Study of Zanzalintinib in Combination With Immuno-Oncology or Other Agents in Participants With Solid Tumors

About This Trial

This early-phase study is testing an experimental drug called zanzalintinib, given on its own or combined with other cancer treatments like immunotherapy or chemotherapy, to evaluate its safety and effectiveness.
The trial is open to men with advanced prostate cancer that has spread and worsened after treatment with standard hormone therapies.
To be eligible, patients must not have received prior chemotherapy for their metastatic prostate cancer.
Because this is an early safety trial, participants will be closely monitored for side effects and will need to pause certain medications for a short period before starting treatment.

More Information

This is a multicenter Phase 1b, open label, dose-escalation and cohort-expansion study, evaluating the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity, and effect of biomarkers of zanzalintinib administered alone, and in combination with nivolumab (doublet), nivolumab + ipilimumab (triplet) and nivolumab + relatlimab (triplet) and in combination with docetaxel and prednisone in participants with advanced solid tumors.
In addition, the study will evaluate the effect of multiple dose administration of zanzalintinib on the single-dose pharmacokinetics of sensitive CYP3A4, CYP2C9, CYP2C19, or CYP1A2 substrates in participants with advanced solid tumors.
In the Expansion Stage, the safety and efficacy of zanzalintinib as monotherapy and in combination therapy will be further evaluated in tumor-specific Expansion Cohorts.

Who Can Enroll

Age Range: 18 years and older
Gender: All
Who This Trial is For: This early-phase study is testing an experimental drug called zanzalintinib, given on its own or combined with other cancer treatments like immunotherapy or chemotherapy, to evaluate its safety and effectiveness.

Study Details

Start Date: December 14, 2021
Lead Sponsor: Exelixis

Full Eligibility Criteria

Inclusion Criteria

Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic.
Dose-Escalation Cohorts: Participants with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.
Expansion Cohort 1 (ccRCC): Participants with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy.
- Note: Prior non-vascular endothelial growth factor (VEGF) targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.
Expansion Cohort 2 (ccRCC): Participants with unresectable advanced or metastatic RCC with a clear cell component.
- Must have radiographically progressed after a combination therapy consisting of a Programmed Cell Death Protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) targeting monoclonal antibody (mAb) with a Vascular endothelial growth factor (receptor) tyrosine kinase inhibitor (VEGFR-TKI) or a PD-1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy.
- Must have received no more than one prior systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma.
Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate.
- Must have progressed during or after one novel hormone therapy (NHT) given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.
Expansion Cohort 4 (UC, ICI-naive): Participants with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
- Must have progressed during or after prior first-line platinum-based combination therapy, including participants who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence 460 ms for females and > 450 ms for males per electrocardiogram (ECG) within 14 days before first dose of study treatment.
Participants with inadequately treated adrenal insufficiency.
Pregnant or lactating females.
Any other active malignancy within two years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.
For Cohort 2 (ccRCC, 2L): Receipt of a prior triplet therapy including a VEGFR-TKI, a PD1 targeting mAb, and a CTLA-4 mAb.
For Cohort 3 (mCRPC): Receipt of a taxane-based chemotherapy for mCRPC.
For Cohort 4 (UC, ICI-naïve): Participants who have had recurrence within the 6 months of completing adjuvant anti-PD-(L)1 treatment.
For Cohort 6 (nccRCC, 1L): Participants with chromophobe, renal medullary carcinoma, or pure collecting duct nccRCC.
For Cohort 7 (HCC):
- Documented hepatic encephalopathy (HE) within 6 months before the first dose.
- Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) within 6 months before randomization.
- Participants who have received any local anticancer therapy including surgery, percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) within 28 days prior to first dose.
- Participants with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma
For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/or trifluridine + tipiracil (TAS-102).
For Cohort 11 (HNSCC): Primary tumor site of the nasopharyngeal area.
For Cohorts 1 (ccRCC, 1L), 2 (ccRCC, 2L), 4, 5 (UC), 7 (HCC), 8 (NSCLC 1L PD-L1 low), 9 (NSCLC, 2L+), 10 (CRC, microsatellite stable [MSS], 2L+), and 11 (HNSCC):
- Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN).
For Cohort 16 (DDI):
- Known hypersensitivity to midazolam, warfarin, omeprazole, or caffeine.
- History of major head trauma (with loss of consciousness) within the past year or minor head trauma (without loss of consciousness) within 3 months prior to first dose of study treatment on Day 1.
- Primary liver tumor.
- Unable to refrain from or anticipates the use of the following:
  - Any drugs known to be inducers or inhibitors of CYP3A4, CYP2C9, CYP2C19, and/or CYP1A2 within 14 days before the first dose of study treatment on Day 1 through the DDI assessments on Day 20.
  - Drugs that are contraindicated with midazolam, warfarin, omeprazole, and/or caffeine during the DDI assessment part.
  - Caffeine-containing beverages, products, and foods at least 3 days prior to and 3 days after probe substrate cocktail administration on Day 1 and Day 16.
    - Poor peripheral venous access. Note: Additional Inclusion and Exclusion criteria may apply.