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

Sponsor

Theseus Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05160168

Collaborator

(none)

140

Enrollment

Locations

Arms

52.9

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumors (GIST) Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasm Digestive System Disease Gastrointestinal Diseases	Drug: THE-630	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Jan 3, 2022

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Dose Escalation (Phase 1): Number of participants with dose-limiting toxicities (DLT) following oral administration of THE-630 [28 days]
Dose Escalation (Phase 1): Determination of RP2D of orally administered THE-630 [28 days]
Dose Escalation (Phase 1): Determination of MTD of orally administered THE-630 [28 days]
Dose Escalation (Phase 1): Safety Analysis - Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 [Up to 24 months after first dose]
Expansion (Phase 2): Expansion Cohorts 1, 2, 3 and 4: confirmed Objective Response Rate (ORR) [Up to 24 months after first dose]

Secondary Outcome Measures

Dose Escalation (Phase 1): Confirmed Objective Response Rate (ORR) [Up to 24 months after first dose]
Expansion (Phase 2): Safety Analysis - Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 [Up to 24 months after first dose]
Cmax; Maximum Observed Concentration of THE-630 and its Metabolite [Cycle 1 Day 1 and Cycle 1 Day 15]
Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of THE-630 and its Metabolite [Cycle 1 Day 1 and Cycle 1 Day 15]
AUC 0-24; Area Under the Concentration-time Curve from Time Zero to 24 hours for THE-630 and its Metabolite [Cycle 1 Day 1 and Cycle 1 Day 15]
AUC0-t: Area Under the Concentration-time Curve from Time Zero to Time t for THE-630 its Metabolite [Cycle 1 Day 1 and Cycle 1 Day 15]
Best overall response [Up to 24 months after first dose]
Best target lesion response [Up to 24 months after first dose]
Time to response [Up to 24 months after first dose]
Duration of Response (DOR) [Up to 24 months after first dose]
Disease Control Rate (DCR) [Up to 24 months after first dose]
Clinical Benefit Rate (CBR) at 16 weeks [16 weeks]
Progression Free Survival (PFS) [Up to 24 months after first dose]
Overall Survival [Up to 24 months after first dose]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Male or female patient ≥ 18 years of age.
For Dose Escalation Phase Cohorts (Phase 1):
Have histologically- or cytologically-confirmed unresectable or metastatic GIST.
Have progressed on or are intolerant to imatinib therapy and have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib.
For Expansion Phase Cohorts (Phase 2):
Cohort 1:
Have histologically- or cytologically confirmed unresectable or metastatic GIST.
Have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib.
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.
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.
Have at least 1 measurable lesion as defined by modified RECIST 1.1
Have archival or new tumor biopsy tissue available to submit for mutational testing.
Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
Adequate renal, hepatic and bone marrow function as defined by the protocol.
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.

Female patients of childbearing potential must agree to abstain from heterosexual intercourse or use a highly effective form of contraception with their sexual partners during the dosing period and for a period of at least 30 days after the end of treatment. 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 during the dosing period until at least 90 days after the last dose of study drug.
All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (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.

Key Exclusion Criteria:

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.
Patients known to be both KIT and PDGFRA wild-type.
Received radiotherapy within 14 days prior to the first dose of study drug.
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.
Have known untreated or active central nervous system metastases.
12-lead electrocardiogram (ECG) demonstrating QT interval corrected by Fridericia's formula (QTcF) >470 msec at screening, or history of long QTc syndrome.
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.
Have an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics.
Any active bleeding excluding hemorrhoidal or gum bleeding.
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.
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.
Pregnant or breastfeeding.
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth	Scottsdale	Arizona	United States	85258
2	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
3	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
6	Oregon Health & Science University	Portland	Oregon	United States	97239
7	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111