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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Theseus Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

completed 2 Feb 2024

Decision date (initial)

2023-06-05

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Theseus Pharmaceuticals, Inc.

External identifiers

EU CT number

2022-502087-21-00

ClinicalTrials.gov

NCT05160168

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Therapy

Dose Escalation (Phase 1): To determine the safety profile of oral THE-630, including the DLTs, MTD, and RP2D.
Expansion (Phase 2): To determine the antitumor activity of oral THE-630 in patients with advanced GIST.

Secondary objectives 4

1. Dose Escalation (Phase 1): To determine the PK profile of oral THE-630 and its active metabolite THE-973.
2. Dose Escalation (Phase 1): To document preliminary evidence of antitumor activity of oral THE-630 in patients with advanced GIST.
3. Expansion (Phase 2): To evaluate the safety profile of oral THE-630.
4. Expansion (Phase 2): To further characterize the PK profile of oral THE-630 and its active metabolite THE-973.

Conditions and MedDRA coding

Gastrointestinal Stromal Tumors (GIST)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Male or female patient ≥ 18 years of age.
2. For Dose Escalation Phase Cohorts (Phase 1): a. Have histologically- or cytologically-confirmed unresectable or metastatic GIST. b. 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): a. Cohort 1: i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. ii. Have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib. b. Cohort 2: i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. ii. 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. c. Cohort 3: i. Have histologically- or cytologically confirmed unresectable or metastatic GIST. ii. Have progressed on or are intolerant to imatinib (including in the adjuvant setting). iii. 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. A tumor sample obtained after most recent prior systemic anticancer therapy is preferred. 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 following criteria: a. Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (<3.0 x ULN for patients with Gilbert syndrome), b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy), and c. Estimated (using Cockcroft-Gault formula or using the method standard for the institution) or measured creatinine clearance ≥60 mL/min.
8. Adequate bone marrow function as defined by the following criteria: a. Absolute neutrophil count (ANC) ≥1.5 × 109/L, b. Platelet count ≥75 × 109/L, and c. Hemoglobin ≥9.0 g/dL.
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. a. 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 during the dosing period and for a period of at least 7 months 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 4 months after the last dose of study drug.
11. 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.
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. Note: Patients are not eligible if they are, for reasons other than the age of legal competence to give informed consent, incapable of giving informed consent according to the law of the country concerned.
13. Willingness and ability to comply with scheduled visits and study procedures and do not have any contraindications to any of the study procedures.

Exclusion criteria 16

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 OR have received medications that are potent inhibitors of the BCRP (refer to Appendix 5 for a list of these medications) 7 days 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: a. Myocardial infarction (MI) within 6 months prior to the first dose of study drug b. Unstable angina within 6 months prior to first dose of study drug c. Symptomatic congestive heart failure (New York Heart Association classes II-IV) within 6 months prior to first dose of study drug d. Clinically significant, uncontrolled atrial arrhythmia (as determined by the Investigator) e. Any history of ventricular arrhythmia f. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug g. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Dose Escalation (Phase 1): Safety profile of oral THE-630, including identification of DLTs and MTD, and determination of the RP2D.
2. Expansion (Phase 2): Confirmed ORR, according to modified RECIST 1.1 for patients with GIST.

Secondary endpoints 5

1. Dose Escalation (Phase 1): Plasma PK parameters of THE-630 and its active metabolite THE-973 after single oral dose and at steady state after multiple oral doses.
2. Dose Escalation (Phase 1): Efficacy assessments, according to modified RECIST 1.1 for patients with GIST including: confirmed ORR, best overall response, best target lesion response, time to response, DOR, DCR, CBR at 16 weeks, PFS, and OS.
3. Expansion (Phase 2): Efficacy assessments, according to modified RECIST 1.1 for patients with GIST, including: DOR, best overall response, best target lesion response, time to response, DCR, CBR at 16 weeks, PFS, and OS.
4. Expansion (Phase 2): Safety profile of oral THE-630.
5. Expansion (Phase 2): Plasma PK parameters of THE-630 and its active metabolite THE-973, after a single oral dose and at steady state after multiple oral doses.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Theseus Pharmaceuticals Inc.

Sponsor organisation

Theseus Pharmaceuticals Inc.

Address

314 Main Street Suite 04-200

City

Cambridge

Postcode

02142-1014

Country

United States

Scientific contact point

Organisation

Theseus Pharmaceuticals Inc.

Contact name

David Kerstein

Public contact point

Organisation

Theseus Pharmaceuticals Inc.

Contact name

David Kerstein

Third parties 12

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications