A Study of TY-2136b in Patients With Advanced Solid Tumors Harboring ALK, ROS1 or NTRK1-3 Alterations

A Phase I, Multicenter, Open-label Study of TY-2136b, Administered Orally in Patients With Advanced or Metastatic Solid Tumors Harboring ALK, ROS1 or NTRK1-3 Alterations

The primary objective of this study is to evaluate the safety and tolerability of TY-2136b and to determine the recommended phase 2 dose (RP2D), with dose-escalation stage and dose-expansion stage.

• To evaluate the pharmacokinetic (PK) characteristics of TY-2136b after single and multiple oral doses.
• To assess preliminary antitumor activity of TY-2136b as a single agent when administered orally to patients with advanced or metastatic solid tumors.
• To identify mutations in the ALK, ROS1 and NTRK1-3, or other molecular alterations in blood or tumor tissues associated with clinical outcome.

Inclusion criteria:

1. Willing and able to provide written informed consent approved by institutional review board (IRB) or independent ethics committee (IEC).

2. In the escalation stage, patients should fulfill the following criterion at Screening:

   1. Age ≥18 years.
   2. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor. Evidence of ALK, ROS1, NTRK1, NTRK2 or NTRK3 alterations in tumor tissue or blood, as determined with prior molecular assays performed in a CLIA-certified or equivalent laboratory.
   3. Patients must have failed established standard medical anti-cancer therapies for a given tumor type or have been intolerant to such therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds. Note: Prior cytotoxic chemotherapy is allowed; prior anti-cancer immunotherapy is allowed.

   In the expansion stage, patients should fulfill the following criteria at Screening:

   1. Age ≥18 years.
   2. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC and other solid tumors.
   3. Subject must have a documented ROS1 or NTRK1-3 gene or ALK fusion or rearrangement determined by CLIA-certified or equivalent testings. Next-generation sequencing (NGS), quantitative polymerase chain reaction (qPCR) test or fluorescence in situ hybridization (FISH).

3. ECOG Performance Status 0-1.

4. Capability to swallow intact tablet without chewing or opening; if the patient cannot swallow many tablets of high dose at one time, the subject can take dissolving tablets orally.

5. At least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumor Version 1.1 (RECIST v1.1) determined by the investigator. Subjects with central nervous system (CNS)-only measurable disease ≥10 mm as defined by RECIST v1.1 are eligible.

6. All acute toxic effects (excluding alopecia of any prior anticancer therapy recovered to grade ≤1 based on NCI CTCAE v5.0).

7. Patients with asymptomatic CNS metastases (treated or untreated) are also eligible if they satisfy the other criteria specified in this protocol.

8. Baseline laboratory results fulfilling the requirements.

9. Life expectancy ≥3 months.

10. For female patients of childbearing potential, the serum or urine pregnancy test within 72 hours prior to the start of TY-2136b treatment should be negative.

11. Male and female patients of childbearing potential must agree to use 2 methods of highly effective contraception from signing ICF, throughout the study and continued for 90 days after the last dose of TY-2136b treatment.

12. Willing and able to comply with all aspects of the protocol.

Exclusion criteria:

1. Concurrent participation in another therapeutic clinical trial. Unless the patient is during follow-up period of a previous interventional clinical trial.

2. Symptomatic CNS metastases, OR leptomeningeal involvement.

3. History of other previous cancer (except for squamous cell or basal-cell carcinoma of the skin, any in situ carcinoma that has been completely resected, or other early-stage malignancies receiving curative treatment which get consensus between the investigators and sponsor), requiring therapy within the previous 2 years.

4. Major surgery within 4 weeks prior to the start of TY-2136b treatment; OR radiation therapy (except palliative to relieve bone pain) within 2 weeks prior to enrollment. Note: Palliative radiation must have been completed at least 48 hours prior to enrollment.

5. Patients receiving long-term systemic immunosuppressant therapy (≤10 mg/ day of prednisone or another equivalent dose of corticosteroid inhalation or topical administration can be included);

6. Clinically significant cardiovascular disease (either active at Screening or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥II), cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or requirement for anti-arrhythmic medication; or cardiac dysrhythmias of NCI CTCAE grade ≥2 deemed of clinical significance by the investigator.

7. Any of the following cardiac criteria:

   1. 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, using the screening clinic electrocardiogram machine derived QTc value.
   2. Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec).
   3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval during Screening.

8. Known active infections, e.g., bacterial, fungal and viral infections, including human immunodeficiency virus (HIV) infection (defined as anti-HIV antibody positive), hepatitis B virus (HBV) infection [defined as Hepatitis B surface antigen (HBsAg) positive and HBV-DNA ≥1000 cps/mL or 200 IU/mL] and hepatitis C virus (HCV) infection (defined as anti-HCV antibody positive and HCV-RNA positive). Human Immunodeficiency Virus (HIV) positive patients could be eligible after discussion with medical monitor based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (e.g., opportunistic infections), and status of HIV treatment.

9. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that will impact drug absorption.

10. Peripheral neuropathy of CTCAE ≥ grade 2.

11. History of extensive, disseminated, bilateral or CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease (ILD) including pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative bronchiolitis, and pulmonary fibrosis. Note: Patients with history of prior radiation pneumonitis will not be excluded.

12. History of strong inhibitors and/or inducers of CYP3A within 2 weeks prior to the first dose of TY-2136b.

13. History of strong inhibitors and/or inducers of P-glycoprotein within 2 weeks prior to the first dose of TY-2136b.

14. History of sensitive substrates and those with a narrow therapeutic index of CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A within 2 weeks prior to the first dose of TY-2136b.

15. History of proton pump inhibitors (PPIs) within 4 days prior to the first dose of TY-2136b; OR history of histamine H2 blockers within 2 days prior to the first dose of TY-2136b.