Zanzalintinib for Metastatic Clear Cell Renal Cell Carcinoma With Bone Metastases

NCT07043608 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 25521NCI-2025-04328
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-institution, phase 2 trial of zanzalintinib plus investigator-choice bone-strengthening agent in patients with metastatic renal cell carcinoma (RCC) with bone metastases whose disease has advanced on 1-3 prior lines of therapy, including at least one immune oncology-based (IO) therapy in the adjuvant or first-line metastatic setting.

Conditions

Clear Cell Renal Cell Cancer (ccRCC); Clear Cell Renal Carcinoma; Clear Cell Renal Cell Carcinoma Metastatic; Clear Cell Renal Cancer; Bone Metastases of a Malignant Tumor; Clear Cell Renal Cell Carcinoma; Bone, Metastatic Cancer; Metastatic Cancer; Metastatic Renal Cell Carcinoma; Metastases to Bone

Outcome Measures

Primary Outcomes (1)

• Proportion of participants who have not progressed at 12 months (PFS12)

  The proportion of participants who have not demonstrated radiographic progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or demonstrated clinical progression-free survival (PFS) at 12 months after the start of study treatment. Twelve-month landmark PFS rate will be obtained with 95% confidence interval using the Kaplan-Meier method.

  Up to 12 months

Secondary Outcomes (7)

• Percentage of participants with Skeletal Related Events (SRE)

  Up to 24 months

• Percentage of participants with osteonecrosis of the jaw (ONJ)

  Up to 24 months

• Percentage of participants with reported treatment-related, systemic, adverse events

  Up to 24 months

• Median PFS

  Up to 24 months

• Median Overall Survival (OS)

  Up to 24 months

Study Arms (1)

Treatment (Zanzalintinib)

EXPERIMENTAL

Participants will receive 100 mg Zanzalintinib administered orally once a day in 28-day cycles, starting on cycle 1, day 1, and continued until criteria for removal from study are met. Investigator-choice bone-strengthening agent (BSA) will be selected and administered at a standard dose/interval starting within 30 days of cycle 1, day 1. Non-investigational RT for symptomatic metastases, including bone metastases, is allowed per investigator discretion. Participants must receive at least 1 dose of zanzalintinib prior to treatment pause for RT. Participants may continue study treatment until they are unable to tolerate treatment due to toxicity or demonstrate progression (per RECIST) from the time of initiating treatment.

Drug: Zanzalintinib; Drug: Investigator Choice of Bone Strengthening Agents (BSA); Radiation: Non-Investigational Radiation Therapy (RT); Procedure: Bone Scan; Procedure: Computerized tomography (CT) Scan

Interventions

Zanzalintinib DRUG

Given orally (PO)

Also known as: XL092

Treatment (Zanzalintinib)

Investigator Choice of Bone Strengthening Agents (BSA) DRUG

One BSA will be chosen, at the discretion of the investigator and given intravenously (IV)

Also known as: Bisphosphonate, Receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, Zoledronic acid, Ibandronate, Denosumab

Treatment (Zanzalintinib)

Non-Investigational Radiation Therapy (RT) RADIATION

Non-investigational RT is permitted for symptomatic bone metastases.

Also known as: Standard-of-Care Radiation Therapy, Radiation Therapy, Non-Investigational RT

Treatment (Zanzalintinib)

Bone Scan PROCEDURE

Undergo Bone Scan

Treatment (Zanzalintinib)

Computerized tomography (CT) Scan PROCEDURE

Undergo Imaging

Treatment (Zanzalintinib)

Eligibility Criteria

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

You may qualify if:

• Participants must have unresectable advanced or metastatic RCC with a predominant clear cell histologic component .
• At least three bone metastases are present and detectable on bone scan, and at least one bone metastasis is NOT planned to be treated with radiation therapy.
• Previously treated with 1-3 prior lines of therapy in at least one of the following settings:
• Metastatic setting; must have received combination therapy containing either programmed cell death protein 1 (PD-1) inhibitor/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor or PD-1 inhibitor/vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKI).
• Adjuvant setting; must have received pembrolizumab and have had documented progression of disease within 1 year of the first dose of pembrolizumab .
• Age ≥18 years.
• Has seen a dentist within 90 days prior to enrollment and been cleared to receive bone-strengthening agents.
• Availability of a representative formalin fixed, paraffin embedded tumor specimen or fresh frozen tissue specimen that enables the definitive diagnosis of RCC, accompanied by an associated pathology report. If stored specimens are not available, an optional biopsy may be performed and specimens can be collected by surgical resection or biopsy of the primary tumor or biopsy or resection of a metastatic lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Demonstrates adequate organ function as defined below within 14 days prior to first study treatment:
• Absolute neutrophil count (ANC) \>=1,500/ μL (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1).
• Platelets ≥100,000/ μL (without transfusion within 2 weeks prior to Cycle 1, Day 1).
• White Blood Cell count (WBC) counts ≥ 2500/μL.
• Lymphocyte count ≥ 500/μL.
• Hemoglobin ≥9.0 g/dL.

You may not qualify if:

• Prior treatment with zanzalintinib for RCC.
• Receipt of any small molecule kinase inhibitor (including investigational) or vascular endothelial growth factor (VEGF)-targeted therapy within 2 weeks before the first dose of study treatment.
• 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.
• Participants requiring whole brain radiotherapy (WBRT).
• Incomplete healing from prior radiotherapy as determined by the treating radiation oncologist or treating investigator.
• Participation in an experimental drug study within 28 days of study enrollment.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Pregnant and lactating women are excluded from this study because zanzalintinib is an investigational product with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with zanzalintinib, breastfeeding should be discontinued if the mother is treated with zanzalintinib.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation); Clinically significant hematuria, hematemesis, or hemoptysis of \>0.5 tsp (2.5ml) of red blood or other history of significant bleeding within 12 weeks before first dose of study treatment.
• Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding.
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
• Concomitant anticoagulation with coumarin agents, direct thrombin inhibitors, factor Xa inhibitor betrixaban, or platelet inhibitors. Other anticoagulants are allowed.
• 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.

Sponsors & Collaborators

• Kelly Fitzgerald, MD: lead
• Exelixis: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell; Clear-cell metastatic renal cell carcinoma; Neoplasm Metastasis

Interventions

Diphosphonates; Zoledronic Acid; Ibandronic Acid; Denosumab; Radiotherapy

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Therapeutics

Study Officials

• Kelly Fitzgerald, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

UCSF Genitourinary Oncology Clinical Trials Recruitment

CONTACT

877-827-3222; GUTrials@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Clinical Professor

Study Record Dates

• First Submitted: June 20, 2025
• First Posted: June 29, 2025
• Study Start (Estimated): May 30, 2026
• Primary Completion (Estimated): February 28, 2029
• Study Completion (Estimated): February 28, 2030
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: During the course of the study

Locations

US (1)