Zanzalintinib + Immunotherapy for Liver Cancer

(ZENOBIA Trial)

Overseen By Debra Diecks

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Anwaar Saeed

Must not be taking: Anticoagulants, Platelet inhibitors, Herbal supplements, Immunosuppressants

Disqualifiers: Brain metastases, Uncontrolled hypertension, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does require stopping certain treatments like oral anticoagulants and complementary medications at least 2 weeks before starting the study. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Zanzalintinib, Durvalumab, and Tremelimumab for liver cancer?

The combination of durvalumab and tremelimumab has shown clinical benefits and a tolerable safety profile in patients with solid tumors, including liver cancer. Additionally, tremelimumab combined with durvalumab has been approved for treating unresectable hepatocellular carcinoma, indicating its effectiveness in liver cancer. ^{1 2 3 4 5}

Is the combination of Zanzalintinib, Durvalumab, and Tremelimumab safe for humans?

The combination of Durvalumab and Tremelimumab has been shown to have a tolerable safety profile in patients with solid tumors, including liver cancer. Common side effects include rash, fatigue, diarrhea, itching, muscle pain, and abdominal pain. Serious side effects occurred in about 32.6% of patients, which is higher than when using Durvalumab alone. ^{2 3 4 6 7}

What makes the drug combination of Zanzalintinib, Durvalumab, and Tremelimumab unique for liver cancer?

This drug combination is unique because it combines Zanzalintinib, a novel agent, with Durvalumab and Tremelimumab, which are immune checkpoint inhibitors that help the immune system attack cancer cells. This approach is different from standard treatments as it targets the cancer in multiple ways, potentially improving effectiveness for patients with advanced liver cancer. ^{1 2 3 5 8}

What is the purpose of this trial?

This study will investigate if modulating the tumor microenvironment with biologic agents like XL-092 will have synergistic effect when combined with checkpoint based immunotherapeutic treatment of patients with hepatocellular carcinoma (HCC).

Research Team

Anwaar Saeed

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

This trial is for individuals with unresectable hepatocellular carcinoma (HCC), which is a type of liver cancer that cannot be removed by surgery. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have no conflicting conditions.

Inclusion Criteria

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.

Urine protein-to-creatinine ratio (UPCR) must be ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine. Tumor tissue fresh biopsies are REQUIRED for ALL study participants at screening/baseline unless an archival tumor tissue block is available and fulfills the criteria.

I am using effective birth control methods if I'm sexually active.

Exclusion Criteria

I have had major surgery recently.

History of psychiatric illness likely to interfere with study compliance.

I have a history of lung conditions or currently have lung inflammation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Safety lead-in to define the Recommended Phase 2 Dose (RP2D) with dose escalation or de-escalation

12 weeks

Multiple visits for dose adjustments and monitoring

Treatment

Participants receive Zanzalintinib (XL-092) in combination with Durvalumab and Tremelimumab

Up to 24 months

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Durvalumab
• Tremelimumab
• Zanzalintinib

Trial Overview The study tests the combination of Zanzalintinib (XL-092) with two immunotherapy drugs, Durvalumab and Tremelimumab, to see if they work better together in treating liver cancer by modifying the tumor environment.

Participant Groups

Group I: Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) Experimental Treatment 3 Interventions

Safety Lead-in: XL-092: Dose escalation or de-escalation - Level 1 = 100 mg; Level 0 = 60 mg; Level -1 = 40 mg. The first dose level (dose level 0) will follow the rolling 6 design. Starting with cycle 1 then cycle 3 and subsequent cycles, participants will receive XL-092 60 mg orally (PO) once daily on days 1 through 28 of every 28-day cycle. Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 2; Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 2 day 1

Group II: Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (First Cyle Durvalumab + Tremelimumab) Active Control 3 Interventions

Phase 2: XL092 dose as determined by results of safety lead-in phase orally (PO). Once daily on days 1 - 28 of every 28-day cycle. Dosing will start with cycle 2. Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 1. Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 1 day 1

Group III: Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (First Cyle Zanzalintinib) Active Control 3 Interventions

Phase 2: XL092 dose as determined by results of safety lead-in phase orally (PO). Once daily on days 1 - 28 of every 28-day cycle. Dosing will start with cycle 1 then cycle 3 and subsequent cycles. Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 2; Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 2 day 1

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Anwaar Saeed

Lead Sponsor

Trials

5

Recruited

240+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among patients with unresectable hepatocellular carcinoma, indicating its potential as an effective treatment option.

All treatment regimens were generally well-tolerated, but T300 + D had the most favorable safety profile, with a significant association between early CD8+ lymphocyte expansion and treatment response, suggesting a promising mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Kelley, RK., Sangro, B., Harris, W., et al.[2022]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

The DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

In the safety run-in of the IMMUNOBIL PRODIGE 57 trial involving 20 patients, the combination of durvalumab and tremelimumab with paclitaxel resulted in a high rate of dose-limiting toxicities (50%), including serious anaphylactic reactions and other severe adverse events.

Due to the safety concerns raised by the combination therapy, the trial will proceed with only the durvalumab and tremelimumab combination, indicating that the addition of paclitaxel may not be safe for patients with advanced biliary tract carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Boilève, A., Hilmi, M., Gougis, P., et al.[2021]

The FDA approved tremelimumab in combination with durvalumab for treating unresectable hepatocellular carcinoma based on the HIMALAYA study, which showed a significant improvement in overall survival (OS) compared to sorafenib, with a median OS of 16.4 months versus 13.8 months.

Common adverse reactions in patients receiving the combination treatment included rash, fatigue, diarrhea, and abdominal pain, occurring in 20% or more of patients, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. Patel, TH., Brewer, JR., Fan, J., et al.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

This phase Ib clinical trial is investigating the safety and efficacy of durvalumab, both alone and in combination with tremelimumab, alongside particle therapy for patients with advanced hepatocellular carcinoma (HCC) and macrovascular invasion, with a focus on monitoring adverse events and overall survival.

The trial will proceed to cohort B only if cohort A shows tolerable treatment outcomes, indicating a careful approach to ensure patient safety while exploring potentially synergistic effects of the therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial. Ogasawara, S., Koroki, K., Makishima, H., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial. [2022]