Zanzalintinib in Combination With Ipilimumab and Nivolumab in Patients With Metastatic Soft Tissue Sarcoma

NCT06968988 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 202507090
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that zanzalintinib in combination with ipilimumab and nivolumab will be well tolerated and serve as a potential therapeutic strategy in metastatic soft tissue sarcoma (mSTS) including myxofibrosarcoma, undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, cutaneous angiosarcoma, and undifferentiated sarcoma histologies.

Conditions

Metastatic Soft-tissue Sarcoma

Keywords

Soft Tissue Sarcoma; Zanzalintinib; Immunotherapy; Nivolumab; Ipilimumab

Outcome Measures

Primary Outcomes (1)

• Occurrence of dose-limiting toxicities (DLTs)

  DLTs are defined in the protocol.

  Through day 42

Secondary Outcomes (5)

• Frequency and grades of treatment-emergent adverse events (TEAEs)

  From start of treatment through 100 days after completion of treatment (estimated to be 24 months and 100 days)

• Rate of treatment discontinuation due to treatment-emergent adverse events (TEAEs)

  From start of treatment through completion of treatment (estimated to be 24 months)

• Objective response rate (ORR) per RECIST 1.1 criteria

  Through completion of treatment (estimated to be 24 months)

• Clinical benefit rate (CBR) per RECIST 1.1 criteria

  Through completion of treatment (estimated to be 24 months)

• Duration of response (DoR)

  Through completion of follow-up (estimated to be 60 months)

Study Arms (4)

Dose Escalation Dose Level 1 (starting dose): Zanzalintinib + Nivolumab + Ipilimumab

EXPERIMENTAL

Zanzalintinib 40 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib.

Drug: Zanzalintinib; Drug: Ipilimumab; Drug: Nivolumab

Dose Escalation Dose Level 2: Zanzalintinib + Nivolumab + Ipilimumab

EXPERIMENTAL

Zanzalintinib 60 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib.

Drug: Zanzalintinib; Drug: Ipilimumab; Drug: Nivolumab

Dose Escalation Dose Level -1: Zanzalintinib + Nivolumab + Ipilimumab

EXPERIMENTAL

Zanzalintinib 20 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib.

Drug: Zanzalintinib; Drug: Ipilimumab; Drug: Nivolumab

Expansion: Zanzalintinib + Nivolumab + Ipilimumab

EXPERIMENTAL

Zanzalintinib dose determined in Dose Escalation by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib.

Drug: Zanzalintinib; Drug: Ipilimumab; Drug: Nivolumab

Interventions

Zanzalintinib DRUG

Zanzalintinib will be supplied by Exelixis, Inc.

Also known as: XL092

Dose Escalation Dose Level -1: Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 1 (starting dose): Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 2: Zanzalintinib + Nivolumab + Ipilimumab; Expansion: Zanzalintinib + Nivolumab + Ipilimumab

Ipilimumab DRUG

Ipilimumab will be commercially sourced.

Also known as: Yervoy

Dose Escalation Dose Level -1: Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 1 (starting dose): Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 2: Zanzalintinib + Nivolumab + Ipilimumab; Expansion: Zanzalintinib + Nivolumab + Ipilimumab

Nivolumab DRUG

Nivolumab will be commercially sourced.

Also known as: Opdivo

Dose Escalation Dose Level -1: Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 1 (starting dose): Zanzalintinib + Nivolumab + Ipilimumab; Dose Escalation Dose Level 2: Zanzalintinib + Nivolumab + Ipilimumab; Expansion: Zanzalintinib + 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.
• Must have received at least one but no more than 3 lines of therapy in the metastatic setting, with progression on last line of therapy. Neoadjuvant or adjuvant therapy completed more than one year prior does not count towards as a line of therapy in the metastatic. Individuals with alveolar soft part sarcoma may enroll without being refractory to at least one line of therapy.
• Measurable disease per RECIST 1.1.
• At least 18 years of age.
• ECOG performance status ≤ 1.
• Adequate bone marrow and organ function as defined below:
• Absolute neutrophil count (ANC) ≥ 1.5 K/cumm without granulocyte colony-stimulating factor support within 2 weeks prior to screening laboratory collection
• Platelets ≥ 100 K/cumm without transfusion within 2 weeks prior to screening laboratory collection
• Hemoglobin ≥ 9.0 g/dL without transfusion within 2 weeks prior to screening laboratory collection
• INR ≤ 1.5 and aPTT ≤ 1.2 x IULN. For subjects on Factor Xa inhibitors, criteria does not apply.
• Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3 x IULN)
• AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN. For subjects with documented bone metastasis, ALP ≤ 5.0 x IULN.
• Serum albumin ≥ 2.8 g/dL.
• Calculated creatinine clearance ≥ 40 mL/min by Cockcroft-Gault.
• UPCR ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine.

You may not qualify if:

• Translocation-driven sarcoma except for ASPS.
• Prior treatment with zanzalintinib, cabozantinib, PD-1 inhibitor (eg, cemiplimab, nivolumab, pembrolizumab), PD-L1 inhibitor (eg, atezolizumab, avelumab, durvalumab), or CTLA-4 inhibitor (eg, ipilimumab).
• 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.
• Radiation therapy for bone metastasis within 2 weeks before first dose of study treatment; any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to zanzalintinib, ipilimumab, nivolumab, or other agents used in the study.
• Concomitant anticoagulation with warfarin or other vitamin-K antagonists, direct thrombin inhibitors, or antiplatelet agents (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. Note: subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.
• Any complementary medications (e.g. herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.
• Uncontrolled, significant intercurrent or recent illness including, but not limited to:
• Unstable or deteriorating cardiovascular disorders:
• Congestive heart failure NYHA Class 3 or 4, or Class 2 or higher unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g. ventricular flutter, ventricular fibrillation, Torsades de pointes).
• Uncontrolled hypertension defined as sustained blood pressure \> 140 mmHg systolic or \> 90 mmHg diastolic despite optimal antihypertensive treatment.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Exelixis: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Related Links

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

MeSH Terms

Conditions

Sarcoma

Interventions

Ipilimumab; Nivolumab

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

Central Study Contacts

Mia Weiss, M.D.

CONTACT

314-747-3096; m.c.weiss@wustl.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2025
• First Posted: May 13, 2025
• Study Start: January 5, 2026
• Primary Completion (Estimated): August 12, 2026
• Study Completion (Estimated): July 31, 2031
• Last Updated: January 8, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be accessible beginning 6 months and ending 36 months following publication of the article
• Access Criteria: Access will be granted to researchers who provide a methodologically sound proposal that aligns with the aims outlined in the approved proposal. The data will be shared specifically for analyses that achieve these aims. Researchers interested in accessing the data should submit a proposal to bvantine@wustl.edu. Following approval of the proposal and completion of a data access agreement, the requested data will be provided.

Locations

US (1)