Lamivudine for Solid Tumors

Overseen By Aleksandra Wawrzyniak

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Thomas Marron

Must be taking: PD-(L)1 blockers

Must not be taking: Antiretrovirals, Immunosuppressants

Disqualifiers: Chemotherapy, Radiotherapy, Autoimmune, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

24 Participants Needed

Trial Summary

What is the purpose of this trial?

Single arm, set dose clinical trial of Lamivudine for Relapsed Refractory Solid Tumors. Accrual 6-24 patients, within 2 years, study completion within 3 years at Mount Sinai Health System. Primary Objective: For Phase 1b to determine the safety and tolerability of Lamivudine with continued PD-(L)1 blockade for patients with relapsed/refractory metastatic solid tumors that have progressed on standard PD-(L)1 blockade. For Phase 2, to determine the effect of adding lamivudine to PD-(L)1 blocking agents in patients with relapsed/refractory solid tumors that have progressed on prior PD-(L)1 agents Secondary Objectives (Phase 1b and 2) Assess 1) Safety and Tolerability, 2) Best overall response rate (BORR), 3) Progression-free survival (PFS), 4) Overall survival (OS) and 5) Duration of response following addition of lamivudine to standard PD-(L)1 blocking agents, 6) Disease control rate (DCR).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on chemotherapy, radiotherapy, or investigational agents close to the start of the trial. If you are on certain medications like systemic steroids or immunosuppressive therapy, you may need to adjust or stop them before joining.

What data supports the effectiveness of the drug lamivudine for solid tumors?

Lamivudine is effective in preventing hepatitis B reactivation in cancer patients undergoing chemotherapy, which can help avoid interruptions in cancer treatment and reduce related complications. ^{1 2 3 4 5}

How is the drug Lamivudine unique for treating solid tumors?

Lamivudine is unique for treating solid tumors because it is traditionally used as an antiviral medication for conditions like HIV and hepatitis B, rather than cancer. This trial explores its potential repurposing for cancer treatment, which is different from the usual targeted or immune-based therapies currently used for solid tumors. ^{6 7 8 9 10}

Research Team

Thomas Marron, MD PhD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for patients with relapsed/refractory metastatic solid tumors that didn't respond to standard PD-(L)1 blockade treatments. It's a small study, aiming to enroll 6-24 participants over two years at Mount Sinai Health System.

Inclusion Criteria

I can care for myself but may not be fully active due to a long-term disability not related to my current illness.

I agree to use birth control during and for 3 months after the study.

Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

I haven't had chemotherapy in the last 14 days.

I have not received a live vaccine in the last 30 days.

I haven't had radiotherapy in the last week, except for palliative care.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1b

Determine the safety and tolerability of Lamivudine with continued PD-(L)1 blockade for patients with relapsed/refractory metastatic solid tumors

21 days per cycle

Cycle 1, each cycle is 21 days

Treatment Phase 2

Determine the effect of adding lamivudine to PD-(L)1 blocking agents in patients with relapsed/refractory solid tumors

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Lamivudine
• PD-L1 Blocker

Trial Overview The trial is testing the safety and effectiveness of Lamivudine when added to ongoing PD-L1 blocker therapy in patients whose solid tumors have not improved with previous treatments. The goal is to see if this combination can better control tumor growth.

Participant Groups

Group I: Participants with Relapsed Refractory Solid Tumors Experimental Treatment 2 Interventions

Participants with Solid Tumors which are typically treated with cancer immunotherapy (PD-1 or PD-L1 blocking antibodies) and their cancer has progressed on immunotherapy will be candidates for the trial. This is a single-arm trial.

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

Approved in United States as Epivir for:

• HIV infection
• hepatitis B (HBV) infection

Approved in European Union as Epivir for:

• HIV infection
• hepatitis B (HBV) infection

Who Is Running the Clinical Trial?

Thomas Marron

Lead Sponsor

Trials

2

Recruited

50+

Findings from Research

Prophylactic use of lamivudine significantly reduces the risk of hepatitis B virus (HBV) reactivation in solid tumor patients undergoing systemic chemotherapy, with a relative risk of 0.17 based on a meta-analysis of 1,101 patients.

Lamivudine not only lowers the risk of HBV reactivation but also decreases related negative outcomes such as hepatitis, chemotherapy disruptions, and potentially mortality, highlighting its efficacy as a preventive measure in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic effect of lamivudine on chemotherapy-induced hepatitis B virus reactivation in patients with solid tumour: A meta-analysis. Xu, Z., Dai, W., Wu, YT., et al.[2018]

Preventive lamivudine significantly reduces the risk of hepatitis B virus (HBV) reactivation and related complications in cancer patients undergoing chemotherapy, with a relative risk for HBV reactivation ranging from 0.00 to 0.21 based on 14 studies involving 275 patients on lamivudine and 475 controls.

None of the patients receiving preventive lamivudine developed HBV-related hepatic failure, and there were significantly fewer deaths attributed to HBV in the lamivudine group (4 deaths) compared to the control group (27 deaths), indicating its efficacy and safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Loomba, R., Rowley, A., Wesley, R., et al.[2022]

Lamivudine has been an effective treatment for chronic hepatitis B since its FDA approval in 1998, particularly for patients who are hepatitis B e antigen-positive.

However, a significant challenge is the development of drug-resistant mutants, which occur in 15 to 30% of patients each year, leading to potential relapse and complications, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lamivudine for chronic hepatitis B. Leung, N.[2021]

In a study of 519 patients with HBeAg-positive chronic hepatitis B treated with lamivudine for an average of 20 months, 37% achieved HBeAg seroconversion, indicating effective suppression of the virus.

Predictive factors for successful HBeAg seroconversion included decreasing HBeAg levels during treatment, initial HBeAg levels, ALT levels, and the duration of therapy, highlighting the importance of monitoring these variables for treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Predictive factors and efficacy of lamivudine treatment in chronic hepatitis B infection]. Park, NH., Shin, JW., Park, JH., et al.[2017]

In a study of 148 chronic hepatitis B patients, those with hepatitis B virus-related hepatocellular carcinoma (HCC) showed significant improvements in liver function after 12 months of lamivudine treatment, including increased albumin levels and decreased ascites and Child-Pugh scores.

Lamivudine demonstrated comparable antiviral effects in both patients with HCC and those without, suggesting that effective treatment of hepatitis B may enhance the potential for curative therapies in patients with HBV-related HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus-related hepatocellular carcinoma. Kim, JH., Park, JW., Koh, DW., et al.[2013]

Recent phase 3 trials have shown that targeted and immune-based therapies significantly improve treatment outcomes for patients with hepatocellular carcinoma, indicating a shift in treatment options.

Several new agents targeting specific pathways and immune checkpoints are currently in clinical development, with some already awaiting FDA approval or recently approved for use as first- and second-line therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted and Immune-Based Therapies for Hepatocellular Carcinoma. Greten, TF., Lai, CW., Li, G., et al.[2023]

Immune checkpoint inhibitors have shown significant survival benefits over traditional chemotherapy for patients with solid organ cancers, highlighting their growing importance in cancer treatment.

The review emphasizes the need for biomarkers, such as PD-L1 expression and tumor mutational burden, to better select patients for these therapies, particularly in cancers like lung and urothelial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers for immune checkpoint inhibitors in solid tumors. Kapoor, V., Kelly, WJ.[2023]

In a study using an orthotopic liver cancer model, the combination of lenalidomide and sorafenib significantly improved anti-tumor efficacy, leading to delayed tumor growth and increased survival in treated animals.

The enhanced anti-tumor effect was linked to an increase in CD8(+) T cells that produce interferon-γ, indicating that lenalidomide boosts the immune response against tumors when used with sorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential synergistic anti-tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma. Ou, DL., Chang, CJ., Jeng, YM., et al.[2022]

Gemcitabine treatment enhances the immune response in hepatocellular carcinoma (HCC) by increasing the infiltration of T cells and reducing suppressive immune cells, without significantly inhibiting tumor growth on its own.

The combination of gemcitabine with PD-1 blockade significantly reduces tumor volume and prevents relapse in HCC, indicating that this combination therapy is more effective than either treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine-facilitated modulation of the tumor microenvironment and PD-1/PD-L1 blockade generate a synergistic antitumor effect in a murine hepatocellular carcinoma model. Wang, H., He, X., Fang, D., et al.[2022]

Sorafenib was the first systemic therapy proven to improve survival in patients with advanced hepatocellular carcinoma (HCC), but recent treatments like lenvatinib and anti-PD-1 antibodies are emerging as effective options.

Combination therapies using anti-PD-1 antibodies with anti-angiogenesis agents are showing enhanced anti-tumor effects in early clinical trials, indicating a promising direction for future HCC treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging agents and regimens for hepatocellular carcinoma. Zhu, XD., Sun, HC.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Prophylactic effect of lamivudine on chemotherapy-induced hepatitis B virus reactivation in patients with solid tumour: A meta-analysis. [2018]

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

Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. [2022]

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

Lamivudine for chronic hepatitis B. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

[Predictive factors and efficacy of lamivudine treatment in chronic hepatitis B infection]. [2017]

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

Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus-related hepatocellular carcinoma. [2013]

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

Targeted and Immune-Based Therapies for Hepatocellular Carcinoma. [2023]

7. Italy pubmed.ncbi.nlm.nih.gov

Biomarkers for immune checkpoint inhibitors in solid tumors. [2023]

8. Australia pubmed.ncbi.nlm.nih.gov

Potential synergistic anti-tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma. [2022]

9. France pubmed.ncbi.nlm.nih.gov

Gemcitabine-facilitated modulation of the tumor microenvironment and PD-1/PD-L1 blockade generate a synergistic antitumor effect in a murine hepatocellular carcinoma model. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Emerging agents and regimens for hepatocellular carcinoma. [2023]