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) 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.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
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.
Disqualifiers
For all Dose-Escalation cohorts: Prior treatment with zanzalintinib. For all Expansion Cohorts: Prior treatment with zanzalintinib, nivolumab, ipilimumab or relatlimab with the following exceptions: Prior PD-1/PD-L1, Lymphocyte-activation gene 3 (LAG-3) and cCytotoxic T lymphocyte associated protein 4 (CTLA-4) targeting therapy for locally advanced or metastatic disease is allowed for Cohort 2 (ccRCC), Cohort 5 (UC), Cohort 9 (NSCLC), and Cohort 12 (ccRCC), and prior treatment in the neoadjuvant or adjuvant setting is allowed for Cohort 13 and Cohort 14 (ccRCC 1L).
For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC), Cohort 10 (CRC), and Cohort 12: Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment.
For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), Cohort 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC) and Cohort 10 (CRC), and Cohort 12: Receipt of any type of anticancer antibody or systemic chemotherapy within 4 weeks before first dose of study treatment.
Trial design
Design model
Sequential
Treatments tested in this trial
Zanzalintinib
Drug
Zanzalintinib orally once daily (qd)
Nivolumab
Drug
360 mg IV infusion once every 3 weeks (q3w)
Ipilimumab
Drug
1 mg/kg IV infusion once every 3 weeks (q3w) for maximum of four doses
Nivolumab
Drug
3 mg/kg IV infusion once every 3 weeks (q3w) for first four doses, and then 480 mg IV infusion once every 4 weeks (q4w)
Nivolumab
Drug
480 mg IV infusion once every 4 weeks (q4w)
Nivolumab + Relatlimab
Drug
IV administration of nivolumab + relatlimab
Treatment groups
1,314 Participants
are divided into 7 treatment groups
7
Treatment groups
See each treatment group below.
Group A: Zanzalintinib + Nivolumab Dose-Escalation CohortsExperimental treatment 2 interventions
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs), Including Immune-Mediated Adverse Events (imAEs)
Time frame
Up to 36 months
2
Expansion Stage: Objective Response Rate (ORR)
To evaluate ORR in participants with measurable disease as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors guideline version 1.1 (RECIST 1.1).
To evaluate duration of radiographic PFS as determined per Prostate Working Group 3 (PCWG3) criteria by Blinded Independent Radiology Committee (BIRC).
