Overview

This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of TY-1091 administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.

Eligibility

Inclusion Criteria:

1. Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.

   All participants treated at doses > 50 mg per day must have MTC, or a RET-altered solid tumor per assessment of tumor tissue and/or blood

   • In the expansion stage phase (Phase 2) , patients should fulfill the following criteria at Screening Patients with histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC, MTC, or other solid tumors.

             Subject must have a documented RET gene fusion or mutation by a CLIA certified or
             equivalent testing. Next-generation sequencing (NGS), quantitative polymerase chain
             reaction (qPCR) test or fluorescence in situ hybridization (FISH) can be used to
             determine molecular eligibility At least one measurable lesion as defined by RECIST
             1.1, not previously irradiated and not chosen for biopsy during the screening period.
             Patients without RECIST 1.1 measurable disease will be eligible for enrollment in
             Cohort 5.
          2. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 with
             no sudden deterioration 2 weeks prior to the first dose of study treatment.
          3. Life expectancy of at least 3 months.
          4. Adequate organ functions.
          5. Ability to swallow capsules and willing and able to provide written informed consent
             approved by institutional review board (IRB) or independent ethics committee (IEC).
          6. Willingness of men and women of reproductive potential to observe conventional and
             effective birth control for the duration of treatment and 6 months following the last
             dose of study treatment; this may include barrier methods such as condom or diaphragm
             with spermicidal gel.
        Exclusion Criteria:
          1. For NSCLC patients, a targetable mutation in EGFR or MET, targetable rearrangement
             involving ALK, ROS1 or NTRK1-3.
          2. History of other previous cancer (except for squamous cell or basal-cell carcinoma of
             the skin, or any in situ carcinoma that has been completely resected), requiring
             therapy within the previous 5 years.
          3. For MTC patients, clinically significant involvement in the trachea, esophagus or
             complete encasement of great vessels (e.g., aorta or pulmonary artery) that in the
             opinion of the Investigator, could result in life-threatening complications due to
             rapid tumor regression.
          4. Symptomatic primary central nervous system (CNS) tumor or metastases; symptomatic
             leptomeningeal carcinomatosis; untreated spinal cord compression.
          5. Cardiovascular and cerebrovascular diseases/symptoms/indications meeting any of the
             following conditions:
             Mean resting corrected QT interval (electrocardiogram interval measured from the onset
             of the QRS complex to the end of the T wave) for heart rate (QTcF) ≥470 msec obtained
             from 3 electrocardiograms; Any clinically significant resting ECG abnormalities in
             rhythm, conduction, or morphology, such as complete left bundle branch block, second
             and third degree heart block, PR interval > 250 ms; Any factors that increase the risk
             of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long
             QT syndrome, family history of long QT syndrome, or unexplained sudden death in a
             first-degree relative under 40 years of age, or any concomitant medication known to
             prolong QT interval; Left ventricular ejection fraction (LVEF) < 50%; Patients with a
             previous history of decreased myocardial contractility who experienced relevant
             symptoms within 6 months prior to study drug administration: such as chronic
             congestive heart failure, pulmonary edema or decreased cardiac ejection fraction;
             Patients with a history of acute or chronic cardiovascular and cerebrovascular
             diseases who had relevant symptoms within 6 months prior to study drug administration:
             such as myocardial infarction, severe or unstable angina, cerebral infarction,
             cerebral hemorrhage or transient ischemic attack.
          6. Patients who have received treatment within 14 days prior to the first dose or need to
             continue treatment with strong CYP3A4 inducers/strong inhibitors,
             CYP3A4/CYP2C9/CYP2C19 sensitive substrate with a narrow treatment window or strong
             p-glycoprotein inhibitors.
          7. Systemic anti-tumor treatment such as standard chemotherapy, biological therapy and
             immunological drug therapy within 28 days prior to the first dose; targeted therapy
             within 14 days or 5 half-lives of the first dose (calculated as a long time);
             anti-tumor traditional Chinese traditional medicine treatment within 7 days prior to
             the first dose.