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

A Phase 1/2 Study of the Safety, Pharmacokinetics and Anti-Tumor Activity of the Oral KIT Inhibitor 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).

Study Overview

• Status: Terminated
• Conditions: Gastrointestinal Diseases; Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Neoplasms, Connective Tissue; Digestive System Neoplasm; Digestive System Disease; Gastrointestinal Stromal Tumors (GIST)
• Intervention / Treatment: Drug: THE-630

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Research Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation; Participants with unresectable or metastatic GIST who will receive orally administered THE-630.	Drug: THE-630; Oral THE-630 administered once daily in a continuous regimen
Experimental: Expansion Cohort 1; Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.	Drug: THE-630; Oral THE-630 administered once daily in a continuous regimen
Experimental: Expansion 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, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.	Drug: THE-630; Oral THE-630 administered once daily in a continuous regimen
Experimental: Expansion 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, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.	Drug: THE-630; Oral THE-630 administered once daily in a continuous regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation (Phase 1): Safety Analysis - Number of Participants With Treatment-emergent Adverse Events (TEAEs) as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0		Up to 24 months after first dose
Dose Escalation (Phase 1): Safety Analysis - Number of Participants With Dose-limiting Toxicities (DLTs) Following Oral Administration of THE-630		28 days
Dose Escalation (Phase 1): Safety Analysis - Maximum Tolerated Dose (MTD) of Orally Administered THE-630	The MTD is defined as the highest dose at which ≤1 of 6 DLT-assessment eligible patients experience a DLT within the first 28 days of treatment (end of Cycle 1).	28 days
Dose Escalation (Phase 1): Recommended Phase 2 Dose (RP2D) of Orally Administered THE-630	The RP2D was expected to be equal to the MTD or less than the MTD, if aspects of tolerability or efficacy not encompassed by the MTD determination suggested utilizing a lower dose.	28 days
Expansion (Phase 2): Efficacy Assessment - For Each Expansion Phase Cohort (Cohorts 1, 2, and 3), Confirmed Objective Response Rate (ORR), According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1		Up to 24 months after first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expansion (Phase 2): Efficacy Assessment - OS		Up to 24 months after first dose
Dose Escalation (Phase 1): Plasma Pharmacokinetic (PK) Parameters of THE-630 and Its Active Metabolite - Cmax (Maximum Observed Concentration)	Cmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Dose Escalation (Phase 1): Plasma PK Parameters of THE-630 and Its Active Metabolite - Tmax (Time of First Occurrence of Cmax)	Tmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Dose Escalation (Phase 1): Plasma PK Parameters of THE-630 and Its Active Metabolite - AUC 0-24 (Area Under the Concentration-time Curve From Time Zero to 24 Hours)	AUC 0-24 of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Dose Escalation (Phase 1): Plasma PK Parameters of THE-630 and Its Active Metabolite - AUC 0-t (Area Under the Concentration-time Curve From Time Zero to Time t)	AUC 0-t of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Dose Escalation (Phase 1): Efficacy Assessment - Confirmed ORR, According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Best Overall Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Best Target Lesion Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Time to Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Duration of Response (DOR), According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Disease Control Rate (DCR), According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Clinical Benefit Rate (CBR) at 16 Weeks, According to Modified RECIST 1.1		16 weeks
Dose Escalation (Phase 1): Efficacy Assessment - Progression Free Survival (PFS), According to Modified RECIST 1.1		Up to 24 months after first dose
Dose Escalation (Phase 1): Efficacy Assessment - Overall Survival (OS)		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - Best Overall Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - Best Target Lesion Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - Time to Response, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - DOR, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - DCR, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Efficacy Assessment - CBR at 16 Weeks, According to Modified RECIST 1.1		16 weeks
Expansion (Phase 2): Efficacy Assessment - PFS, According to Modified RECIST 1.1		Up to 24 months after first dose
Expansion (Phase 2): Safety Analysis - Number of Participants With Treatment-emergent Adverse Events as Assessed by NCI CTCAE v5.0		Up to 24 months after first dose
Expansion (Phase 2): Plasma PK Parameters of THE-630 and Its Active Metabolite - Cmax (Maximum Observed Concentration)	Cmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Expansion (Phase 2): Plasma PK Parameters of THE-630 and Its Active Metabolite - Tmax (Time of First Occurrence of Cmax)	Tmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Expansion (Phase 2): Plasma PK Parameters of THE-630 and Its Active Metabolite - AUC 0-24 (Area Under the Concentration-time Curve From Time Zero to 24 Hours)	AUC 0-24 of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)
Expansion (Phase 2): Plasma PK Parameters of THE-630 and Its Active Metabolite - AUC 0-t (Area Under the Concentration-time Curve From Time Zero to Time t)	AUC 0-t of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses	Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Theseus Pharmaceuticals
• Investigators: Study Director: Stew Kroll, Theseus Pharmaceuticals (a subsidiary of Concentra Biosciences)

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2022
• Primary Completion (Actual): February 2, 2024
• Study Completion (Actual): February 2, 2024

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: December 3, 2021
• First Posted (Actual): December 16, 2021

Study Record Updates

• Last Update Posted (Actual): June 5, 2024
• Last Update Submitted That Met QC Criteria: June 4, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: GIST; PDGFRA; GIST TKI; GIST tyrosine kinase inhibitor; Advanced GIST; GIST treatments; KIT-mutant GIST; Gastrointestinal Stromal Tumor; KIT inhibitor; THE-630; THE630; THE 630; GIST Imatinib relapse; GIST Sunitinib relapse; GIST Regorafenib relapse; GIST Ripretinib relapse
• Additional Relevant MeSH Terms: Neoplasms by Site; Connective Tissue Diseases; Neoplasms; Gastrointestinal Diseases; Digestive System Diseases; Gastrointestinal Stromal Tumors; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue
• Other Study ID Numbers: THE630-21-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No