Phase Ⅰ/Ⅱ Study of the HS-10365 in Patients With Advanced Solid Tumors

A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Single and Multiple Doses of Oral Administration of HS-10365 in Patients With Locally Advanced or Metastatic Solid Tumors

HS-10365 is a small molecular, oral potent, selective RET inhibitor. The purpose of this study is to investigate the safety/tolerability、the pharmacokinetic profile and efficacy of HS-10365 in Chinese advanced solid tumor patients.

This is a multicenter, open-label phase 1/2 study in participants with advanced solid tumors, including RET fusion-positive non-small cell lung cancer and other tumors with RET activation. The trial will be conducted in 2 parts: Phase 1 and phase 2. Participants with advanced cancer are eligible if they have progressed on or intolerant to available standard therapies, or no standard or available curative therapy exists. The phase 1 study is a dose-escalation study, which is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of single dose and multiple doses of HS-10365 given once every day (QD) or twice every day (BID). A dose of 160 milligrams (mg) twice a day (BID) has been selected as the recommended phase 2 dose (RP2D). Approximately 273 participants with advanced solid tumors harboring a RET gene alteration will be enrolled to one of nine phase 2 cohorts:

Cohort 1: RET fusion non-small cell lung cancer (NSCLC) that has progressed after at least first-line therapy Cohort 2: RET fusion NSCLC not previously treated for metastatic disease Cohort 3: Medullary thyroid carcinoma that has progressed after at least first-line therapy Cohort 4: RET mutation-positive MTC not previously treated for metastatic disease Cohort 5: RET fusion Radioiodine-refractory thyroid cancer Cohort 6: Advanced solid tumors with RET gene fusion except for cohort 1 to 5 Cohort 7: Advanced solid tumors with RET gene abnormalities and drug resistance or intolerance previously treated with RET inhibitors except for cohort 1 to 6 Cohort 8: Advanced solid tumors with RET gene abnormality except for cohort 1 to 7 Cohort 9: NSCLC with RET gene abnormality except for cohort 1 to 2

For phase 1:

1. Men or women aged more than or equal to (≥) 18 years.
2. Locally advanced or metastatic cancer patients confirmed by histology or cytology for who that standard treatment is invalid, unavailable or intolerable
3. Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor as determined by local or central testing. And tumor tissue samples should be provided before the first administration for retrospective detection of RET gene status; blood samples are also allowed.
4. At least one extra-cranial measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1.
5. Eastern Cooperative Oncology Group (ECOG) performance status: 0~1.
6. Estimated life expectancy greater than (>) 12 weeks.
7. Men or women should be using adequate contraceptive measures throughout the study; Females should not be breastfeeding at the time of screening, during the study and until 6 months after completion of the study
8. Females must have evidence of non-childbearing potential.
9. Signed and dated Informed Consent Form.

For phase 2:

As for phase 1 with the following modifications:

1. For Cohort 1: Participants must have progressed following at least first-line treatment following platinum-based chemotherapy combined with or sequential PD-1/PD-L1 immunotherapy； For Cohort 2: Recurrence after previous surgical treatment must meet the conditions of having completed radical surgery for at least 6 month； For Cohort 4: Stage III patients with MTC who are unfit/intolerant or refuse radical surgical treatment and have symptoms or rapid disease progression； For Cohort 5: Recurrence after previous surgical treatment must meet the requirements of 12 months or more after the completion of radical surgery;

2. For Cohort 1 and Cohort 2: Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor as determined by central testing.

   For Cohort 3~9: Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor as determined by local or central testing.

3. For Cohort 1 ~7: At least one measurable lesion as defined by RECIST 1.1.

Exclusion Criteria:

1. For Cohort 1 and Cohort 2，patient's cancer has a known primary driver alteration other than RET.

2. For Cohort 1~6 and Cohort 8~9，patients previously treated with a selective RET inhibitor.

3. Treatment with any of the following:

   Previous or current treatment with selective RET inhibitors(except for cohort 7). Any cytotoxic chemotherapy, investigational agents and anticancer drugs within 14 days of the first dose of study drug (except for cohort 3 and 7).

   Radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study drug, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose.

   Major surgery within 4 weeks of the first dose of study drug.

4. Inadequate bone marrow reserve or organ function.

5. Uncontrolled pleural effusion or ascites or pericardial effusion.

6. Known and untreated, or active central nervous system metastases.

7. Refractory nausea, vomiting, or chronic gastrointestinal diseases, or inability to swallow the study drug that would preclude adequate absorption of HS-10365.

8. History of hypersensitivity to any active or inactive ingredient of HS-10365 or to drugs with a similar chemical structure or class to HS-10365.

9. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

10. Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments. Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.

11. History of neuropathy or mental disorders, including epilepsy and dementia

12. Determined by the physician, any coexisting disease might lead to life threatening complications or avoid the patients from accomplishing the treatment.