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) and nivolumab + ipilimumab (triplet) and nivolumab + relatlimab fixed-dose combination (FDC) (triplet) in subjects with advanced solid tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exelixis Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Jan 2023 → ongoing

Decision date (initial)

2024-04-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Exelixis, Inc.

External identifiers

EU CT number

2023-510061-10-00

EudraCT number

2021-004855-18

ClinicalTrials.gov

NCT05176483

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Dose response, Safety, Efficacy, Pharmacokinetic, Pharmacogenomic, Others

The objectives of the Dose-Escalation Stage are to determine the recommended dose (RD) and evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of zanzalintinib in combination with the immuno-oncology agents nivolumab (doublet), nivolumab + ipilimumab (triplet), and nivolumab + relatlimab FDC (triplet) in participants with advanced cancers.

The objectives of the Expansion Stage are to assess the preliminary efficacy of zanzalintinib alone and in combination therapy regimens in tumor specific cohorts, determine the safety of the combination therapy regimens, isolate the contribution of treatment components, and further evaluate the plasma pharmacokinetics of daily oral XL092 administered as a single agent or in combination therapy in participants with advanced solid tumors.

Conditions and MedDRA coding

Clear cell renal cell carcinoma (ccRCC, first-, second- and third-line) - metastatic castration-resistant prostate cancer (mCRPC, second-line post NHT) - urothelial carcinoma (UC) ICI naïve and ICI-experienced - non-clear cell renal (nccRCC, first-line) cell carcinoma - Colorectal cancer (CRC) - Hepatocellular cancer (HCC) - Non-small cell lung caner (NSCLC) - Head and Neck Squamous Cell Carcinoma (HNSCC)

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic: Dose-Escalation Stage: a. 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 Stage: The tumor cohorts are: Cohort 1: ccRCC (1L); Cohort 2: ccRCC (2L); Cohort 3: mCRPC (post 1 NHT); Cohort 4: UC ICI-naïve; Cohort 5: UC (post EV and ICI); Cohort 6: nccRCC (1L); Cohort 7: HCC (1L); Cohort 8: NSCLC (PD-L1 low TPS 149%, 1L); Cohort 9: NSCLC (2L+; Cohort 10: CRC (MSS, 2L or 3L and beyond); Cohort 11: HNSCC (ICI-naïve); Cohort 12: ccRCC (2-3L); Cohort 13 and Cohort 14: ccRCC (1L) - please refer to protocol for additional details on inclusion criteria for specific Cohorts.
2. 2. For all expansion cohorts except Cohort 3 measurable disease per RECIST 1.1 (Eisenhauer et al 2009) as determined by the Investigator with exception of mCRPC.
3. 3. For expansion cohorts 1-11 only: archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained.
4. 4. Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
5. 5. Age 18 years or older on the day of consent.
6. 6. Karnofsky Performance Status (KPS) ≥ 70%.
7. 7. Adequate organ and marrow function.
8. 8. Capable of understanding and complying with the protocol requirements and must have signed the ICF.
9. 9. Sexually active fertile participants and their partners must agree to use highly effective methods of contraception during the course of the study and for the following durations after the last dose of treatment (whichever is later).
10. 10. Female participants of childbearing potential must not be pregnant at screening.

Exclusion criteria 19

1. 1. For all Dose-Escalation Cohorts: Prior treatment with zanzalintinib. For all Expansion Cohorts: Prior treatment with zanzalintinib, nivolumab, ipilimumab, or relatlimab with some exceptions.
2. 2. For Dose-Escalation Cohorts and Cohort 2 (ccRCC 2L), Cohort 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC, 2L+), Cohort 10 (CRC, 2L or 3L or beyond) and Cohort 12 (ccRCC 2-3L): Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
3. 3. 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.
4. 4. For all Dose-Escalation Cohorts and Cohort 2 (ccRCC 2L), Cohort 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC (2L+), Cohort 10 (CRC, 2L or 3L and beyond), and Cohort 12 (ccRCC 2-3L): Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before first dose of study treatment.
5. 5. Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.
6. 6. Prior radiation therapy for bone metastasis within 2 weeks, for other tumor sites within 4 weeks, and prior radium-223 therapy within 6 weeks before first dose of study treatment unless otherwise specified.
7. 7. 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.
8. 8. Concomitant anticoagulation with oral anticoagulants with some exceptions (refer to protocol)
9. 9. Administration of a live, attenuated vaccine 30 days prior to first dose.
10. 10. Uncontrolled, significant intercurrent or recent illness.
11. 11. Major surgery within 8 weeks prior to first dose. Prior laparoscopic nephrectomy within 4 weeks prior to first dose. Minor surgery (eg, simple excision, tooth extraction) within 10 days before first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to first dose.
12. 12. Corrected QT interval calculated by the Fridericia formula (QTcF) 460 ms for females and > 450 ms for male per electrocardiogram (ECG) within 14 days before first dose of study treatment. Furthermore, participants must not have family history of sudden cardiac death before age 50, heart disease, history of arrhythmia, bradycardia defined as < 50 beats per minute, or acute neurologic events within 6 months prior to inclusion.
13. 13. Participants with inadequately treated adrenal insufficiency.
14. 14. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent
15. 15. Pregnant or lactating females.
16. 16. Inability to swallow tablets or ingest a suspension either orally or by a nasogastric or gastrostomy tube.
17. 17. Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions (IRRs) to monoclonal antibodies.
18. 18. 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.
19. 19. Other conditions, which in the opinion of the investigator or Sponsor, would compromise the safety of the subject’s ability to complete the study. Please refer to the protocol for detailed cohort specific exclusion criteria.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Dose-Escalation Stage (Zanzalintinib Combination Therapy): -Incidence and severity of AEs and serious adverse events (SAEs), including immune-mediated adverse events (imAEs)
2. Expansion Stage ( Zanzalintinib Monotherapy and Combination Therapy): -Objective Response Rate (ORR) in participants with measurable disease as assessed by the Investigator per RECIST 1.1
3. -For Cohort 3 (mCRPC): duration of radiographic PFS as determined per Prostate Working Group 3 (PCWG3) criteria (Scher et al 2016) by Blinded Independent Radiology Committee (BIRC)
4. - For Cohort 10 (CRC): Overall survival (OS) rate at 6 months.
5. - Incidence and severity of nonserious AEs and SAEs, including imAEs

Secondary endpoints 8

1. Expansion Stage (Zanzalintinib Monotherapy and Combination Therapy): • DOR based on assessment by the Investigator per RECIST 1.1
2. • PFS for subjects with measurable disease as assessed by the Investigator per RECIST 1.1
3. • For Cohort 3 (mCRPC): o Proportion of subjects achieving a > 50% decrease in prostate-specific antigen (PSA) from baseline confirmed by a second consecutive PSA assessment at least 3 weeks later o Change in bone biomarkers - Duration of radiographic PFS as determined by Investigator per PCWG3 criteria (Scher et al 2016)
4. • ORR, DOR, and PFS for subjects with measurable disease as assessed by a BIRC per RECIST 1.1 for selected cohorts as determined by the Sponsor
5. • Overall survival (OS)
6. • Concentration of study treatments (zanzalintinib, nivolumab, ipilimumab and relatlimab) in plasma or serum at different timepoints
7. • Change in tumor and blood biomarkers
8. • The number and percentage of subjects who develop ADA response to nivolumab, ipilimumab or relatlimab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exelixis Inc.

Sponsor organisation

Exelixis Inc.

Address

1851 Harbor Bay Parkway

City

Alameda

Postcode

94502-3010

Country

United States

Scientific contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Information

Public contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Information

Third parties 11

Locations

7 EU/EEA countries · 52 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 112 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications