Neoplasms

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Skin and Connective Tissue Diseases

Rare Diseases

Sarcoma

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Histiocytoma, Malignant Fibrous

Chondrosarcoma

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Histiocytoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Adipose Tissue

Neoplasms, Connective Tissue

Neoplasms, Fibrous Tissue

Soft Tissue Sarcoma

Undifferentiated Pleomorphic Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood throughout the trial.

Patients receive cabozantinib PO QD in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV and ipilimumab IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood throughout the trial.

Biopsy

Biospecimen Collection

Cabozantinib

Computed Tomography

Magnetic Resonance Imaging

A P Chen

This phase II trial compares the effect of immunotherapy with ipilimumab and nivolumab alone to their combination with cabozantinib in treating patients with soft tissue sarcoma that has spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). 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. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply and may also prevent the growth of new blood vessels that tumors need to grow. By these actions it may help slow or stop the spread of cancer cells. Adding cabozantinib to the combination of ipilimumab and nivolumab may be better in stopping or slowing the growth of tumor compared to ipilimumab and nivolumab alone in patients with advanced soft tissue sarcoma.

PRIMARY OBJECTIVE:

I. Assess progression free survival (PFS) of ipilimumab + nivolumab versus (vs.) the cabozantinib + nivolumab + ipilimumab combination in patients with metastatic, or locally advanced, surgically unresectable soft tissue sarcoma (STS) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

SECONDARY OBJECTIVES:

I. Evaluate the response rate (complete response \[CR\]+partial response \[PR\]) of ipilimumab + nivolumab vs. the cabozantinib + nivolumab + ipilimumab combination.

II. Evaluate the response rate (CR+PR) of cabozantinib + ipilimumab + nivolumab in (crossover) patients whose disease has progressed on ipilimumab + nivolumab therapy.

III. Assess the number of tumor-infiltrating CD8+ T cells in tumor biopsies before and after treatment.

EXPLORATORY OBJECTIVES:

I. Measure tumor-infiltrating CD3+ T cells and CD68+ macrophages in biopsy specimens.

II. Evaluate genomic alterations in circulating tumor DNA (ctDNA) and their potential association with therapy response or resistance.

III. Investigate whether response is associated with genetic aberrations and/or tumor mutational burden.

IV. Analyze total MET and activated MET (p1235-MET) in biopsy specimens before and after study treatment and evaluate molecular target engagement by cabozantinib (as shown by a lower phosphorylated \[p\]MET/MET ratio).

V. Evaluate the objective response rate in patients treated with ipilimumab + nivolumab or the cabozantinib + nivolumab + ipilimumab combination using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans, tumor biopsies, and collection of blood throughout the trial.

ARM B: Patients receive cabozantinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV and ipilimumab IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood throughout the trial.

After completion of study treatment, patients are followed for 30 days.

Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma

Randomized Phase 2 Study of Cabozantinib, Ipilimumab, and Nivolumab in Patients With Soft Tissue Sarcoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be evaluated in tumor biopsies. Non-parametric analyses will be used.

Will investigate whether response is associated with genetic aberrations and/or tumor mutational burden. Non-parametric analyses will be used.

Will be evaluated in biopsy specimens before and after study treatment. Will evaluate molecular target engagement by cabozantinib (as shown by a lower phosphorylated \[p\]MET/MET ratio). Non-parametric analyses will be used.

Will be assessed using Immune-Modified RECIST as an exploratory endpoint, for comparison to RECIST v1.1. Non-parametric analyses will be used.

Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. The primary analysis will be a logrank test and will be performed once 52 PFS events have been observed. For Arm A (ipilimumab + nivolumab), a within-arm interim futility analysis will be performed; if at least one PR, CR, or SD (SD with duration of at least 6 months) is observed among the first 14 patients enrolled to this arm. In addition, a single interim futility analysis (Wieand rule) will be performed at 50% information (26 PFS events).

Defined as complete response or partial response by RECIST v1.1. Response rates within the two study arms will be (separately) reported and will be directly compared using a two-sample test of proportions. In addition, will report the rate of objective response to cabozantinib + ipilimumab + nivolumab triplet therapy in patients who have crossed over after their disease progressed on ipilimumab + nivolumab doublet.

Will be evaluated in tumor biopsies before and after treatment. Changes between paired samples will be interpreted as being likely treatment-induced if they exceed the sampling, biological, and technical variabilities determined for the assay. Unpaired baseline and post-treatment measurements may also be assessed for correlation with response, which will shed light on possible CD8+ T cell density or infiltration requirements that could inform future trial designs.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma	NCT05836571	Locally Advance... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Metastatic Undi...	Biopsy Biospecimen Col... Cabozantinib Computed Tomogr... Ipilimumab Magnetic Resona... Nivolumab	18 Years -	National Cancer Institute (NCI)
Testing Ipilimumab and Nivolumab Combination With or Without Cabozantinib in People >= 18 Years Old With Advanced Soft Tissue Sarcoma	NCT05836571	Locally Advance... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Metastatic Undi...	Biopsy Biospecimen Col... Cabozantinib Computed Tomogr... Ipilimumab Magnetic Resona... Nivolumab	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for locally advanced unresectable soft tissue sarcoma