Tegavivint + Pembrolizumab for Liver Cancer

Recruiting at 8 trial locations

Overseen By Gilberto Botello

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Iterion Therapeutics

Must be taking: Antiviral therapy

Must not be taking: CYP3A4/5 inhibitors, CYP3A4/5 inducers

Disqualifiers: Other malignancies, CNS involvement, heart disease, others

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

Compensation: Varies

Number of Visits: Unknown

178 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for liver cancer that has progressed despite other treatments. Researchers are testing a drug called tegavivint (also known as Tegatrabetan, BC-2059, or APL-121) alone and in combination with two other drugs, cabozantinib and lenvatinib, to determine if they better control the cancer. The trial aims to find the best dose and assess how well these treatments work together. It seeks participants with liver cancer who have not responded well to at least one previous treatment. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires a washout period, meaning you must stop taking any prior systemic anticancer treatments at least 21 days before starting the study. If you are on certain medications that strongly affect liver enzymes (CYP3A4/5), you may need to stop them 7 to 14 days before the trial, depending on the type. Please discuss your specific medications with the study team to determine if any changes are needed.

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

A previous study found tegavivint to be safe for patients with advanced liver cancer. Most side effects were mild, with 62.5% of patients experiencing minor treatment-related issues. Importantly, no severe side effects occurred.

When combined with cabozantinib, tegavivint resulted in mostly mild to moderate side effects. Past studies have shown that cabozantinib alone is safe for liver cancer patients.

For the combination of tegavivint and lenvatinib, lenvatinib has been used in liver cancer and is generally well-tolerated. One study showed lenvatinib had a 20% partial response rate and a 70% disease control rate in liver cancer patients, indicating it is fairly safe.

These findings suggest that tegavivint and its combinations are generally safe, with mostly mild side effects. However, since this trial is in its early stages, more research is needed to confirm these findings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for liver cancer, which often involve chemotherapy or targeted therapies like sorafenib and lenvatinib, Tegavivint stands out due to its novel mechanism of action. Tegavivint targets the Wnt/β-catenin signaling pathway, which plays a critical role in cancer cell growth and survival, offering a fresh approach distinct from traditional treatments. Researchers are excited about this because targeting this pathway could lead to more effective treatments with potentially fewer side effects. Additionally, Tegavivint is being tested both as a monotherapy and in combination with other drugs like cabozantinib and lenvatinib, which could pave the way for versatile treatment regimens tailored to individual patient needs.

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

Research shows that tegavivint may help reduce tumor growth in liver cancer, particularly in cases with specific genetic changes. Early studies found it effective and safe for patients with advanced liver cancer, with most side effects being mild. In this trial, participants may receive tegavivint with cabozantinib, a drug already proven effective for liver cancer, which might improve treatment results. Another group will receive tegavivint with lenvatinib, another effective liver cancer drug, to potentially enhance its effectiveness. This trial studies these combinations for their potential to provide better outcomes for patients with advanced liver cancer. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

Adults with advanced liver cancer (HCC) who've had at least one prior systemic therapy can join. They must have measurable disease, certain blood and organ function levels, controlled hepatitis B or cured hepatitis C, and no severe heart issues. Pregnant women and those with other active cancers or recent major surgeries cannot participate.

Inclusion Criteria

My liver function is classified as Child-Pugh A or B (score ≤ 7) without brain issues.

Ascertainment from fresh biopsy or liquid biopsy during screening is allowed

My liver cancer is at an advanced stage and cannot be cured with local treatments.

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to tegavivint, or other agents used in study

Pregnant and breastfeeding women

I am not taking strong CYP3A4/5 inhibitors, or can stop them as required before starting the treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single Agent Dose Escalation

Tegavivint is administered as a single-agent in a dose escalation, optimization, and expansion study to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).

28 days

Combination Dose Escalation

Combination of tegavivint with pembrolizumab is assessed with a dose escalation to determine the combination MTD and RP2D.

21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with tumors assessed every 8 weeks for single agent and every 6 weeks for combination therapy.

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Tegavivint

Trial Overview The trial has two parts: first testing Tegavivint alone in different doses for HCC patients after other treatments failed; second combining Tegavivint with Pembrolizumab to find the best dose. Participants are chosen based on specific genetic markers in their tumors.

How Is the Trial Designed?

Group I: Tegavivint single agent dosing regimen Experimental Treatment 1 Intervention

Tegavivint as monotherapy

Group II: Tegavivint plus lenvatinib combination dosing regimen Experimental Treatment 2 Interventions

Tegavivint in combination with lenvatinib

Group III: Tegavivint plus cabozantinib combination dosing regimen Experimental Treatment 2 Interventions

Tegavivint in combination with cabozantinib

Who Is Running the Clinical Trial?

Iterion Therapeutics

Lead Sponsor

Trials

2

Recruited

130+

Published Research Related to This Trial

In a study of 100 patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, further stratification of PD-L1 tumor proportion score (TPS) beyond 50% did not significantly affect progression-free survival (PFS).

Smoking status was associated with improved PFS, while prior radiotherapy was linked to decreased PFS, indicating that these factors, along with performance status, may serve as important biomarkers for predicting response to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study. Mander, ES., Merrick, CB., Nicholson, HA., et al.[2023]

In the Asian subgroup of the KEYNOTE-240 trial, pembrolizumab significantly improved progression-free survival (PFS) to 2.8 months compared to 1.4 months for placebo, indicating its efficacy in treating advanced hepatocellular carcinoma (HCC).

The overall survival (OS) was also better with pembrolizumab at 13.8 months versus 8.3 months for placebo, with a manageable safety profile, as no treatment-related deaths occurred and most adverse events were of low grade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: A Subgroup Analysis of Asian Patients in the Phase 3 KEYNOTE-240 Trial. Kudo, M., Lim, HY., Cheng, AL., et al.[2023]

In a study of 104 patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib, pembrolizumab showed an objective response rate of 18.3% and a median duration of response of 21 months, indicating its effectiveness as a treatment option.

After approximately 2.5 years of follow-up, pembrolizumab demonstrated durable anti-tumor activity with manageable safety, as most treatment-related adverse events were low grade, and no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Kudo, M., Finn, RS., Edeline, J., et al.[2022]

Two patients with advanced melanoma and chronic viral infections (HCV and HIV) were treated with the PD-1 inhibitor pembrolizumab, showing that it can be administered safely without significant toxicities.

One patient experienced an initial partial response to pembrolizumab, and after subsequent HCV treatment, their viral load became undetectable, suggesting potential for effective cancer treatment in patients with chronic infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV. Davar, D., Wilson, M., Pruckner, C., et al.[2022]

In a phase 2 trial involving 104 patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib, pembrolizumab demonstrated an objective response rate of 17%, indicating its potential efficacy as a treatment option for this patient population.

While 73% of patients experienced treatment-related adverse events, most were manageable, with serious events occurring in 15% of patients, suggesting that pembrolizumab is generally tolerable for patients with advanced liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Zhu, AX., Finn, RS., Edeline, J., et al.[2022]

In a phase 3 trial involving 548 patients with PD-L1-positive metastatic cervical cancer, adding pembrolizumab to chemotherapy significantly improved progression-free survival, with a median of 10.4 months compared to 8.2 months for the placebo group.

Overall survival at 24 months was also better in the pembrolizumab group (53.0%) compared to the placebo group (41.7%), indicating that pembrolizumab enhances the effectiveness of chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. Colombo, N., Dubot, C., Lorusso, D., et al.[2023]

In a phase III study involving 413 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, pembrolizumab showed a median overall survival of 13.9 months compared to 10.6 months for placebo, indicating its potential effectiveness as a treatment option.

While pembrolizumab demonstrated improved overall survival and progression-free survival compared to placebo, the study noted a higher incidence of grade 3 or higher adverse events, suggesting a need to weigh the benefits against the risks when considering this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. Finn, RS., Ryoo, BY., Merle, P., et al.[2020]

In a phase III trial involving 453 patients with advanced hepatocellular carcinoma (HCC), pembrolizumab significantly improved overall survival (14.6 months vs. 13.0 months for placebo) and progression-free survival (2.6 months vs. 2.3 months for placebo).

The objective response rate (ORR) was notably higher in the pembrolizumab group (12.7%) compared to the placebo group (1.3%), although treatment-related adverse events were more common in the pembrolizumab group (66.9% vs. 49.7% for placebo).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. Qin, S., Chen, Z., Fang, W., et al.[2023]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

In a phase II trial involving 51 patients with advanced hepatocellular carcinoma (HCC) who had not received prior systemic therapy, pembrolizumab demonstrated a 16% objective response rate, indicating its potential effectiveness in this patient population.

The treatment showed a median overall survival of 17 months and a median duration of response of 16 months, with a safety profile that included grade ≥3 treatment-related adverse events in 16% of patients, suggesting it is tolerable for use in advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Verset, G., Borbath, I., Karwal, M., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4192

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059 ... Tegavivint treatment of established β-cateninexon3 activated tumors resulted in reduced tumor growth and burden. Based on these promising ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05797805

NCT05797805 | A Study of Tegavivint (BC2059) in Patients ... This study will be conducted in patients with advanced hepatocellular carcinoma (HCC) who have progressed after at least one prior line of systemic therapy.

3. onclive.com onclive.com/view/tegavivint-demonstrates-preliminary-efficacy-tolerability-in-advanced-hcc

Tegavivint Demonstrates Preliminary Antitumor Activity, ... Tegavivint demonstrated early efficacy and safety in advanced HCC, with low-grade TRAEs in 62.5% of patients and no grade 4 or 5 TRAEs observed.

4. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/CT032/761572/Abstract-CT032-Phase-1-2-trial-of-the-TBL1

Abstract CT032: Phase 1/2 trial of the TBL1 inhibitor, tegavivint ... β-Catenin plays a key role in cancer initiation, progression, and metastasis by promoting cell proliferation, survival, and stemness through ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00392-8/fulltext

176P Tegavivint, a downstream Wnt/β-catenin inhibitor Tegavivint is tolerable and demonstrates preliminary efficacy in aHCC, with more pronounced benefits observed in pts with β-catenin activating mutations.

6. researchgate.net researchgate.net/publication/381976789_A_phase_12_study_of_the_TBL1_inhibitor_tegavivint_BC2059_in_patients_pts_with_advanced_hepatocellular_carcinoma_aHCC_with_b-catenin_activating_mutations

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059 ... In these models tegavivint decreased Wnt target gene expression and enhanced CD3+ T-cell infiltration in liver tumors. Tegavivint treatment of established β- ...