Phase 1b and Phase 2 Arms A and B: Adults with tumor protein 53 wild type (TP53wt) Philadelphia chromosome positive (Ph+) CML in chronic phase who are refractory or intolerant to = 2 prior TKIs and meeting European LeukemiaNet (ELN) criteria for treatment failure on their current TKI. Phase 2 Arm C: Adults with TP53wt Ph+ CML in accelerated phase who are refractory or intolerant to = 2 prior TKIs and meeting ELN criteria for treatment failure on their current TKI. MedDRA version: 21.1 Level: L
Conditions
Interventions
Product Code: KRT-232
Pharmaceutical Form: Tablet
INN or Proposed INN: Not yet
CAS Number: 1352066-68-2
Current Sponsor code: KRT-232
Other descriptive name: AMG 232
Concentration unit: mg milligram(s
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Phase 1b and Phase 2 Arms A and B: Documented TP53wt, Ph+, BCR ABL+ CML-CP according to definitions provided in Appendix 6. 2. Phase 2 Arm C ONLY: Documented TP53wt, Ph+, BCR-ABL+ CML AP according to definitions provided in Appendix 6 with no alternative therapeutic options likely to produce clinical benefit. 3. Subject is resistant (relapsed or refractory) and/or intolerant to at least 2 prior TKIs. a. Resistance is defined as meeting at least one of the following criteria: i. No cytogenetic response (> 95% Ph+) or failure to achieve CHR 3 months after the initiation of therapy; ii. Less than a minor cytogenetic response (> 65% Ph+) 6 months after the initiation of therapy; iii. Less than a PCyR (> 35% Ph+) 12 months after the initiation of therapy; iv. The development of new BCR-ABL kinase domain mutations in the absence of CCyR at any time after the initiation of therapy; v. The development of new clonal evolution in the absence of CCyR at any time after the initiation of therapy; OR vi. The loss of cytogenetic response (from complete [0%], partial [1 to 35%], minor [36 to 65%], or minimal [66 to 95%] to a response at least 1 grade worse), confirmed in at least 2 consecutive analyses, separated by at least 4 weeks, at any time after the initiation of therapy. b. Intolerant is defined as either: i. Non-hematologic intolerance: subjects with Grade 3 or 4 toxicity while on therapy, or with persistent Grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the subject if response is already suboptimal) in the absence of CCyR; OR ii. Hematologic intolerance: subjects with Grade 3 or 4 absolute neutrophil count (ANC) or platelets while on therapy that is recurrent after dose reduction to the lowest recommended doses by the manufacturer in the absence of CCyR. 4. Treatment failure on current TKI therapy (as per ELN criteria) defined as either: a. No CHR or > 95% Ph+ metaphases 3 months after initiation of therapy, OR b. BCR-ABL1 ratio > 10% International Standards (IS) and/or > 65% Ph+ metaphases 6 months after initiation of therapy, OR c. BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases 12 months after initiation of therapy. 5. On a stable dose for at least 4 weeks on the current TKI therapy prior to the first dose of study treatment. This TKI will be continued on the study. 6. Adults = 18 years of age. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 8. Adequate hematologic function independent of growth factor support for at least 7 days with the exception of pegylated granulocyte-colony stimulating factor and darbepoetin which require at least 14 days, defined as: a. ANC = 1.0 x 10(9)/L. b. Platelet count = 100 x 10(9)/L for subjects with CML-CP; platelet count = 75 x 109/L for subjects with CML-AP. 9. Adequate hepatic function within 28 days prior to the first dose of study treatment defined as: a. Total serum bilirubin within normal limits; if total bilirubin > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is = 1.5 x ULN. b. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) = 2.5×ULN. 10. Adequate renal function defined by an estimated creatinine clearance = 30 mL/min by Cockcroft-Gault formula. 11. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effecti
Exclusion criteria
Exclusion criteria: 1. Phase 1b and Phase 2 Arms A and B: Documented Ph+, BCR-ABL+ CML-AP according to definitions provided in Appendix 6. 2. Documented Ph+, BCR-ABL+ CML-BC according to definitions provided in Appendix 6. 3. Known history of T315I mutation. 4. Known history of central nervous system (CNS) leukemia involvement. 5. Prior treatment with MDM2 antagonist therapies. 6. Concurrent anticancer treatment such as chemotherapy, cytoreductive therapy, immune therapy, investigational new drug, or cytokine therapy within 28 days of the first dose of study treatment. Current TKI dosing is permitted. 7. Intolerance to current TKI therapy 8. Active participation in any other therapeutic clinical trials including supportive care trials. 9. History of major hemorrhage or intracranial hemorrhage within 6 months prior to the first dose of study drug. 10. Known infection with human immunodeficiency virus. 11. Known active hepatitis B or C infection. 12. 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. 13. 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, unstable ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements 14. Grade 2 or higher corrected QT interval (QTc) prolongation > 480 msec per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. 15. Subjects who 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 study treatment. 16. History of major organ transplant. 17. 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 judgment of the treating physician, these subjects may be on antibiotics at the time of enrollment. 18. Subjects who are pregnant or breast feeding. 19. Subjects with 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Phase 1b: To determine the KRT 232 maximum tolerated dose/ maximum administered dose (MTD/MAD) and recommended Phase 2 dose (RP2D) in combination with dasatinib or nilotinib. - Phase 2: To determine the rate of major cytogenetic response rate (MCyR) at 6 months in Arms A and B (Adults with tumor protein 53 wild type (TP53wt) Philadelphia chromosome positive (Ph+) CML in chronic phase who are refractory or intolerant to = 2 prior TKIs and meeting European LeukemiaNet (ELN) criteria for treatment failure on their current TKI). - Phase 2: To determine the rate of major hematologic response (MaHR) in Arm C (Adults with TP53wt Ph+ CML in accelerated phase who are refractory or intolerant to = 2 prior TKIs and meeting ELN criteria for treatment failure on their current TKI).;Secondary Objective: - Phase 1b: To determine the pharmacokinetics (PK) of KRT-232 - Phase 1b: To evaluate the effect of KRT-232 in combination with dasatinib or nilotinib on select PK, pharmacodynamics, disease biomarkers and markers of resistance - Phase 2: To determine the rate of MCyR at 12 months in Arms A and B - Phase 2: To determine the rate of MCyR in Arm C - Phase 2: To determine the duration of response (DOR) in each Arm - Phase 2 : To determine the rate of complete hematologic response (CHR) in Arms A and B - Phase 2: To determine progression-free survival (PFS) in each Arm - Phase 2: To determine overall survival (OS) in each Arm - Phase 2: To determine the proportion of subjects who transition to ASCT in each Arm - Phase 2: To determine the safety and tolerability of KRT 232 in combination with dasatinib or nilotinib - Phase 2: To evaluate the effect of KRT-232 in combination with dasatinib or nilotinib on select PK, PD, disease biomarkers and markers of resistance;Primary end point(s): - Phase 1b: Determination of the dose limiting toxicities (DLTs) will be used to establish the MTD/MAD of KRT-232 in combination with dasatinib or nilotinib. - Phase 2: The proportion | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: KRT-232 and acyl glucuronide metabolite (M1) PK parameters including but not limited to: • Maximum observed concentration (Cmax) • Minimum observed concentration (Cmin) • Area under the plasma concentration-time curve (AUC) • Time to maximum plasma concentration (Tmax) - Phase 1b: Biomarkers including but not limited to: TP53, BCR-ABL1 status, myeloid markers of CML and myeloproliferative neoplasms (MPN) • Ex vivo drug sensitivity in bone marrow aspirate (United States [US] sites only) • Pharmacodynamic pathway activation/modulation • Inflammatory markers (C-reactive protein [CRP] and other serum analytes) • Peripheral blood cell phenotyping - Phase 2: The proportion of subjects who achieved CCyR or PCyR according to modified ELN criteria (Appendix 5). - Phase 2: DOR (Kaplan-Meier estimate) defined as the time from first observation of response to progression/relapse or death, whichever comes first- - - - - Phase 2: The proportion of subjects who achieve a CHR according to modified ELN criteria (Appendix 5). - Phase 2: PFS is defined as the time from the first treatment dose date to progression/relapse or death, whichever comes first - Phase 2: OS is defined as the time from the first treatment dose date to death from any cause - Phase 2: The proportion of subjects who transition to allogeneic transplant - Phase 2: Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious adverse events (SAEs), electrocardiograms (ECGs), and vital signs - Phase 2: KRT-232 and acyl glucuronide metabolite (M1) PK parameters including but not limited to: • Observed concentration 2 hours post dose (C2hr) • Cmin ;Timepoint(s) of evaluation of this end point: Secondary Efficacy Endpoints - The secondary efficacy endpoints (DOR, PFS, and OS) will be summarized by Kaplan Meier analyses with estimated medians, 95% CI, and ranges reported in months. The MCyR | — |
Countries
Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Spain, United States
Contacts
Public ContactJohn Mei
Kartos Therapeutics, Inc.
Outcome results
None listed