Zanzalintinib + Immunotherapy for Liver Cancer

(ZENOBIA Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Anwaar Saeed

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Anwaar Saeed

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

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

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

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).

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}

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.

I am 18 or older and can care for myself with minimal assistance.

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.

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.

Trial 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 (Checkpoint Inhibitor)
• Tremelimumab (Checkpoint Inhibitor)
• Zanzalintinib (Other)

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 Japan for the following indications:

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

UPMC Hillman Cancer Center Pittsburgh, PA

Who Is Running the Clinical Trial?

Anwaar Saeed

Lead Sponsor

Trials

5

Patients Recruited

240+

Exelixis

Industry Sponsor

Trials

126

Patients Recruited

20,500+

Findings from Research

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]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

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]

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]

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]

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]

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]