Relapsed or refractory Acute Myeloid Leukemia (AML), AML secondary to myeloproliferative neoplasms (MPN) MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: KRT-232
Product Code: KRT-232 (formerly AMG-232)
Pharmaceutical Form: Tablet
INN or Proposed INN: Navtemadlin
Current Sponsor code: KRT-232
Other descriptive name: AMG-232
Concentration
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Part A Inclusion Criteria Part A subjects must meet all the following criteria to be eligible for the study: 1. Adults = 18 years of age 2. ECOG performance status of 0 to 2 3. 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 FLT3inhibitor (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 IDH2inhibitors are approved and available in the country in which the patient is to be treated. 4. Adequate hepatic and renal function within 28 days prior to the first dose of KRT-232 as described in the protocol. 5. 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 we 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. Part B Inclusion Criteria Part B subjects must meet all of the following criteria to be eligible for the study: 1. Adults = 18 years of age who are able to provide informed consent 2. ECOG performance status of 0 to 2 3. Patients with relapsed or refractory AML secondary to MPN (myelofibrosis [MF],polycythemia vera [PV], or essential thrombocythemia [ET]). Diagnosis of AML must be according to WHO criteria with at least 20% blasts in the marrow and/or extramedullary leukemia. 4. Patients with TP53 wild-type disease, based on local or central testing. 5. Patients may have been treated with =1 prior lines of therapy for their AML secondary to MPN. 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 IDH1or 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 7 days prior to the first dose of KRT-232: • Hepatic: Total bilirubin =2.0 times the upper limit of normal (ULN). Subjects with known Gilbert's Syndrome or disease-related hemolysis must have a total bilirubin=3.0 X ULN; aspartate transaminase/serum glutamic oxaloacetic transaminase(AST/SGOT)
Exclusion criteria
Exclusion criteria: Part A Exclusion Criteria Part A subjects who meet any of the following criteria will not be eligible for the study: 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. Patients with 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; patients with psychiatric illness/social situations that would limit compliance with study requirements; and patients who have been committed to an institution by judicial or administrative authority 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) Part B Exclusion Criteria Subjects who meet any of the following cri
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 RP2D of KRT-232.;Secondary Objective: Part A Only: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh); Part B Only: To determine the rates of complete remission (CR), CR with partial hematological improvement (CRh) and CR with incomplete hematologic recovery (CRi); To determine the overall response rate (ORR), CRc and best overall response (BOR); To determine the rate of return to chronic phase MPN with peripheral blast count <10%; To determine proportion of subjects who transition to allogeneic stem cell transplant; To determine duration of response (DOR) in Part A; To determine DOR in Part B; To determine progression-free survival (PFS); To determine overall survival (OS); Safety and tolerability of KRT-232; To monitor pharmacokinetics (PK) of KRT-232 and metabolites. ;Primary end point(s): • Part A: Dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine and DLTs of KRT-232 in combination with decitabine at each dose level. • Part B: The safety review committee (SRC) will determine the RP2D based on safety and tolerability data obtained from each arm. ;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. Part A: Bone marrow aspirate and/or biopsy, and peripheral blood, 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. Part B: Bone marrow aspirate and/or biopsy, and peripheral blood, will be obtained at: Screening; Within 4 days of the e | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: Responses will be assessed per the Modified 2017 ELN response criteria. Blasts in the bone marrow will be defined morphologically by exam of the aspirate and/or biopsy. CRh is defined as 50,000/µL and ANC >500/µL). Part B: Responses will be assessed per the Modified 2017 European Leukemia Net (ELN) response criteria. Blasts in the bone marrow will be defined morphologically by exam of the aspirate and/or biopsy. • Overall response includes morphologic leukemia-free state (MLFS), CR, CRh, CRi and PR. • Composite complete remission (CRc = CR + CRh) rate. • The proportion of patients that return to chronic phase (peripheral blast count <10%). • Number of subjects who transition to allogeneic transplant. • Duration of response (DOR) is defined as the time from response initiation to PD/death in subjects who have achieved CR or CRh. Subjects with MLFS by bone marrow aspirate and/or biopsy performed earlier in the course of therapy who convert to CRh or CR do not require a separate bone marrow aspirate and/or biopsy at time of CRh or CR to document this. • Progression-free survival (PFS )is defined as the time from first dose date to PD per modified 2017 ELN response criteria or death due to any cause, whichever is sooner. • Overall survival (OS) is defined as the time from first dose date to death due to any cause. • Analyses of the 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: - Cycle 1, Cycle 2 on Day 1: Pre-dose and a single point taken anytime from 0.5 to 6 hr post-dose in Part A; pre-dose and 2 hours post-dose in Part B; - Cycle 1 Day 8: 24 hours after the Day 7 dose.;Timepoint(s) of evaluation of this end point: • | — |
Countries
Australia, Belgium, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Poland, Spain, United Kingdom, United States
Contacts
Public ContactClinical Operations
Kartos Therapeutics, Inc.
Outcome results
None listed