Details

IRB Study Number 26-120

Status Recruiting

Phase Phase 2

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Description

Primary Objectives

To evaluate the efficacy of KQB198 in combination with imatinib in GIST

Secondary Objectives

To evaluate the secondary efficacy endpoints of KQB198 and imatinib in GIST

To evaluate the safety and tolerability of KQB198 in combination with imatinib

To evaluate the plasma pharmacokinetics (PK) of KQB198 and imatinib

Exploratory Objectives

To evaluate different mutations and co-mutations and correlate with outcome measures

To evaluate ctDNA and correlate with response to treatment

Inclusion Criteria

Inclusion Criteria

  1. Capable of giving signed informed consent as described in Section 10.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  2. Must be at least 18 years of age at the time of signing the ICF.
  3. Locally advanced or metastatic disease which is not amenable to curative therapy (e.g., surgery) as deemed by the investigator.
  4. Histologically confirmed diagnosis of GIST (report to be reviewed by sponsor)
  5. Molecular:
    A. Valid results from local testing of blood or tumor tissue documenting the presence of the KIT or PDGFRA mutation (must not have exon 9 mutation, wild type, and/or PDGFRA D842V).
    B. Local testing must be performed at a CLIA or equivalently certified laboratory.
    C. The presence of tumor KIT or PDGFRA mutation for the purpose of continued participation will be reviewed by the Sponsor by C2D1.
  6. Measurable disease per RECIST v1.1
  7. Participants with brain metastases may participate provided the following:
    A. Radiographic stability (defined as brain imaging obtained at least 4 weeks after treatment of brain metastases showing no evidence of intracranial progression).
    B. Stable neurological symptoms (i.e., must have returned to baseline or resolved).
    C. Steroid dosing must be < 10 mg prednisone equivalent per day
  8. Line of Therapy: Patients must be in 1st line of treatment for advanced or metastatic disease. Prior imatinib is allowed in adjuvant or neoadjuvant setting. Most recent imatinib must be 1 year or more from D1C1.
  9. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 1).
  10. Has adequate organ function.
    A. ANC ≥ 1.0 × 109/L
    B. Hemoglobin ≥ 8.0 g/dL
    C. Platelets ≥ 100 × 109/L
    D. Total Bilirubin ≤ 1.5 × ULN
    i. For participants with Gilbert’s Syndrome or liver metastases ≤ 3.5 × ULN
    E. ALT and AST ≤ 3 × ULN
    i. For participants with liver metastases ≤ 5 × ULN
    F. Estimated Creatinine Clearance ≥ 50 mL/min
    G. LVEF ≥ 50% or institutional LLN
  11. Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade ≤ 1 as per the NCI-CTCAE v5.0, except for alopecia and/or autoimmune endocrinopathies with stable endocrine replacement therapy
  12. A male participant is eligible to participate if they agree to the following during the study intervention period and for at least 6 months after the last dose of KQB198 or for the length of time directed by local guidelines for imatinib, whichever is longer:
    A. Refrain from donating sperm;
    B. Must agree to use contraception as detailed below in Appendix 2. Contraception use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    C. Agree to use a male condom and consider female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year as described in Appendix 2 when having sexual intercourse with a woman of childbearing potential. Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
  13. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
    A. Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 2
    B. Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, as described in Appendix 2 during the study intervention period and for at least 6 months after the last dose of KQB198 or for the length of time directed by local guidelines for imatinib, whichever is longer. Contraception use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
    C. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) with 24 hours before the first dose of study intervention, see Section 8.4.6.
    D. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.4.6.
    E. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a women with an early undetected pregnancy.
  14. Female participants must not donate or retrieve for their own use, ova from the time of screening to 6 months after the last dose of KQB198 or for the length of time directed by local guidelines for imatinib, whichever is longer.

Exclusion Criteria

Exclusion Criteria

  1. Unable to swallow or GI condition that prevents absorption.
  2. Active primary central nervous system (CNS) tumors and/or leptomeningeal metastases.
  3. Other active malignancies within the last 2 years. Nonmelanoma skin cancers, localized malignancies treated with curative intent that have a minimal likelihood of recurrence as deemed by the investigator, and malignancies that do not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia) may be eligible after discussion with the medical monitor or designee
  4. History of significant hemoptysis or hemorrhage within 4 weeks of the first dose of study intervention.
  5. Major surgery or significant traumatic injury within 4 weeks of first dose of study intervention or anticipation of the need for major surgery during study intervention.
  6. Significant cardiac disease:
    a. New York Heart Association class III or IV congestive heart failure;
    b. Unstable angina;
    c. Myocardial infarction within the past 24 weeks; or
    d. Unstable cardiac arrhythmias
  7. Prolongation of QT/QTc interval defined as > 470 msec (average of triplicate screening measurements) using Frederica’s QT correction formula (QTcF) at Screening.
  8. Active interstitial lung disease (ILD), drug-induced ILD or radiation pneumonitis.
  9. Poorly controlled ascites and/or pleural effusion (i.e., requiring paracentesis or thoracentesis weekly or less).
  10. Any uncontrollable intercurrent illness, infection, or other conditions that could limit study compliance or interfere with assessments.
  11. Exposure to any other investigational or commercial anticancer agents or therapies administered with the intention to treat malignancy within 14 days before the first dose administration.
  12. Radiotherapy administered less than 21 days prior to the first dose of study medication or localized palliative radiotherapy administered less than 7 days prior to the first dose of study medication.
  13. Active Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infection. If hepatitis B surface antigen (HBsAg) is positive, quantitative HBV DNA must be undetectable to be eligible. If HCV antibody is positive, quantitative HCV RNA must be undetectable to be eligible.
  14. Active HIV infection (i.e., participants with no detectable viral load for at least 1 month are permitted). HIV testing is not required for the screening unless required by the local health authorities.
  15. Receipt of live attenuated vaccine within 14 days prior to first dose of study intervention.
  16. Use of a strong CYP3A inhibitor within 7 days (or 5 half-lives) and/or strong CYP3A inducer within 14 days (or 5 half-lives) prior to the first dose of study intervention or required concomitant use of a CYP3A strong or moderate inducer or inhibitor during study intervention.
  17. Use of proton pump inhibitor within 7 days prior to the first dose of study intervention or required concomitant use of a proton pump inhibitor during the course of study intervention.
  18. History of hypersensitivity to any component of KQB198 or imatinib.
  19. Pregnant or breast feeding