RET Inhibitor for Solid Cancers
(MARGARET Trial)
Recruiting in Palo Alto (17 mi)
+7 other locations
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.
12345Is 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.
14567What 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.
13458Eligibility 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.
+9 more
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: TAS0953/HM06 Phase 2Experimental Treatment1 Intervention
Treatment phase at recommended Phase 2 dose in three different populations
Group II: TAS0953/HM06 Phase 1Experimental Treatment1 Intervention
Dose escalation and dose expansion until recommended Phase 2 dose determined
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
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Who Is Running the Clinical Trial?
Taiho Pharmaceutical Co., Ltd.Lead Sponsor
Helsinn Healthcare SALead Sponsor
ICON Clinical ResearchIndustry Sponsor
References
Precision therapy for RET-altered cancers with RET inhibitors. [2023]Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.
D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms. [2023]We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case.
Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. [2022]The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.
Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. [2023]RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.
Lung cancer treated abroad with receptor tyrosine kinase inhibitor. [2021]Activating RET fusions are oncogenic drivers in multiple cancers and are identified in 1-2 % of non-small cell lung cancers (NSCLC). Selpercatinib and pralsetinib are tyrosine kinase inhibitors selectively targeting RET and with clinical activity in RET-positive NSCLC.
State-of-the-Art Strategies for Targeting RET-Dependent Cancers. [2021]Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non-small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors. [2023]On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy.
A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants. [2022]Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.