RET Inhibitor for Solid Cancers

(MARGARET Trial)

Recruiting at 7 trial locations

Overseen By Kazuo Koba

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Taiho Pharmaceutical Co., Ltd.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Cardiovascular disease, QT syndrome, others

No Placebo Group

Trial Summary

What is the purpose of this 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. The drug aims to block this gene to stop or slow down cancer growth. The initial part will find the safest dose, and the later part will test how well it works.

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.

What data supports the effectiveness of the drug TAS0953/HM06 (Vepafestinib) for treating solid cancers?

Research shows that Vepafestinib is a highly selective RET inhibitor that works well against certain mutations in RET-driven cancers, including those that affect the brain. It has shown improved tumor control in preclinical models compared to other RET drugs, suggesting it could be effective for treating solid cancers with RET alterations. ^{1 2 3 4 5}

Is the RET inhibitor Vepafestinib safe for humans?

Vepafestinib, a RET inhibitor, has been studied for its safety and effectiveness in treating cancers with RET alterations. While specific safety data for Vepafestinib is not detailed, similar RET inhibitors like selpercatinib have shown common side effects such as swelling, diarrhea, fatigue, dry mouth, high blood pressure, abdominal pain, constipation, rash, nausea, and headache. ^{1 4 5 6 7}

What makes the drug Vepafestinib unique for treating solid cancers?

Vepafestinib is unique because it is a next-generation RET inhibitor with high selectivity and the ability to penetrate the brain effectively, addressing limitations of current RET inhibitors that struggle with brain metastasis and resistance mutations. ^{1 3 4 5 8}

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• TAS0953/HM06 (Kinase Inhibitor)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Precision therapy for RET-altered cancers with RET inhibitors. [2023]

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

D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms. [2023]

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

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. [2022]

4. England 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. [2023]

5. Norway pubmed.ncbi.nlm.nih.gov

Lung cancer treated abroad with receptor tyrosine kinase inhibitor. [2021]

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

State-of-the-Art Strategies for Targeting RET-Dependent Cancers. [2021]

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

FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors. [2023]

8. United States 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. [2022]