Clinical Trial TitleAn Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined with KRT-232 in Subjects with Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia (AML)
National Clinical Trial Number:NCT04669067
Clinical Trial Protocol Description:
This is a phase 1b/2 study of KRT-232 (study drug) in combination with TL-895 (study drug) in adults 18 years and older with Acute myeloid leukemia (AML) that has come back or is not responding to other treatment. Acute myeloid leukemia (AML) is a type of cancer of the blood and bone marrow with excess immature white blood cells. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, with a median age at diagnosis of 67 years, and more than a third of patients being 75 years or older.
This multisite treatment study will be conducted in 2 parts. Part 1 is being done to find the dose of TL-895 in combination with KRT-232 to be tested in Part 2. In part 1 of the study, subjects will take TL-895 twice a day, continuously in 28-day cycles. Subjects will also take KRT-232 once a day on days 1-7 of each cycle. In part 2 of the study, subjects will take TL-895 twice a day and KRT-232 once a day on days 1-7 of each 28-day cycle at the doses identified in Part 1.
Clinical Trial Eligibility Criteria:
In order to participate in the Phase 1b and Phase 2 Dose Expansion you must meet the following criteria:
- Are ≥18 years of age.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Have documented primary TP53wt AML or TP53wt AML secondary to myelodysplastic syndrome (MDS), as defined by World Health Organization (WHO) criteria.
- Are refractory to and/or relapsed after at least one prior therapy with no alternative therapeutic options likely to produce clinical benefit. Subjects must have received a FLT3 inhibitor (unless contraindicated), if FLT3 inhibitors are approved and available in the country in which the subject is to be treated.
- Have presence of the FLT3 activating mutation tyrosine kinase domain (TKD) or FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in bone marrow or peripheral blood detected by a test approved by the local health authority or, if not available, by a validated test.
- Have adequate renal function defined by an estimated creatinine clearance ≥30 mL/min by Cockcroft-Gault formula.
- Have adequate hepatic function within 28 days prior to the first dose of study treatment defined as:
- Total serum bilirubin within normal limits; if total bilirubin > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is ≤ 2. 0 x ULN.
- Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN.
- Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male and female subjects must continue to use contraception for 3 months (+1 week) and 1 month (+1 week), respectively after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females ncludes (a) combined estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method;(d) bilateral tubal occlusion or ligation; (e) vasectomized partner; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject.
- Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
You will be excluded from the Phase 1b and Phase 2 Dose Expansion if any of the following criteria apply to you:
- Have acute promyelocytic leukemia (AML subtype M3).
- Have known active central nervous system involvement with AML.
- Have had prior treatment with murine double minute chromosome 2 (MDM2) antagonist therapies.
- Have had prior treatment with a Bruton’s tyrosine kinase (BTK) inhibitor.
- Have had chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 14 days prior to first dose of study treatment. Subjects on hydroxyurea therapy may continue treatment until one day prior to the first dose of study drug. Subjects on FLT3 inhibitor therapy must discontinue treatment at least 2 days prior to first dose of study drug.
- Are an active participant in other therapeutic clinical trials including supportive care trials.
- have had allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment.
- Are eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) per the opinion of the investigator and have a donor. Subjects who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
- Have a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment.
- Have known infection with human immunodeficiency virus.
- Have known active hepatitis B or C infection.
- Have a history of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection or superficial transitional cell bladder carcinoma.
- Have uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Class III or IV); symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
- Have grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
- Have a history of myocardial infarction within 3 months of first dose of study treatment.
- Have a history of major organ transplant.
- Require or are receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of the first dose of study drug.
- Require treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole); subjects receiving proton pump inhibitors (PPIs) who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study provided the proton pump inhibitor is discontinued at least 5 days prior to first dose of study drug.
- Phase 1b only: Subjects receiving medications, herbal supplements, or food known to be strong inhibitors of Cytochrome P450 3A4 (CYP3A) within 7 days prior to the first dose of TL-895
- Have a history of difficulty swallowing, gastric or small bowel surgery with history of malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the KRT-232 or TL-895 treatment.
- Have had major surgery or planned major surgery within 28 days prior to first dose of study treatment.
- Have clinically significant active infection requiring parenteral therapy.
- Are pregnant or breastfeeding.
- Have a medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives.
This is a partial list of eligibility requirements. To inquire about your eligibility, please call the contact number provided. If you wish to inquire via email, please include the title of the study in your message.