This phase I trial investigates the side effects of cabozantinib and nivolumab in treating patients with cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and who are undergoing treatment for human immunodeficiency virus (HIV). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and nivolumab may shrink or stabilize cancer in patients undergoing treatment for HIV.
PRIMARY OBJECTIVES: I. To determine the safety of combined nivolumab and cabozantinib s-malate (XL184 \[cabozantinib\]) in human immunodeficiency virus (HIV) patients with advanced solid tumors. II. To determine the feasibility to deliver the combined nivolumab and XL184 (cabozantinib) for a minimum of 4 cycles in at least 75% of the subjects in the expanded cohort with Kaposi sarcoma (KS) or to achieve a confirmed objective response. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity in subjects with Kaposi sarcoma (KS). II. To assess the effect of treatment on participants' immune status (CD4 and CD8 cell counts) and HIV viral loads. III. To preliminarily evaluate the objective response rate (ORR) to the combination treatment in subjects with KS. EXPLORATORY OBJECTIVES: I. To assess duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in subjects with KS. II. To assess the PD-L1 immunohistochemistry (IHC) status in tumors and tumor microenvironment and its association with clinical outcome. III. To assess the expression characteristics and cellular distribution of immune checkpoints (PD-L1, B7x, HHLA2, B7H3), infiltrating immune cells (CD4 T cells, CD8 T cells, regulatory T-cells \[Treg\], myeloid-derived suppressor cell \[MDSC\]), and other tumor microenvironment biomarkers (VEGF, VEGFR, MET, and AXL) in the tissue by multiplex quantitative immunofluorescence (MQIF). IV. To correlate markers of immune activation and expansion of immune cell subsets and cytokines with clinical outcomes. V. To assess the treatment effects on latent HIV reservoir. VI. To investigate the dynamic changes of immune checkpoints, angiogenesis markers, and infiltrating immune cells among subjects with available pre- and post-treatment biopsy samples (including subjects with Kaposi sarcoma \[KS\]). OUTLINE: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 of each cycle and nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days for up to 1 year or 1 year after a partial response is achieved, or 6 months after a complete response is achieved in the absence of disease progression or unacceptable toxicity. Patients also undergo a computed tomography (CT) scan and/or magnetic resonance imaging (MRI) as well as blood sample collection throughout the trial. After completion of study treatment, patients are followed up for 16 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
8
Undergo blood sample collection
Given PO
Undergo CT
Undergo MRI
Given IV
Northwestern University
Chicago, Illinois, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Incidence of Dose Limiting Toxicities (DLTs)
Dose-limiting toxicity (DLT) were defined as any treatment-related grade 3 or 4 nonhematologic toxicity during the first cycle of therapy, including grade 3 nausea and/or vomiting and grade 3 diarrhea despite prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities during the first cycle of therapy: thrombocytopenia and neutropenia of more than 7 days duration, neutropenia of any duration with fever or documented infection; additionally, treatment delay of 14 days or greater during Cycle 1 due to unresolved toxicity will be considered a DLT.
Time frame: 28 days
Objective Response Rate (ORR)
Percentage of participants who experienced either a Complete Response (CR) or Partial Response (PR) to treatment. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to 24 months
Best Overall Response
Percentage of patients who experienced either a Complete Response (CR) or Partial Response (PR) to treatment. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Time frame: Up to 24 months
Best Overall Response (Off Treatment)
Percentage of patients (who are off treatment) who experienced either a Complete Response (CR) or Partial Response (PR) during off treatment period. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Time frame: Up to 24 months
12-month Progression-free Survival (PFS)
Percentage of patients without progressive disease at 12 months.
Time frame: At 12 months (from start of treatment)
24-month Progression-free Survival (PFS)
Percentage of patients without progressive disease at 24 months.
Time frame: At 24 months (from start of treatment)
12-month Overall Survival (OS)
Percentage of patients alive at 12 months.
Time frame: At 12 months
24-month Overall Survival (OS)
Percentage of patients alive at 24 months.
Time frame: At 24 months
CD4 Immune Status
CD4 immune status at baseline.
Time frame: At baseline
CD4 Immune Status
CD4 immune status at treatment Cycle 1.
Time frame: At Treatment Cycle 1
CD4 Immune Status
CD4 immune status at treatment Cycle 2.
Time frame: At Treatment Cycle 2
CD4 Immune Status
CD4 immune status at treatment Cycle 3.
Time frame: At Treatment Cycle 3
CD4 Immune Status
CD4 immune status at treatment Cycle 4.
Time frame: At Treatment Cycle 4
CD4 Immune Status
CD4 immune status at treatment Cycle 5.
Time frame: At Treatment Cycle 5
CD4 Immune Status
CD4 immune status at treatment Cycle 8.
Time frame: At Treatment Cycle 8
CD4 Immune Status
CD4 immune status at treatment Cycle 11.
Time frame: At Treatment Cycle 11
CD8 Immune Status
CD8 immune status at baseline.
Time frame: At baseline
CD8 Immune Status
CD8 immune status at treatment Cycle 1.
Time frame: At Treatment Cycle 1
CD8 Immune Status
CD8 immune status at treatment Cycle 2.
Time frame: At Treatment Cycle 2
CD8 Immune Status
CD8 immune status at treatment Cycle 3.
Time frame: At Treatment Cycle 3
CD8 Immune Status
CD8 immune status at treatment Cycle 4.
Time frame: At Treatment Cycle 4
CD8 Immune Status
CD8 immune status at treatment Cycle 5.
Time frame: At Treatment Cycle 5
CD8 Immune Status
CD8 immune status at treatment Cycle 8.
Time frame: At Treatment Cycle 8
CD8 Immune Status
CD8 immune status at treatment Cycle 11.
Time frame: At Treatment Cycle 11
Human Immunodeficiency Virus (HIV) Viral Loads
Human immunodeficiency virus (HIV) viral loads at baseline.
Time frame: At baseline
Human Immunodeficiency Virus (HIV) Viral Loads
Human immunodeficiency virus (HIV) viral loads at treatment Cycle 1.
Time frame: Up to 4 weeks from start of combination treatment
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 2.
Time frame: Up to 8 weeks from start of combination treatment
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 3.
Time frame: At Treatment Cycle 3
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 4.
Time frame: At Treatment Cycle 4
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 5.
Time frame: At Treatment Cycle 5
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 8.
Time frame: At Treatment Cycle 8
Human Immunodeficiency Virus (HIV) Viral Loads
HIV viral loads at treatment Cycle 11.
Time frame: At Treatment Cycle 11
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