A Study of THE-630 in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)

This study will assess the safety, efficacy, and pharmacokinetics of THE-630 in participants with advanced gastrointestinal stromal tumors (GIST).

The drug being tested in this study is called THE-630, an orally administered KIT tyrosine kinase inhibitor. The study will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (Phase 1) of the trial will include patients with unresectable or metastatic GIST. Patients must have disease progression on or be intolerant to imatinib therapy and have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of oral THE-630, including the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).

Once a recommended dose has been determined in the escalation phase, the expansion phase (Phase 2) will enroll 3 cohorts of patients with unresectable or metastatic GIST defined by prior therapy:

* Cohort 1: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib (≥5th Line).
* Cohort 2: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting (3rd-4th Line).
* Cohort 3: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for advanced GIST (2nd Line).

The safety and tolerability of orally administered THE-630 will continue to be assessed in the expansion cohorts. However, the primary objective of the expansion component of the trial is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female patient ≥18 years of age.
2. For Dose Escalation Phase Cohorts (Phase 1):

   1. Have histologically- or cytologically-confirmed unresectable or metastatic GIST.
   2. Have progressed on or are intolerant to imatinib therapy and have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib.
3. For Expansion Phase Cohorts (Phase 2):

   1. Cohort 1:

      * Have histologically- or cytologically confirmed unresectable or metastatic GIST.
      * Have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib.
   2. Cohort 2:

      * Have histologically- or cytologically confirmed unresectable or metastatic GIST.
      * Have progressed on or are intolerant to imatinib and sunitinib. Patients in this cohort are allowed to have received up to 1 additional line of therapy in the advanced/metastatic setting.
   3. Cohort 3:

      * Have histologically- or cytologically confirmed unresectable or metastatic GIST.
      * Have progressed on or are intolerant to imatinib (including in the adjuvant setting).
      * Have not received additional systemic therapy for advanced GIST.
4. Have at least 1 measurable lesion as defined by modified RECIST 1.1.
5. Have archival or new tumor biopsy tissue available to submit for mutational testing. Patients without appropriate archival tissue available may be discussed with the study Medical Monitor and approved for enrollment on a case-by-case basis.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
7. Adequate renal and hepatic function as defined by the protocol.
8. Adequate bone marrow function as defined by the protocol.
9. For female patients of childbearing potential, have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test within 7 days prior to the first dose of study drug.

   o Note: female patients of nonchildbearing potential (postmenopausal; hysterectomy; bilateral salpingectomy; or bilateral oophorectomy) do not require a pregnancy test.
10. Female patients of childbearing potential must agree to abstain from heterosexual intercourse or use a highly effective form of contraception with their sexual partners as defined in the study protocol. Male patients with partners of childbearing potential must agree that they will abstain from heterosexual intercourse or use condoms and their partners will use highly effective contraceptive methods as defined in the study protocol.
11. All toxicities from prior therapy have resolved to Grade ≤1 according to NCI CTCAE v5.0, or have resolved to baseline, at the time of first dose of study drug. Note: treatment-related Grade \>1 alopecia, treatment related Grade 2 peripheral neuropathy, and treatment-related Grade 2 hypothyroidism on a stable dose of thyroid hormone replacement therapy are allowed if deemed irreversible.
12. Patient or legal guardian, if permitted by local regulatory authorities, signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.
13. Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

1. Received systemic anticancer therapy (including cytotoxic chemotherapy, investigational agent, antineoplastic monoclonal antibodies, or immunotherapy) less than 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug.
2. Patients known to be both KIT and PDGFRA wild-type.
3. Received radiotherapy within 14 days prior to the first dose of study drug.
4. Major surgical procedure within 28 days of the first dose of study drug. Minor surgical procedures such as central venous catheter placement or minimally invasive biopsy are allowed.
5. Have known untreated or active central nervous system metastases.
6. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected by Fridericia's formula (QTcF) \>470 msec at screening, or history of long QTc syndrome.
7. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to:

   * Myocardial infarction (MI) within 6 months prior to the first dose of study drug
   * Unstable angina within 6 months prior to first dose of study drug
   * Symptomatic congestive heart failure (New York Heart Association classes II-IV) within 6 months prior to first dose of study drug
   * Clinically significant, uncontrolled atrial arrhythmia (as determined by the Investigator)
   * Any history of ventricular arrhythmia
   * Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug
   * Uncontrolled hypertension at study entry. Patients with hypertension should be under treatment on study entry to control blood pressure.
8. Have an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics.
9. Patients with a known allergy or hypersensitivity to any component of the study drug. Patients with a history of Stevens-Johnson syndrome on a prior tyrosine kinase inhibitor (TKI) are excluded.
10. Any active bleeding excluding hemorrhoidal or gum bleeding.
11. For patients with a known human immunodeficiency virus (HIV) infection, have CD4+ T-cell counts \<350 cells/uL or history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months. Patients with HIV infection should be on established antiretroviral therapy (ART) for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment.
12. Has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as evidenced by detectable viral load (HBV-DNA or HCV-RNA, respectively). Risk of HBV reactivation should be considered in all patients and the need for anti-HBV prophylaxis should be carefully assessed. Patients with chronic HBV infection with history of active disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral therapy to be eligible for enrollment. Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible. Patients on concurrent HCV treatment at the time of enrollment are allowed if HCV RNA negative.
13. Pregnant or breastfeeding.
14. Malabsorption syndrome or other illness that could affect oral absorption.
15. Patients with prior or concurrent malignancies other than GIST are allowed, except in the case where, in the opinion of the Investigator, the natural history or treatment of the other malignancy has the potential to interfere with the safety or efficacy assessment of the study drug.
16. Have any condition or illness that, in the opinion of the Investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug.