An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined with Low-Dose Cytarabine (LDAC) or Decitabine in Patients with Acute Myeloid Leukemia (AML).
- Conditions
- Relapsed or refractory AML, AML secondary to myeloproliferative neoplasms (MPN), and JAK2 mutationpositive AML.MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-001201-24-ES
- Lead Sponsor
- Kartos Therapeutics, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 135
1. Adults = 18 years of age
2. ECOG performance status of 0 to 2
3. Part A: Patients with relapsed or refractory AML, or treatment naïve AML secondary to MPN. Diagnosis of AML must be according to World Health Organization (WHO) criteria with at least 20% blasts in the marrow and/or extramedullary leukemia. Patients with known fms-like tyrosine kinase 3 (FLT3) mutations must have been treated with a FLT3 inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients who are known isocitrate dehydrogenase 1 (IDH1) or IDH2 mutation positive must have been previously treated with an IDH1 or IDH2 inhibitor, respectively, (unless contraindicated) if IDH1 or IDH2 inhibitors are approved and available in the country in which the patient is to be treated.
4. Part B: Patients with AML secondary to MPN,as defined by =20% blasts in the bone marrow or peripheral blood,or JAK2 mutation positive AML.
5. Part B: Patients may have been treated with 0 to 2 prior lines of therapy for their AML. Patients with known FLT3 mutations must have been treated with a FLT3 inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients with relapsed or refractory disease who are known IDH1 or IDH2 mutation positive, must have been previously treated with an IDH1 or IDH2 inhibitor (respectively) (unless contraindicated) if IDH1 or IDH2 inhibitors are approved and available in the country in which the patient is be treated.
6. Adequate hepatic and renal function within 28 days prior to the first dose of KRT-232.
Hepatic: Direct bilirubin =2.0 times the upper limit of normal (ULN), unless Gilbert’s Syndrome; aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) =2.5 ULN. Renal: Estimated creatinine clearance =30 mL/min by Cockcroft Gault.
7. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the study. In addition, males must continue to use contraception for 3 months and 1 week after the last dose of study drug and females must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control includes (a) combined, estrogen and progestogen containing, hormonal contraception (oral, intravaginal, transdermal); (b) progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; (f) vasectomized partner; and (g) 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 67
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 68
1. Patients who are TP53 mutation positive
2. Participants who are either refractory to or relapsed within 90 days of receiving a regimen containing a cumulative dose of = 18 g/m2 of cytarabine are not eligible to be treated with cytarabine on this study but may be treated with decitabine on this study
3. Patients who have received prior treatment with decitabine are not eligible to receive decitabine in this study but may be treated with cytarabine on this study
4. Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy and have a donor
5. Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
6. Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
7. Patients with acute promyelocytic leukemia
8. Patients with a history of bleeding diathesis
9. Patients with known active CNS involvement with AML
10. Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 14 days of the first dose of KRT-232, provided they have recovered from treatment toxicity. Patients on hydroxyurea may continue therapy with hydroxyurea until the day before starting therapy on this study. Patients on FLT3 inhibitors may continue therapy with FLT3 inhibitors until the day before starting therapy on this study. Subjects on JAK inhibitors should be tapered off JAK inhibitor therapy prior to starting treatment on this study per the JAK inhibitor tapering guidelines outlined in Section 7.4.1 of this protocol.
11. Patients previously treated with MDM2 antagonist therapies
12. Patients who have had major surgery within 28 days prior to the first treatment with KRT-232
13. Women who are pregnant or breastfeeding
14. Uncontrolled intercurrent illness including, but not limited to, known active hepatitis A, B, or C; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
15. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these patients may be on antibiotics at enrollment.
16. Other 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 nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
17. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method