Zanzalintinib + Immunotherapy for Liver Cancer

(ZENOBIA Trial)

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new combination treatment for individuals with liver cancer that cannot be surgically removed. It combines the drug Zanzalintinib with two immunotherapy drugs, Durvalumab and Tremelimumab, to determine if they work better together against cancer. The trial tests different methods of administering these drugs to find the most effective approach. Suitable candidates for this trial are those with inoperable liver cancer who have not yet undergone other systemic treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is exploring the use of a combination of three drugs—Zanzalintinib, Durvalumab, and Tremelimumab—to treat liver cancer. Past patients have generally tolerated this combination well. Durvalumab and Tremelimumab have already received approval for treating unresectable hepatocellular carcinoma (HCC), indicating they have passed safety checks for that condition.

The current trial is in the early stages of testing Zanzalintinib with these two immunotherapy drugs. While specific safety information about Zanzalintinib in this combination is still being collected, the trial's phase two status suggests that initial safety results have been positive. Treatments typically reach this stage only if they have shown acceptable safety in earlier tests. It is important to note that side effects can occur, and these are being closely monitored in the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Zanzalintinib combined with durvalumab and tremelimumab for liver cancer because this combo brings a fresh approach to treatment. Unlike traditional therapies mainly relying on surgery, chemotherapy, or other single-agent immunotherapies, Zanzalintinib works by targeting specific pathways in cancer cells, potentially blocking their growth. Additionally, the combination with durvalumab and tremelimumab—both immunotherapy drugs—could amplify the immune system's response against cancer cells, offering a more comprehensive attack on the disease. This multi-pronged strategy might lead to better outcomes for patients who haven't responded well to standard treatments.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research shows that using durvalumab and tremelimumab together yields promising results for liver cancer patients. Previous studies found that this combination led to an average survival time of 18.7 months, with about 24% of patients experiencing tumor shrinkage or disappearance. This means nearly one in four patients saw positive changes in their tumors. In this trial, participants will receive a combination of durvalumab, tremelimumab, and zanzalintinib. Adding zanzalintinib is expected to enhance these effects by altering the tumor environment to make it more responsive to treatment. Early evidence suggests this could improve outcomes for people with advanced liver cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Anwaar Saeed

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

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

History of psychiatric illness likely to interfere with study compliance.

I have had major surgery recently.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Safety Lead-in: XL-092: The first dose level (dose level 0) will follow the rolling 6 design\*. The participants enrolled in this study part will receive one cycle of XL-092 60 mg orally (PO) daily plus durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. In cycle 2 and subsequent cycles, participants will receive XL-092 60 mg orally (PO) daily and durvalumab 1500mg IV every 28-day cycles. DLT period will be 28 days. One level dose reduction will be pursued based DLT read of the dose level 0 participants. For dose level -1, XL-092 will be used at 40mg daily dosing, in combo with the same flat dosings for Durvalumab and Tremelimumab. Safety lead in will be 6-12 patients.

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

Phase 2: One cycle of XL-092 RP2D PO daily + durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. XL- 092 RP2D daily and durvalumab will then be continued every 28 days cycles until discontinuation due to disease progression, intolerability, or withdrawal of consent.

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

Phase 2: One cycle of durvalumab 1500 mg IV + tremelimumab 300 mg IV once followed by XL-092 RP2D mg PO Daily + durvalumab 1500 mg IV every 28 days until discontinuation due to disease progression, intolerability, or withdrawal of consent.

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

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS4216

Phase II trial of zanzalintinib (XL-092) in combination with ... Safety and efficacy of durvalumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from the phase 2 study 22 (NCT02519348).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06698250

Study Details | NCT06698250 | Zanzalintinib (XL-092) Plus ... This study will investigate if modulating the tumor microenvironment with biologic agents like XL-092 will have synergistic effect when combined with checkpoint ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT07226063?locStr=United+States&country=United+States

Maintenance Zanzalintinib and Durvalumab in Participants ... The purpose of this study is to find out if taking zanzalintinib with durvalumab will improve how long people with advanced liver cancer will live. Detailed ...

4. withpower.com withpower.com/trial/phase-2-carcinoma-11-2024-1abcd

Zanzalintinib + Immunotherapy for Liver Cancer The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among ...

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/imfinzi-plus-imjudo-demonstrated-unprecedented-overall-survival-alc-with-one-in-five-patients-surviving-five-years-himalaya-phase-iii-trial.html

IMFINZI® (durvalumab) plus IMJUDO® (tremelimumab-actl ... AstraZeneca's IMFINZI (durvalumab) plus IMJUDO (tremelimumab-actl) demonstrated a sustained, clinically meaningful overall survival (OS) benefit at five years.

6. imfinzi.com imfinzi.com/hepatocellular-carcinoma.html

Immunotherapy for Unresectable Hepatocellular Carcinoma IMFINZI combined with one dose of IMJUDO * is an immunotherapy treatment approved for adults with unresectable hepatocellular carcinoma (uHCC).

7. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).