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

Primary Purpose

Gastrointestinal Stromal Tumors (GIST), Neoplasms, Connective Tissue, Neoplasms, Connective and Soft Tissue

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
THE-630
Sponsored by
Theseus Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Stromal Tumors (GIST) focused on measuring Gastrointestinal Stromal Tumor, GIST, KIT inhibitor, THE-630, THE630, THE 630, GIST TKI, GIST tyrosine kinase inhibitor, GIST treatments, GIST Imatinib relapse, GIST Sunitinib relapse, GIST Regorafenib relapse, GIST Ripretinib relapse, PDGFRA, KIT-mutant GIST, Advanced GIST

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • HonorHealth
  • Mayo Clinic Florida
  • Sylvester Comprehensive Cancer Center
  • Dana Farber Cancer Institute
  • Memorial Sloan Kettering Cancer Center
  • Oregon Health & Science University
  • Fox Chase Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Escalation

Expansion Cohort 1

Expansion Cohort 2

Expansion Cohort 3

Arm Description

Participants with unresectable or metastatic GIST who will receive orally administered THE-630.

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
November 22, 2021
Last Updated
July 27, 2023
Sponsor
Theseus Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT05160168
Brief Title
A Study of THE-630 in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 3, 2022 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Theseus Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
Gastrointestinal Stromal Tumor, GIST, KIT inhibitor, THE-630, THE630, THE 630, GIST TKI, GIST tyrosine kinase inhibitor, GIST treatments, GIST Imatinib relapse, GIST Sunitinib relapse, GIST Regorafenib relapse, GIST Ripretinib relapse, PDGFRA, KIT-mutant GIST, Advanced GIST

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation
Arm Type
Experimental
Arm Description
Participants with unresectable or metastatic GIST who will receive orally administered THE-630.
Arm Title
Expansion Cohort 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Expansion Cohort 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Expansion Cohort 3
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
THE-630
Intervention Description
Oral THE-630 administered once daily in a continuous regimen
Primary Outcome Measure Information:
Title
Dose Escalation (Phase 1): Number of participants with dose-limiting toxicities (DLT) following oral administration of THE-630
Time Frame
28 days
Title
Dose Escalation (Phase 1): Determination of RP2D of orally administered THE-630
Time Frame
28 days
Title
Dose Escalation (Phase 1): Determination of MTD of orally administered THE-630
Time Frame
28 days
Title
Dose Escalation (Phase 1): Safety Analysis - Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0
Time Frame
Up to 24 months after first dose
Title
Expansion (Phase 2): Expansion Cohorts 1, 2, 3 and 4: confirmed Objective Response Rate (ORR)
Time Frame
Up to 24 months after first dose
Secondary Outcome Measure Information:
Title
Dose Escalation (Phase 1): Confirmed Objective Response Rate (ORR)
Time Frame
Up to 24 months after first dose
Title
Expansion (Phase 2): Safety Analysis - Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0
Time Frame
Up to 24 months after first dose
Title
Cmax; Maximum Observed Concentration of THE-630 and its Metabolite
Time Frame
Cycle 1 Day 1 and Cycle 1 Day 15
Title
Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of THE-630 and its Metabolite
Time Frame
Cycle 1 Day 1 and Cycle 1 Day 15
Title
AUC 0-24; Area Under the Concentration-time Curve from Time Zero to 24 hours for THE-630 and its Metabolite
Time Frame
Cycle 1 Day 1 and Cycle 1 Day 15
Title
AUC0-t: Area Under the Concentration-time Curve from Time Zero to Time t for THE-630 its Metabolite
Time Frame
Cycle 1 Day 1 and Cycle 1 Day 15
Title
Best overall response
Time Frame
Up to 24 months after first dose
Title
Best target lesion response
Time Frame
Up to 24 months after first dose
Title
Time to response
Time Frame
Up to 24 months after first dose
Title
Duration of Response (DOR)
Time Frame
Up to 24 months after first dose
Title
Disease Control Rate (DCR)
Time Frame
Up to 24 months after first dose
Title
Clinical Benefit Rate (CBR) at 16 weeks
Time Frame
16 weeks
Title
Progression Free Survival (PFS)
Time Frame
Up to 24 months after first dose
Title
Overall Survival
Time Frame
Up to 24 months after first dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. Patients without appropriate archival tissue available may be discussed with the study medical monitor and approved for enrollment on a case-by-case basis. 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 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. 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 prolonged QT interval corrected by Fridericia's formula at screening as defined by study protocol, 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Kerstein, MD
Organizational Affiliation
Theseus Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
HonorHealth
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Sylvester Comprehensive Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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