Relapsed or refractory AML, AML secondary to myeloproliferative neoplasms (MPN), and JAK2 mutationpositive AML. MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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
Exclusion criteria
Exclusion criteria: 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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Objective for Part A: To determine KRT-232 recommended phase 2 dose (RP2D). Primary Objective for Part B: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh).;Secondary Objective: (Secondary Obj. Part A/Part B): Part A Only-to determine rates complete remission (CR), complete remission w/partial hematological improvement (CRh). To determine Overall Response Rate.To determine rate of return chronic phase MPN w/peripheral blast count 50,000/µL and ANC >500/ µL).;Timepoint(s) of evaluation of this end point: • DLTs are defined as the following study treatment-related adverse events (TEAEs) occurring in the 1st cycle (i.e., in the first 28 days) of Part A. • 2017 ELN response criteria will be used to assess the Bone marrow aspirate and biopsy results. Bone marrow aspirate and biopsy will be obtained at: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9, 12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle while on study treatment; At suspected disease progression. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Responses (in Part A and B) will be assessed per the 2017 European LeukemiaNet (ELN) response criteria (Appendix 3) to determine rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) (in Part A); to determine the overall response rate (ORR); rate of return to chronic phase MPN with peripheral blast count 50,000/µL and ANC >500/ µL). • Number of subjects who transition to allogeneic transplant • Efficacy analyses will be evaluated in subjects who are JAK2 V617F positive and negative • Safety endpoints will include the following measurements or assessments: physical examinations; laboratory tests; KRT-232 dose reductions, interruptions and discontinuations; adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), vital signs • KRT-232 and acyl glucuronide metabolite (M1) PK will be monitored on Cycles 1 and 2 with sparse sampling. (Exploratory endpoints): • Biomarkers including but not limited to: -TP53 mutation status, JAK2 mutations, and other AML-, sAML-, and MPN-related genes -TP53-related gene expression: p21 (CDKN1A), MDM2, MDMX (MDM4), PUMA (BBC3) -Flow cytometry of peripheral blood blasts -MIC-1 protein in serum • UGT1A1*28 genotype (*1*1, *1*28, *28*28);Timepoint(s) of evaluation of this end point: • 2017 ELN response criteria will be used to assess the Bone marrow aspirate and biopsy results. Bone marrow aspirate and biopsy will be obtained at: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9, 12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle while on study treatment; At suspected disease progression • Safety endpoints will be assessed at various timepoints as per the Schedule of Assessments (Appendix 1 of the Protocol). • PK: At Cycle 1, Cycle 2, Day 1: Pre-dose and a single point taken anytime from 0.5 to 6 hours post-dose. At Cycle 1 Day 8: 24 hours (window ±1 hour) after the Day 7 dose (Exploratory endpoints): • Biomarkers and UGT1A1*28 gen | — |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Korea, Republic of, Norway, Poland, Romania, Russian Federation, Singapore, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
Public ContactClinical Operations
Kartos Therapeutics, Inc.
Outcome results
None listed