Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma

NCT04551430 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 202011041
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 4

Brief Summary

The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to cabozantinib, and that cabozantinib priming will increase the response to nivolumab and ipilimumab.

Conditions

Metastatic Soft-tissue Sarcoma

Outcome Measures

Primary Outcomes (1)

• Radiographic response rate by RECIST 1.1

  * Response rate = proportion of participants who achieve complete response or partial response * Complete response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). * Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

  From start of treatment until disease progression/recurrence or the date of subsequent therapy (estimated to be 24 months)

Secondary Outcomes (6)

• Clinical benefit rate

  Through end of treatment (estimated to be 24 months)

• Progression-free survival

  Up to 3 years from end of treatment

• Overall survival

  Up to 5 years from end of treatment

• Response rate to ipilimumab + nivolumab after cabozantinib priming

  Through end of treatment (estimated to be 24 months)

• Change in quality of life as measured by FACT-G7

  Baseline, day 1 of each cycle (each cycle is 4 weeks), and at time of disease progression (estimated to be up to 5 years)

Study Arms (3)

Cohort A: Cabozantinib

EXPERIMENTAL

Patients randomized to Cohort A will take cabozantinib at a dose of 60 mg by mouth once each day of each 28-day cycle. Treatment may continue indefinitely. At time of progression, patients will continue on cabozantinib daily but will reduce their dose to 40 mg. They will cross over into Cohort B and initiate treatment.

Drug: Cabozantinib

Cohort B: Cabozantinib + Nivolumab + Ipilimumab

EXPERIMENTAL

-Patients randomized to Cohort B will take cabozantinib at a dose of 40 mg by mouth once each day. Nivolumab will given IV at a dose of 3 mg/kg over approximately 30 minutes every 3 weeks for 4 doses, followed by 480 mg over approximately 30 minutes every 4 weeks until treatment discontinuation. Ipilimumab will be given IV at a dose of 1 mg/kg over approximately 30 minutes every 3 weeks for 4 doses. Treatment may continue for up to 2 years.

Drug: Cabozantinib; Drug: Nivolumab; Drug: Ipilimumab

Crossover from Cohort A to Cohort B: Cabozantinib + Nivolumab + Ipilimumab

EXPERIMENTAL

-Participants who cross-over from Cohort A into Cohort B will initiate treatment with nivolumab at a dose of 3 mg/kg IV over approximately 30 minutes and ipilimumab at a dose of 1 mg/kg IV over approximately 30 minutes. Nivolumab and ipilimumab will be given every 3 weeks for 4 doses. Nivolumab will then be continued at a dose of 480 mg IV over approximately 30 minutes every 4 weeks, with cabozantinib to continue at 40 mg every day. Treatment may continue for up to 2 years.

Drug: Cabozantinib; Drug: Nivolumab; Drug: Ipilimumab

Interventions

Cabozantinib DRUG

Cabozantinib will be supplied by Exelixis.

Cohort A: Cabozantinib; Cohort B: Cabozantinib + Nivolumab + Ipilimumab; Crossover from Cohort A to Cohort B: Cabozantinib + Nivolumab + Ipilimumab

Nivolumab DRUG

Nivolumab will be provided free of charge (as investigational supply) by Bristol-Myers Squibb.

Also known as: Opdivo

Cohort B: Cabozantinib + Nivolumab + Ipilimumab; Crossover from Cohort A to Cohort B: Cabozantinib + Nivolumab + Ipilimumab

Ipilimumab DRUG

Ipilimumab will be provided free of charge (as investigational supply) by Bristol-Myers Squibb.

Also known as: Yervoy

Cohort B: Cabozantinib + Nivolumab + Ipilimumab; Crossover from Cohort A to Cohort B: Cabozantinib + Nivolumab + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed soft tissue sarcoma that is metastatic or unresectable.
• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
• Refractory to at least one and no more than two lines of therapy, with progression on last line of therapy. Neoadjuvant or adjuvant therapy completed more than one year prior does not count towards these two lines of therapy. Individuals with alveolar soft part sarcoma may enroll without being refractory to at least one line of chemotherapy. Any inappropriate therapies (ie hormonal therapies) should be discussed with the PI to determine if they are to be counted toward the two lines of therapy.
• At least 18 years of age.
• ECOG performance status ≤ 1
• Normal bone marrow and organ function as defined below:
• Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating factor support
• White blood cell count ≥ 2,000/mm3
• Platelets ≥ 100,000/mm3 without transfusion
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, ≤ 3.0 x IULN)
• AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x IULN with documented bone metastases
• Serum albumin ≥ 2.8 g/dl.
• Serum creatinine ≤ 1.5x IULN or calculated creatinine clearance ≥ 40 mL/min by MDRD
• Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)

You may not qualify if:

• Translocation-driven sarcoma except for ASPS
• Previous treatment with cabozantinib or a PD-1 inhibitor (eg, cemiplimab, nivolumab, pembrolizumab), PD-L1 inhibitor (eg, atezolizumab, avelumab, durvalumab), or CTLA-4 inhibitor (eg, ipilimumab).
• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Exceptions include basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix, or other tumors discussed with the study PI.
• Currently receiving any other investigational agents.
• Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab, or other agents used in the study.
• Inability to swallow tablets.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Exelixis: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (4)

Stanford University Medical Center

Stanford, California, 94305, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Abramson Cancer Center at Pennsylvania Hospital

Philadelphia, Pennsylvania, 19106, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Sarcoma

Interventions

cabozantinib; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Mia Weiss, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2020
• First Posted: September 16, 2020
• Study Start: January 5, 2021
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2029
• Last Updated: November 12, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)