncontrolled Kaposi sarcoma are permitted (KS must be increasing despite HAART and HIV suppression for greater than or equal to 2 months, or stable KS despite HAART for greater than or equal to 3 months)
- •For participants in the 24 participant solid tumor cohort, only those histologies not known to respond to single agent nivolumab (such as pancreas, prostate, and microsatellite stable \[MSS\] colorectal cancer) will be excluded
- •For participants in the relapsed refractory HIV-cHL expansion cohort, participants must have histologically confirmed, relapsed/refractory (defined as relapsed/refractory to one or greater lines of therapy) HIV-associated classical Hodgkin lymphoma
- •HIV-1 infection, as documented by any federally approved, licensed HIV rapid test performed in conjunction with screening (or enzyme linked immunosorbent assay \[ELISA\], test kit, and confirmed by Western blot or other approved test); alternatively, this documentation may include a record demonstrating that another physician has documented the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the referring physician's written record that HIV infection was documented, with supporting information on the participant's relevant medical history and/or current management of HIV infection
- •Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; scans must have been performed within 4 weeks prior to registration; Note: for participants with Kaposi sarcoma, the following apply: at least five measurable cutaneous KS lesions or any number of lesions with systemic unresectable disease with no previous local radiation, surgical, or intralesional cytotoxic therapy that would prevent response assessment
- •Prior therapy for metastatic disease permitted; at least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; radiotherapy must be completed at least 4 weeks prior to registration
- •Age \> 18 years, because no dosing or AE data are currently available on the use of ipilimumab in combination with nivolumab in participants \<18 years of age, children are excluded from this study.
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
- •PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Leukocytes \>= 2,000/mm\^3 (within 2 weeks prior to enrollment)
- •PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Absolute neutrophil count \>= 1,000/mm\^3 (within 2 weeks prior to enrollment)
Exclusion Criteria
- •for this cohort are the same as above, with the following rule for CD4 count based on tolerability in Phase I; if, participants with lymphocyte T CD4 count between 100-200/mm\^3 (Stratum 2) are shown to tolerate treatment in the Phase I dose de-escalation portion at the same dose level as those with CD4 counts \> 200/mm\^3 (Stratum 1), participants in the expansion cohort with CD4 counts \>= 100/mm\^3 are permitted; otherwise, the expansion is open to all solid tumor patients except those whose tumors are known not to respond to nivolumab (pancreas, prostate and MSS colon cancer); for the relapsed refractory HIV-cHL cohort, participants with CD4 count \>= 100/mm\^3 are permitted
- •Exclusion Criteria:
- •Participants who have received any other investigational agents within the 4 weeks prior to enrollment; concurrent radiation therapy is not permitted, except palliative (limited-field) radiation therapy, if all of the following criteria are met:
- •Repeat imaging demonstrates no new sites of bone metastases
- •The lesion being considered for palliative radiation is not a target lesion
- •Participants with known brain metastases or leptomeningeal metastases must be excluded unless they qualify for enrollment as described below because of poor prognosis and concerns regarding progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; participants with brain metastases are permitted if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks or more after treatment is complete and within 4 weeks prior to the first dose of nivolumab administration
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab, nivolumab, or other agents used in study, or history of severe hypersensitivity reaction to any monoclonal antibody
- •Participants should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of study drug administration; these drugs may interfere with the activity of ipilimumab and nivolumab if administered at the time of the first ipilimumab dose; inhaled or topical steroids and adrenal replacement doses =\< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if \>= 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted; use of anabolic steroids is permitted
- •Participants with clinical or radiographic evidence of pancreatitis are excluded
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Arms & Interventions
Dose De-escalation Single Agent Nivolumab Stratum 1
Stratum 1 will enroll participants with T lymphocyte CD4+ count above 200/mm3. Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; after evaluating dosing for single agent nivolumab. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Biospecimen Collection
Dose De-escalation Single Agent Nivolumab Stratum 1
Stratum 1 will enroll participants with T lymphocyte CD4+ count above 200/mm3. Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; after evaluating dosing for single agent nivolumab. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Computed Tomography
Dose De-escalation Single Agent Nivolumab Stratum 1
Stratum 1 will enroll participants with T lymphocyte CD4+ count above 200/mm3. Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; after evaluating dosing for single agent nivolumab. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Nivolumab
Dose De-escalation Single Agent Nivolumab Stratum 2
Stratum 2 will enroll participants with T lymphocyte CD4+ count between 100 to 200/mm3. Stratum 2 will start enrolling after completion of stratum 2 dose deescalation. The dosing will begin at the single-agent therapy MTD for Stratum 1 (dose level 1 or -1). Stratum 2 will not be allowed to escalate beyond the MTD for Stratum 1. Only 1 dose de-escalation will be allowed.
Intervention: Biospecimen Collection
Dose De-escalation Single Agent Nivolumab Stratum 2
Stratum 2 will enroll participants with T lymphocyte CD4+ count between 100 to 200/mm3. Stratum 2 will start enrolling after completion of stratum 2 dose deescalation. The dosing will begin at the single-agent therapy MTD for Stratum 1 (dose level 1 or -1). Stratum 2 will not be allowed to escalate beyond the MTD for Stratum 1. Only 1 dose de-escalation will be allowed.
Intervention: Computed Tomography
Dose De-escalation Single Agent Nivolumab Stratum 2
Stratum 2 will enroll participants with T lymphocyte CD4+ count between 100 to 200/mm3. Stratum 2 will start enrolling after completion of stratum 2 dose deescalation. The dosing will begin at the single-agent therapy MTD for Stratum 1 (dose level 1 or -1). Stratum 2 will not be allowed to escalate beyond the MTD for Stratum 1. Only 1 dose de-escalation will be allowed.
Intervention: Nivolumab
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 1
Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Biospecimen Collection
Classical Hodgkin Lymphoma Cohort
Single agent Nivolumab therapy at MTD dose from dose-de-escalation will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week.
Intervention: Positron Emission Tomography
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 1
Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Computed Tomography
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 1
Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Ipilimumab
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 1
Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose level 1) and one dose de-escalation is allowed; Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Nivolumab
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 2
Stratum 2 will enroll participants with lymphocyte T CD4+ count between 100-200/mm3 Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Biospecimen Collection
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 2
Stratum 2 will enroll participants with lymphocyte T CD4+ count between 100-200/mm3 Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Computed Tomography
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 2
Stratum 2 will enroll participants with lymphocyte T CD4+ count between 100-200/mm3 Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Ipilimumab
Dose De-escalation Cohort Combination Therapy (Nivolumab and Ipilimumab) Stratum 2
Stratum 2 will enroll participants with lymphocyte T CD4+ count between 100-200/mm3 Participants will be treated with 240 mg of nivolumab and 1 mg/kg of ipilimumab will be added to evaluate combination therapy (dose level 2) with one dose de- escalation allowed. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level.
Intervention: Nivolumab
Solid Tumors Dose Expansion Cohort Single Agent Nivolumab
Participants with incurable solid tumors will be treated at single agent nivolumab 240 mg every 2 weeks. Only those histologies that are not known to respond to single agent nivolumab will be excluded (i.e., pancreas, prostate, MSS colorectal cancer, unless results from another clinical trial showing non-response in another tumor type become available in the future). Up to 24 participants will be enrolled.
Intervention: Biospecimen Collection
Solid Tumors Dose Expansion Cohort Single Agent Nivolumab
Participants with incurable solid tumors will be treated at single agent nivolumab 240 mg every 2 weeks. Only those histologies that are not known to respond to single agent nivolumab will be excluded (i.e., pancreas, prostate, MSS colorectal cancer, unless results from another clinical trial showing non-response in another tumor type become available in the future). Up to 24 participants will be enrolled.
Intervention: Computed Tomography
Solid Tumors Dose Expansion Cohort Single Agent Nivolumab
Participants with incurable solid tumors will be treated at single agent nivolumab 240 mg every 2 weeks. Only those histologies that are not known to respond to single agent nivolumab will be excluded (i.e., pancreas, prostate, MSS colorectal cancer, unless results from another clinical trial showing non-response in another tumor type become available in the future). Up to 24 participants will be enrolled.
Intervention: Nivolumab
Combination Regimen Expansion Cohort
The combination therapy at MTD of Nivolumab and Ipilimumab regimen will be studied in a dose expansion cohort (up to 12 participants) limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer.
Intervention: Biospecimen Collection
Combination Regimen Expansion Cohort
The combination therapy at MTD of Nivolumab and Ipilimumab regimen will be studied in a dose expansion cohort (up to 12 participants) limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer.
Intervention: Computed Tomography
Combination Regimen Expansion Cohort
The combination therapy at MTD of Nivolumab and Ipilimumab regimen will be studied in a dose expansion cohort (up to 12 participants) limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer.
Intervention: Ipilimumab
Combination Regimen Expansion Cohort
The combination therapy at MTD of Nivolumab and Ipilimumab regimen will be studied in a dose expansion cohort (up to 12 participants) limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer.
Intervention: Nivolumab
Classical Hodgkin Lymphoma Cohort
Single agent Nivolumab therapy at MTD dose from dose-de-escalation will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week.
Intervention: Biospecimen Collection
Classical Hodgkin Lymphoma Cohort
Single agent Nivolumab therapy at MTD dose from dose-de-escalation will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week.
Intervention: Bone Marrow Biopsy
Classical Hodgkin Lymphoma Cohort
Single agent Nivolumab therapy at MTD dose from dose-de-escalation will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week.
Intervention: Computed Tomography
Classical Hodgkin Lymphoma Cohort
Single agent Nivolumab therapy at MTD dose from dose-de-escalation will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Maximum Tolerated Dose of Nivolumab
Time Frame: Each patient will be evaluated for DLT for the safety evaluation period of 6 weeks
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.
Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts
Time Frame: 6 weeks from the first dose of Nivolumab
Incidence of DLTs during the safety evaluation period of 6 weeks at a given dose from the first dose of treatment.
Incidence of Adverse Events According to NCI CTCAE v5.0
Time Frame: Participants will be followed for 16 weeks or 112 days after removal from study treatment, or until death, whichever occurs first.
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.
Secondary Outcomes
- Objective Response Rate(Up to 3 years)
- Immune Function(Up to 3 years)
- Change in Immune Status(Baseline up to 3 years)
- Change in HIV Viral Load(Baseline up to 3 years)