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

Running, not enrolling · Phase 2

Conditions studied: Metastatic Soft-tissue Sarcoma

In brief

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.

Key facts

Study ID

NCT04551430

Run by

Washington University School of Medicine

People needed

105

Starts

2021-01-05

Expected to finish

2029-02-01

Last updated by the study team

2025-11-12

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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)
• PT/INR or PTT < 1.3 x IULN (within 7 days before first dose of study treatment, if not receiving any anticoagulation therapy)
• Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG within 14 days before the first dose of study treatment).
• Lesion amenable to biopsy for assessment of PD-L1 expression if no archival tissue is available
• Recover to baseline or ≤ grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
• The effects of cabozantinib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 5 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and for at least 7 months after the last dose of study treatment.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

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:
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose of study treatment.
• Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with anticoagulation for at least 1 week before first dose of study treatment.
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
• The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose.
• Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose.
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose.
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.

Where it is running

• Stanford University Medical Center — Stanford, California, United States
• University of Colorado — Aurora, Colorado, United States
• Washington University School of Medicine — St Louis, Missouri, United States
• Abramson Cancer Center at Pennsylvania Hospital — Philadelphia, Pennsylvania, United States

Full record on ClinicalTrials.gov

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