study of ret inhibitor tas0953/hm06 in patients with advanced solid tumors with ret gene abnormalities

Conditions: RET-altered Non Small Cell Lung Cancer; RET-altered Solid Tumors

Summary: 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. phase 1 aims to determine the maximum tolerated dose (mtd) and identify the recommended phase 2 dose (rp2d) to be used in phase 2.


Eligibility criteria:
inclusion criteria: phase i - common inclusion criteria for dose-escalation / dose-expansion: * eastern cooperative oncology group (ecog) performance score of 0 or 1 * available ret-gene abnormalities determined on tissue biopsy or liquid biopsy. if deemed appropriate by the investigator, determination on a pleural cell block is also acceptable. * adequate hematopoietic, hepatic and renal function phase i dose-escalation - specific inclusion criteria: * advanced solid tumors * measurable and/or non-measurable disease as determined by recist 1.1 * if patient has brain and/or leptomeningeal metastases, (s)he should be asymptomatic. phase i dose-expansion - specific inclusion criteria: * patient with ret gene fusion : * cohort 1, 3: locally advanced or metastatic nsclc patients naïve to ret selective inhibitors and no prior systemic anti-cancer treatment. patients who have been treated with neo-adjuvant or adjuvant chemotherapy may be included if it has been completed at least 6 months prior to the first dose of the study. * cohort 2, 4: locally advanced or metastatic nsclc patients with ret gene fusion and prior exposure to ret selective inhibitors. * measurable disease as determined by recist 1.1 * if patient has brain and/or leptomeningeal metastases,(s)he should have: * asymptomatic untreated brain/leptomeningeal metastases off steroids and anticonvulsant for at least 7 days or * asymptomatic brain metastases already treated with local therapy and be clinically stable on steroids and anticonvulsant for at least 7 days before study drug administration. phase ii : * available ret-gene abnormalities determined on tissue or liquid biopsy * locally advanced or metastatic: * nsclc patients with primary ret gene fusion and prior exposure to ret selective inhibitors; * nsclc patients with ret gene fusion and without prior exposure to ret selective inhibitors * patients with advanced solid tumors that harbour ret gene abnormalities (other than nsclc patients with primary ret gene fusions) and has failed all the available therapeutic options * eastern cooperative oncology group (ecog) performance score of 0-2 * measurable disease as determined by recist 1.1 * if patient has brain and/or leptomeningeal metastases,(s)he should have: * asymptomatic untreated brain/leptomeningeal metastases off steroids and anticonvulsant for at least 7 days or * asymptomatic brain metastases already treated with local therapy and be clinically stable on steroids and anticonvulsant for at least 7 days before study drug administration. * adequate hematopoietic, hepatic and renal function exclusion criteria: common exclusion criteria for phase 1 and phase 2 * investigational agents or anticancer therapy within 5 half-lives prior to the first dose of study drug * major surgery (excluding placement of vascular access) within 4 weeks prior to the first dose of study drug or planned major surgery during the course of study treatment. * whole brain radiotherapy within 14 days or other palliative radiotherapy within 7 days prior to the first dose of study drug, or persisting side effects of such therapy, in the opinion of the investigator. * clinically significant, uncontrolled, cardiovascular disease including myocardial infarction within 3 months prior to day 1 of cycle 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (chf) new york heart association (nyha) class iii-iv, and severe uncontrolled arterial hypertension, according to the investigator's opinion. * qt interval corrected using fridericia's formula (qtcf) \>470 msec; personal or family history of prolonged qt syndrome or history of torsades de pointes (tdp). history of risk factors for tdp * treatment with strong cyp3a4 inhibitors within 1 week prior to the first dose of study drug or strong cyp3a4 inducers within 3 weeks prior to the first dose of study drug. phase i dose-expansion - and phase ii specific exclusion criteria: * presence of known egfr, kras, alk, her2, ros1, braf and metex14 activating mutations.