Previously untreated metastatic and/or unresectable gastrointestinal stromal tumors

In previously untreated patients with metastatic and/or unresectable GIST, the efficacy (clinical activity) of velzatinib compared to imatinib was evaluated using progression-free survival (PFS) as a measure.

Imatinib tablets 100mg
Imatinib tablets 400mg
Velzatinib (GSK6042981) Tablets 100mg

IMATINIB MESYLATE
IMATINIB MESYLATE
GSK6042981

Tablets
Tablets
Tablets

100 mg
400 mg
100mg

PFS is defined as the period from the randomly assigned date to the date the disease worsens, or the date of death from any cause (whichever occurs first).

1. Must be 18 years of age or older, or of legal consent age in the region where the trial is being conducted, at the time of signing the informed consent form.
2. Must have a histologically or cytologically confirmed gastrointestinal stromal tumor that is metastatic and/or surgically unresectable.
3. Must not have received systemic therapy for metastatic and/or surgically unresectable gastrointestinal stromal tumors.
4. Tumor tissue must be provided to the central laboratory. Tumor tissue may be preserved tissue (preferred) or freshly collected slides obtained under standard care (slides must be collected prior to randomization).
5. Must have ≥ 1 target lesion.
6. Must be willing to use appropriate contraception [male and/or female participants].
7. Must be able to sign an informed consent form, including compliance with the requirements and restrictions listed therein.
8. ECOG performance status ≤ Level 1.
9. Must have adequate organ function.

1. Having been diagnosed with a malignant tumor that has worsened or requires active treatment within the past 24 months (excluding the trial disease), except for resected basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the skin [e.g., breast, cervix, bladder] without evidence of metastasis.

2. Having any clinically significant gastrointestinal abnormality that may alter absorption, such as malabsorption syndrome, or extensive gastrectomy and/or bowel resection.

3. Having undergone any major surgery within 14 days prior to receiving the first dose of the investigational drug (minor procedures such as central venous catheter placement and tumor biopsy are not considered major procedures), or not yet fully recovered from surgery.

4. Having a history of allogeneic or autologous bone marrow transplantation or other solid organ transplantation. Participants with a history of autologous stem cell transplantation are eligible to participate in the trial if they meet the following eligibility criteria: a) the transplant was performed >100 days prior to screening, and b) the participant did not have an active infection at screening.

5. Participants are ineligible to participate in the trial due to a known allergy or anaphylactic reaction to velzatinib or imatinib, as determined by the trial administrator or medical monitor.

6. Participants have a history of clinically significant or uncontrolled heart disease, unstable angina, acute myocardial infarction, New York Heart Association class III or IV congestive heart failure, or clinically significant arrhythmias, ventricular arrhythmias, cerebrovascular accidents, transient ischemic attacks, or uncontrolled hypertension that are not controlled by standard care within the past 6 months.

7. Participants have untreated brain or central nervous system (CNS) metastases, or worsening brain/CNS metastases [e.g., new or expanding evidence of brain metastases, or new neurological symptoms attributable to brain/CNS metastases]. Participants with previously treated and clinically stable brain/CNS metastases who have completed ≥2 weeks of all corticosteroid therapy prior to randomization are not ineligible to participate.

8. Having a persistent adverse reaction from prior treatment that has not yet recovered to grade ≤1 or the baseline state before prior treatment (excluding conditions such as hair loss, hearing impairment, vitiligo, endocrine disorders controlled by alternative therapy, and grade 2 neuropathy), or conditions deemed clinically irrelevant to tolerability of the investigational drug in this clinical trial by the trial administrator and agreed upon by the trial commissioner.

9. Having any active renal condition (e.g., infection, requiring dialysis, or any other serious renal condition that may affect participant safety).

10. Having any serious and/or unstable medical condition, mental abnormality, or other condition (including abnormal laboratory assessments) that may interfere with participant safety, obtaining informed consent, or compliance with trial procedures.

11. Having received radiation therapy within 14 days prior to the first dose of the investigational drug.

12. Having received any live vaccine within 30 days of randomization. Receipt of a Covid-19 vaccine authorized through an appropriate regulatory mechanism (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization) will not be excluded.

13. Received any blood products (including platelets or red blood cells) or used colony-stimulating factors (including G-CSF, granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin) within 14 days prior to randomization.

14. Previously used a drug known as a moderate/potent clinical inhibitor or inducer of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); for inhibitors, this means use within 5 days or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug; for inducers, this means use within 14 days prior to the first dose of the investigational drug.

15. Currently participating in, or having participated in before signing an informed consent form, any other clinical trial or other type of medical research involving the investigational drug.

16. Has a positive result in a drug/alcohol screening assessment.

17. Known HIV (human immunodeficiency virus) infection, and meeting at least one of the following criteria:

• Documented evidence of plasma HIV-1 RNA ≥ 50 c/mL within 3 months prior to screening or at the time of screening. To be eligible for the trial, plasma HIV-1 RNA concentration must be maintained < 50 c/mL for 3 to 12 months prior to screening. Participants with multiple plasma HIV-1 RNA levels ≥ 50 c/mL within 3 to 12 months prior to screening are ineligible unless, according to the trial administrator's assessment, the increase is neither persistent nor related to antiretroviral resistance.

Or
• No CD4 cell count has been measured in the past 12 months (i.e., at least two independent measurements, each at least 28 days apart, with one measurement required at screening time).

Or
• Any CD4 cell count ≤ 200 cells/mm3 within the past 12 months.

Or
More than one change (excluding permitted conversions) to a combined antiretroviral therapy regimen during the 3 months prior to screening, or receiving an antiretroviral therapy regimen inconsistent with local guidelines.

Or
• HIV-related non-Hodgkin's lymphoma within the 5 years prior to screening. 17. Medical history, or history of HIV-related invasive cervical cancer;

or
• Received HIV-1 immunotherapy within 90 days of screening.

18. Pregnant or breastfeeding.

19. Unable to adhere to the program protocol, including trial follow-up requirements.

20. Alanine transaminase (ALT) level > 2.5 times the upper limit of normal (ULN), or (for participants with documented liver metastases/tumor invasion) ALT level > 5 times the ULN.

21. Total bilirubin level > 1.5 times the ULN.

22. Has cirrhosis or, according to the trial administrator's assessment, currently has unstable liver or biliary disease, defined as ascites, encephalopathy, coagulation disorders, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

23. Evidence suggests that patients with chronic hepatitis B virus (HBV) infection can still be detected despite receiving antiviral therapy with a high resistance threshold.

24. A 12-lead electrocardiogram showing a mean QTc > 480 msec at screening, corrected by the Fridricia formula, or a history of long QT syndrome.