Advanced Malignant Solid Neoplasm, Anal Carcinoma, HIV-associated Cancers, HIV Infection, Kaposi Sarcoma, Lung Carcinoma, Metastatic Malignant Solid Neoplasm, Recurrent Classic Hodgkin Lymphoma, Refractory Classic Hodgkin Lymphoma, Unresectable Solid Neoplasm
Conditions
Keywords
Immunotherapy, Immune check point blockade, Anti-CTLA-4 antibody, Anti-PD1 antibody, Phase 1, Dose de-escalation, Dose expansion
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).
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
PROCEDUREComputed Tomography
Undergo CT scan
BIOLOGICALIpilimumab
Given IV
BIOLOGICALNivolumab
Given IV
PROCEDUREPositron Emission Tomography
Undergo PET scan
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Platelets \>= 75,000/mm\^3 (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) =\< 3 x ULN for subjects with Gilbert's disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia without aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation and must have a total bilirubin less than 3.0 mg/dL (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum lipase and amylase \< 1.5 x ULN (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: AST (serum glutamic oxaloacetic transaminase \[SGOT\])/ALT (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x ULN (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Creatinine \< 1.5 UNL or creatinine clearance (CrCl) \> 50 ml/min (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Hemoglobin \>= 9 g/dL (within 2 weeks prior to enrollment) * PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum albumin \>= 2.8 g/dL (within 2 weeks prior to enrollment) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Leukocyte count: no lower limit (within 2 weeks prior to enrollment) (participants may receive granulocyte colony stimulating factor \[GCSF\] and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Absolute neutrophil count: \>= 1,000/mm\^3, unless decreased due to bone marrow involvement with lymphoma (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Platelets: \>= 75,000/mm\^3, unless decreased due to bone marrow involvement with lymphoma (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Hemoglobin: \>= 9 g/dL unless bone marrow involvement secondary to Hodgkin lymphoma is present (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Total bilirubin: =\< 1.5 x institutional upper limit of normal (ULN), or =\< 3 x ULN for participants with Gilbert's disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia without AST or ALT elevation, and must have a total bilirubin less than 3.0 mg/dL) (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum lipase and amylase \< 1.5 x ULN (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: AST (SGOT)/ALT (SGPT): =\< 3 x ULN (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Creatinine: \< 1.5 x upper normal limit (UNL) or CrCl \> 50ml/min (within 2 weeks prior to enrollment) (participants may receive GCSF and transfusions to meet these parameters) * HIV viral load should be well suppressed, defined as below the limit of detection of the local assay or below 75 copies/mL by Food and Drug Administration (FDA)-approved assays, within 4 weeks prior to registration * CD4 counts: * For Stratum 1: CD4+ cell count greater than 200 cells/mm\^3 obtained within 2 weeks prior to enrollment at any United States (U.S.) laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent * For Stratum 2: CD4 cell count between 100-200 cells/mm\^3 obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent * Expansion Cohort: CD4 cell count for this cohort will be specified once Stratum 1 and Stratum 2 have completed enrollment * Solid Tumor Expansion Cohort: CD4+ cell count greater than 200 cells/mm\^3 obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent * cHL Cohort: CD4 cell count of at least 100 cells/mm\^3 * Participants must be purified protein derivative (PPD) negative; alternatively, the QuantiFERON-tuberculosis (TB) Gold In-Tube (QFT-GIT) assay can be used; an individual is considered positive for M. tuberculosis infection if the IFN-gamma response to TB antigens is above the test cut-off (after subtracting the background IFN-gamma response in the negative control); the result must be obtained within 12 weeks prior to enrollment; PPD positive (or Quantiferon assay positive) participants are permitted if prophylaxis has been completed prior to enrollment * The effects of nivolumab and ipilimumab on the developing human fetus are unknown; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of childbearing 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; WOCBP should use an adequate method to avoid pregnancy for 6 months after the last dose of investigational drug; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic \[HCG\]) within 72 hours prior enrollment and the start of nivolumab; women must not be breastfeeding; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception; WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 6 months after the last dose of investigational product; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately * Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 12 weeks following enrollment * Participants who have hepatitis C (both reactive anti-hepatitis C virus \[HCV\] antibody and detectable HCV ribonucleic acid \[RNA\]) and hepatitis B (hepatitis B surface antigen \[HBsAg\] positive and anti-hepatitis B core \[HBc\]-total positive), may be enrolled, provided total bilirubin is =\< 1.5 x institutional ULN, and AST (SGOT) and ALT (SGPT) must be =\< 3 X institutional upper limit of normal, and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) \< 100 IU/mL (if hepatitis B positive) within 2 weeks prior to enrollment * Ability to understand and to sign a written informed consent document * Criteria for Solid Tumor Expansion and Lymphoma Cohorts: * Inclusion and
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Nivolumab | 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 | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Up to 3 years | 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. |
| Immune Function, Defined as CD4 and CD8 Cell Counts at Baseline and at End of 46 Cycles of Treatment+ 6 Weeks | 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. |
| Immune Function, Defined as CD4 and CD8 Cell Counts at Baseline and at End of 46 Cycles of Treatment+ 16 Weeks | 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. |
| HIV Viral Load at Baseline and at End of 46 Cycles of Treatment+ 6 Weeks | 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. |
| HIV Viral Load at Baseline and at End of 46 Cycles of Treatment+ 16 Weeks | 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. |
Countries
Australia, United States
Contacts
PRINCIPAL_INVESTIGATORLakshmi Rajdev
AIDS Malignancy Consortium
Participant flow
Recruitment details
Enrollment started in October 2015 and ended June 2023 across 7 different cohorts, and 17 study sites.
Pre-assignment details
Participants with histologically confirmed solid malignancy and HIV infection. Solid malignancy must be metastatic or unresectable and standard curative or palliative measures are nonexistent or no longer effective. Uncontrolled Kaposi sarcoma is permitted. Participants with relapsed refractory HIV-associated classical Hodgkin lymphoma (HIV-cHL) as a separate cohort.
Participants by arm
| Arm | Count |
|---|---|
| Dose De-escalation Nivolumab 3mg/kg (Stratum 1) Stratum 1 will enroll participants with CD4+ count above 200/mm3. 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 then participants will be treated with 240 mg of nivolumab. No intra-participant dose escalations will be allowed. The safety evaluation period is 6 weeks at a given dose level. | 6 |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) Stratum 2 will enroll participants with CD4+ count between 100-200/mm3. Enrollment in Stratum 2 will begin after Stratum 1 has completed. Stratum 2 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. | 9 |
| Dose De-escalation Nivolumab 240mg and Ipilimumab 1 mg/kg (Stratum 1) Stratum 1 will enroll participants with CD4+ count above 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. | 7 |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (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. | 4 |
| Dose Expansion Nivolumab 240 mg q2w in Solid Tumors 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. | 24 |
| Dose Expansion Nivolumab 240 mg q2w and Ipilimumab 1 mg/kg q6w The combination therapy MTD will be studied in a dose expansion cohort (up to 12 participants) limited to only participants with Kaposi sarcoma, lung cancer, and anal cancer. | 20 |
| Nivolumab 240 mg q2w in Classical Hodgkin Lymphoma Single agent Nivolumab therapy will be administered in participants with classical Hodgkin's Lymphoma with a fixed dose of 240 mg q 2 week. | 9 |
| Total | 79 |
Baseline characteristics
| Characteristic | Total | Dose De-escalation Nivolumab 240mg and Ipilimumab 1 mg/kg (Stratum 1) | Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) | Dose De-escalation Nivolumab 3mg/kg (Stratum 1) | Dose Expansion Nivolumab 240 mg q2w in Solid Tumors | Dose Expansion Nivolumab 240 mg q2w and Ipilimumab 1 mg/kg q6w | Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 2) | Nivolumab 240 mg q2w in Classical Hodgkin Lymphoma |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 12.3 | 57.0 years STANDARD_DEVIATION 6.6 | 59.4 years STANDARD_DEVIATION 4.3 | 55.0 years STANDARD_DEVIATION 6.2 | 49.6 years STANDARD_DEVIATION 11.2 | 52.6 years STANDARD_DEVIATION 17 | 45.8 years STANDARD_DEVIATION 16.8 | 46.1 years STANDARD_DEVIATION 9.8 |
| Count by cancer type Anal Cancer | 9 Participants | 0 Participants | 5 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Count by cancer type Colon cancer | 4 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Count by cancer type Head and Neck Cancer | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Count by cancer type Hodgkin's lymphoma | 9 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants |
| Count by cancer type Kaposi's Sarcoma | 33 Participants | 2 Participants | 0 Participants | 0 Participants | 15 Participants | 15 Participants | 1 Participants | 0 Participants |
| Count by cancer type Lung cancer | 6 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Count by cancer type Other cancer types | 15 Participants | 2 Participants | 1 Participants | 4 Participants | 5 Participants | 1 Participants | 2 Participants | 0 Participants |
| ECOG Grade of Performance Status ECOG Grade 0 | 33 Participants | 2 Participants | 2 Participants | 3 Participants | 11 Participants | 10 Participants | 1 Participants | 4 Participants |
| ECOG Grade of Performance Status ECOG Grade 1 | 46 Participants | 5 Participants | 7 Participants | 3 Participants | 13 Participants | 10 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 4 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 5 Participants | 8 Participants | 6 Participants | 19 Participants | 15 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants | 6 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 50 Participants | 4 Participants | 6 Participants | 4 Participants | 16 Participants | 12 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 72 Participants | 5 Participants | 9 Participants | 5 Participants | 21 Participants | 19 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 3 / 9 | 1 / 7 | 2 / 4 | 5 / 24 | 1 / 20 | 0 / 9 |
| other Total, other adverse events | 5 / 6 | 8 / 9 | 6 / 7 | 4 / 4 | 22 / 24 | 20 / 20 | 9 / 9 |
| serious Total, serious adverse events | 3 / 6 | 6 / 9 | 3 / 7 | 3 / 4 | 9 / 24 | 6 / 20 | 2 / 9 |
Outcome results
Primary
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
Population: Patients evaluated for safety during 6 weeks from the first dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 1) | Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts | 0 Participants |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) | Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts | 0 Participants |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 1) | Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts | 1 Participants |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 2) | Dose Limiting Toxicities (DLTs) Observed in Dose De-escalation Cohorts | 0 Participants |
Primary
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 1) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 27 Events |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 1) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 3 Events |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 29 Events |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 5 Events |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 1) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 26 Events |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 1) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 2 Events |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 2) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 8 Events |
| Dose De-escalation Nivolumab 240 mg and Ipilimumab 1mg/kg (Stratum 2) | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 1 Events |
| Dose Expansion Nivolumab 240 mg q2w in Solid Tumors | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 54 Events |
| Dose Expansion Nivolumab 240 mg q2w in Solid Tumors | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 5 Events |
| Dose Expansion Nivolumab 240 mg and Ipilimumab 1 mg/kg | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 72 Events |
| Dose Expansion Nivolumab 240 mg and Ipilimumab 1 mg/kg | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 3 Events |
| Nivolumab 240 mg q2w in Classical Hodgkin Lymphoma | Incidence of Adverse Events According to NCI CTCAE v5.0 | Adverse Events | 29 Events |
| Nivolumab 240 mg q2w in Classical Hodgkin Lymphoma | Incidence of Adverse Events According to NCI CTCAE v5.0 | Serious Adverse Events | 2 Events |
Primary
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
Population: Safety evaluable population treated with at least a single dose of Nivolumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 1) | Maximum Tolerated Dose of Nivolumab | 3 mg/kg |
| Dose De-escalation Nivolumab 3 mg/kg (Stratum 2) | Maximum Tolerated Dose of Nivolumab | 3 mg/kg |
Secondary
Change in HIV Viral Load
Change in HIV viral load from pre-study to the end of study will be examined using a nonparametric Wilcoxon signed-rank test.
Time frame: Baseline up to 3 years
Secondary
Change in Immune Status
Change in immune status from pre-study to the end of study will be examined using a nonparametric Wilcoxon signed-rank test.
Time frame: Baseline up to 3 years
Secondary
Immune Function
Descriptive statistics will be generated to evaluate the effects of single agent nivolumab, and the combination of ipilimumab and nivolumab, on immune function (human immunodeficiency virus \[HIV\] viral load, CD4 and CD8 cells).
Time frame: Up to 3 years
Secondary
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
Other Pre-specified
Circulating Cytokine Markers
Will be assessed by multiplex assay. Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Herpesvirus Loads (Epstein-Barr Virus [EBV], Kaposi Sarcoma Herpes Virus [KSHV], Cytomegalovirus [CMV]) in Plasma
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Herpesvirus Specific CD8 and CD4 T Cells in PBMC
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
HIV Reactive T Cells
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Human Papillomavirus Types in Anal Swabs (Anal Cancer Cases)
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Intratumor Immune Cells
Will be assessed by immunohistochemistry. Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Latent Herpesvirus (EBV, KSHV, CMV) in Peripheral Blood Mononuclear Cell (PBMC)
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Latent HIV Loads in PBMC
Will be assessed using outgrowth assay. Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years
Other Pre-specified
Viral Transcription in Tumor Biopsies (Kaposi Sarcoma Cases)
Descriptive statistics will be generated. Changes from pre-study to end of study will be explored using nonparametric Wilcoxon signed-rank test.
Time frame: Up to 3 years