An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined with a Tyrosine Kinase Inhibitor (TKI) in Patients with Relapsed or Refractory Ph+ Chronic Myeloid Leukemia (CML)
- Conditions
- 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: 21.1Level: LLTClassification code 10009015Term: Chronic myeloid leukemiaSystem Organ Class: 100000004864MedDRA version: 21.0Level: LLTClassification code 10054352Term: Chronic phase chronic myeloid leukemiaSystem Organ Class: 100000004864MedDRA version: 22.0Level: LLTClassification code 10082178Term: Philadelphia positive chronic myeloid leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-004699-16-FR
- Lead Sponsor
- Kartos Therapeutics, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 133
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
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.
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