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

Trial Summary

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.

What data supports the effectiveness of the drug Pembrolizumab for liver cancer?

Research shows that Pembrolizumab, used alone, has been effective and safe for patients with advanced liver cancer, especially those who have already been treated with another drug called sorafenib. Studies like KEYNOTE-224 and KEYNOTE-240 have demonstrated its ability to help control the disease in these patients. ^{1 2 3 4 5}

What safety data exists for Tegavivint + Pembrolizumab in humans?

Pembrolizumab, also known as KEYTRUDA, has been studied for safety in patients with advanced liver cancer, showing it is generally tolerable. However, there have been reports of hepatitis B reactivation (a return of the virus) in some patients using similar treatments, which could lead to treatment delays or changes. ^{1 2 4 6 7}

What makes the drug Tegavivint + Pembrolizumab unique for liver cancer?

Tegavivint + Pembrolizumab is unique because it combines Tegavivint, which targets a specific protein involved in cancer cell growth, with Pembrolizumab, a PD-1 inhibitor that helps the immune system attack cancer cells. This combination may offer a novel approach for treating liver cancer, especially for patients who have already been treated with other drugs like sorafenib. ^{4 5 8 9 10}

What is the purpose of this trial?

This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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 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]

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 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]

References

1. Switzerland 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. [2023]

2. England 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. [2022]

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

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. [2023]

4. England 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. [2022]

5. United States 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. [2023]

6. United States 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. [2020]

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

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. [2023]

8. England 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. [2023]

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

PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV. [2022]

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

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. [2023]