RET Inhibitor for Solid Cancers

(MARGARET Trial)

Recruiting at 10 trial locations

Overseen By Kazuo Koba

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Taiho Pharmaceutical Co., Ltd.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Cardiovascular disease, QT syndrome, others

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

Compensation: Varies

Number of Visits: 30

244 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called TAS0953/HM06 (also known as Vepafestinib) for individuals with advanced solid tumors that have changes in the RET gene. The main goal is to determine the treatment's safety and effectiveness and to identify the best dose for future studies. Suitable candidates for this trial include those with advanced solid cancers showing RET gene abnormalities who have exhausted other treatment options. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial requires that you stop taking any investigational agents or anticancer therapy at least 5 half-lives before starting the study drug. Additionally, you must not take strong CYP3A4 inhibitors within 1 week or strong CYP3A4 inducers within 3 weeks before the first dose of the study drug.

Is there any evidence suggesting that TAS0953/HM06 is likely to be safe for humans?

Research shows that TAS0953/HM06, also known as Vepafestinib, has been studied for its safety and effectiveness in treating solid tumors with RET gene issues. In animal studies, Vepafestinib significantly slowed tumor growth without causing weight loss in mice, suggesting it might be well-tolerated.

However, since this treatment remains in early clinical trials, all safety details for humans are not yet known. Early trials aim to find the right dose and check for side effects. Researchers continue to study the treatment carefully to ensure it is safe for people.

Participants in these trials help researchers learn more about the potential effects of TAS0953/HM06. While results in animal studies are encouraging, ongoing human trials will provide more detailed safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for solid cancers, which often include chemotherapy and other targeted therapies, TAS0953/HM06 works by specifically inhibiting the RET protein, a key player in the growth of certain cancer cells. This targeted approach can potentially lead to fewer side effects and improved outcomes for patients whose tumors are driven by RET alterations. Researchers are excited about TAS0953/HM06 because it may offer a more precise and effective treatment option, especially for patients who have not responded well to conventional therapies.

What evidence suggests that TAS0953/HM06 might be an effective treatment for solid cancers?

Studies have shown that TAS0953/HM06 holds promise for treating cancers with RET gene alterations. In animal tests, this treatment stopped tumors from growing or reduced their size in up to 65% of cases. It has also significantly reduced tumor growth in certain lung cancers. TAS0953/HM06 seems more effective at reaching and treating brain cancer compared to some other treatments, suggesting it might lead to better outcomes for patients with these specific cancer types. Participants in this trial will receive TAS0953/HM06, with the trial including both a Phase 1 dose escalation and a Phase 2 treatment phase to evaluate its effectiveness across different populations. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have specific RET gene abnormalities. Participants should be in good physical condition (ECOG score of 0-1 or 2), have adequate organ function, and no major recent surgeries. They must not have certain genetic mutations like EGFR or KRAS, uncontrolled heart issues, or a history of severe heart rhythm problems.

Inclusion Criteria

You have a disease that can be measured or seen on medical tests according to specific guidelines.

I have an advanced solid tumor.

My tests show RET-gene abnormalities.

Exclusion Criteria

Common Exclusion Criteria: - You have received experimental or anticancer treatment in the last 5 drug half-lives before starting the study. - You had major surgery within 4 weeks before starting the study or plan to have major surgery during the study. - You had whole brain radiotherapy within 14 days or other palliative radiotherapy within 7 days before starting the study, and still have side effects from it. - You have uncontrolled heart problems, high blood pressure, or a history of certain heart conditions. - Your corrected QT interval is longer than 470 milliseconds, or you have a history of certain heart rhythm problems. - You have taken strong CYP3A4 inhibitors within 1 week or strong CYP3A4 inducers within 3 weeks before starting the study.

My cancer does not have mutations in EGFR, KRAS, ALK, HER2, ROS1, BRAF, or METex14.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Dose escalation and dose expansion to determine Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

21 days per cycle

Visits every 21 days

Phase 2: Treatment

Treatment phase at recommended Phase 2 dose in three different populations

6 months, then every 9 weeks

Approximately every 6 weeks for 6 months, then every 9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months after the last dose

What Are the Treatments Tested in This Trial?

Interventions

• TAS0953/HM06

Trial Overview

The study tests TAS0953/HM06's safety and effectiveness on patients with RET-related tumors. Phase 1 determines the safest high dose to use; Phase 2 uses this dose to further evaluate treatment effects.

How Is the Trial Designed?

Group I: TAS0953/HM06 Phase 2 Experimental Treatment 1 Intervention

Treatment phase at recommended Phase 2 dose in three different populations

Group II: TAS0953/HM06 Phase 1 Experimental Treatment 1 Intervention

Dose escalation and dose expansion until recommended Phase 2 dose determined

Who Is Running the Clinical Trial?

Taiho Pharmaceutical Co., Ltd.

Lead Sponsor

Trials

67

Recruited

18,600+

Masayuki Kobayashi

Taiho Pharmaceutical Co., Ltd.

Chief Executive Officer since 2012

Background in political and law studies

Harold Keer

Taiho Pharmaceutical Co., Ltd.

Chief Medical Officer since 2024

MD

Helsinn Healthcare SA

Lead Sponsor

Trials

43

Recruited

9,600+

ICON Clinical Research

Industry Sponsor

Trials

52

Recruited

15,100+

Published Research Related to This Trial

Vepafestinib (TAS0953/HM06) is a next-generation RET inhibitor that shows superior selectivity and effectiveness against common resistance mutations in RET, making it a promising option for treating RET-driven cancers.

This new drug also demonstrates better ability to penetrate the brain compared to existing RET inhibitors, leading to improved tumor control in models of brain metastasis associated with RET-driven cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. Miyazaki, I., Odintsov, I., Ishida, K., et al.[2023]

Compound 6i is a highly selective and potent RET inhibitor that effectively targets RET gatekeeper mutants, which are resistant to existing treatments like cabozantinib and vandetanib, making it a promising option for patients with certain thyroid cancers.

In laboratory studies, 6i significantly suppressed the growth of thyroid cancer cells and induced apoptosis without affecting normal thyroid cells, indicating its potential for targeted cancer therapy with reduced side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. Yoon, H., Kwak, Y., Choi, S., et al.[2022]

Selpercatinib (Retevmo) received accelerated FDA approval for treating adult patients with advanced solid tumors that have RET gene fusions, showing a 44% overall response rate in a study of 41 patients with various tumor types.

The treatment demonstrated a median duration of response of 24.5 months, indicating its potential long-term efficacy, while common side effects included edema, diarrhea, and fatigue, affecting over 25% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors. Duke, ES., Bradford, D., Marcovitz, M., et al.[2023]

RET alterations are significant oncogenic drivers in various cancers, including non-small cell lung cancer and thyroid cancer, leading to the development of targeted therapies.

Recent FDA-approved RET-specific inhibitors, selpercatinib and pralsetinib, show improved efficacy and reduced toxicity compared to earlier multikinase inhibitors, marking a significant advancement in targeted cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision therapy for RET-altered cancers with RET inhibitors. Thein, KZ., Velcheti, V., Mooers, BHM., et al.[2023]

Activating RET gene alterations are significant drivers of various cancers, including papillary thyroid cancer and non-small-cell lung cancer, making RET a promising target for therapy.

Recent selective RET inhibitors like pralsetinib and selpercatinib show improved efficacy and fewer side effects compared to older multikinase inhibitors, which had off-target effects and a narrow therapeutic index.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art Strategies for Targeting RET-Dependent Cancers. Subbiah, V., Yang, D., Velcheti, V., et al.[2021]

A male patient with advanced lung adenocarcinoma, who had previously not responded to standard treatments, showed significant improvement after being treated with pralsetinib, a selective RET inhibitor, following the identification of a KIF5B-RET fusion through next generation sequencing.

The patient experienced symptom relief within weeks and a partial radiological response after two months, with no reported side effects after six months, highlighting the efficacy and safety of targeted therapies in precision medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung cancer treated abroad with receptor tyrosine kinase inhibitor. Eide, IJZ., Brustugun, OT.[2021]

BLU-667 is a highly potent and selective RET inhibitor that shows over 10-fold increased potency against oncogenic RET variants compared to existing multikinase inhibitors, which often have significant side effects.

In first-in-human trials, BLU-667 effectively inhibited RET signaling and led to durable clinical responses in patients with RET-altered non-small cell lung cancer and medullary thyroid cancer, demonstrating its potential as a targeted therapy with minimal off-target toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Subbiah, V., Gainor, JF., Rahal, R., et al.[2022]

The RET Δ898-901 deletion mutation in a patient with medullary thyroid cancer showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months, indicating that while these treatments are initially effective, resistance can develop over time.

In vitro studies revealed that the RET Δ898-901 mutant has a higher autophosphorylation rate and is sensitive to selpercatinib, but less responsive to vandetanib and cabozantinib, suggesting that different RET mutations may require tailored therapeutic approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms. Porcelli, T., Moccia, M., De Stefano, MA., et al.[2023]

Citations

1.

aacrjournals.org

aacrjournals.org/mct/article/20/12_Supplement/P233/676104/Abstract-P233-TAS0953-HM06-is-effective-in

Abstract P233: TAS0953/HM06 is effective in preclinical ...

In vivo, HM06 blocked tumor growth and/or induced regression of up to 65% in seven patient-derived xenograft (PDX) models with RET fusions (five ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04683250

NCT04683250 | Study of RET Inhibitor TAS0953/HM06 in ...

Phase 1 and 2 trial to study the safety, pharmacokinetics, and efficacy of TAS0953/HM06 in patients with advanced solid tumors with RET gene abnormalities.

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10518257/

Vepafestinib is a pharmacologically advanced RET-selective ...

Vepafestinib was more effective at inhibiting growth of all tumor cell lines than vandetanib and as effective as selpercatinib and pralsetinib ( ...

4.

jto.org

jto.org/article/S1556-0864(22)00492-0/fulltext

MA13.05 TA0953/HM06, a Novel RET-specific Inhibitor ...

Oral administration of TAS0953/HM06 (50 mg/kg, BID or 100 mg/kg QD) to five NSCLC PDX models resulted in substantial reduction in tumor growth. TAS0953/HM06 was ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2024

Comparison of TAS0953/HM06 and selpercatinib in RET ...

Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and ...

6.

medchemexpress.com

medchemexpress.com/vepafestinib.html?srsltid=AfmBOoohsx7ZbymDzpg05dsX8WMdlpC-2DybK0iu4wC5496xYXXICNOv

Vepafestinib (TAS0953/HM06) | RET Inhibitor

Vepafestinib (12.5-100 mg/kg; oral administration) significantly inhibits tumor growth and has no significant effect on animal body weight in mouse models ...

7.

jto.org

jto.org/article/S1556-0864(25)01970-7/fulltext

P3.12.58 Initial Results From Phase 1/2 Study of the RET- ...

Vepafestinib (TAS0953/HM06), a RET-selective inhibitor, is being evaluated in patients with locally advanced or metastatic solid tumors harboring RET ...

8.

withpower.com

withpower.com/trial/phase-2-congenital-abnormalities-11-2020-780cb

RET Inhibitor for Solid Cancers (MARGARET Trial)

This trial is testing a new drug called TAS0953/HM06 for patients with advanced cancers that have specific genetic changes in the RET gene.