Phlebotomy-dependent polycythemia vera. Polycythemia Vera (PV) is classified as a myeloproliferative neoplasm (MPN). MedDRA version: 21.1 Level: LLT Classification code 10036061 Term: Polycythemia vera System Organ Class: 100000004864
Conditions
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adults > 18 years of age 2. Documentation that the patient has met the World Health Organization (WHO) criteria for the diagnosis of PV 3. Subjects must be phlebotomy dependent. The definition of phlebotomy dependent is: • Hematocrit is 40–45% with two phlebotomies or more spaced at least 4 weeks apart within 24 weeks before Screening or • Hematocrit level is higher than 45% with at least one phlebotomy within 16 weeks before Screening 4. In Part A, subjects with splenomegaly (defined as spleen volume =450 cubic centimeters cm3) and without splenomegaly by MRI (or CT) are eligible. In Part B, only subjects with splenomegaly by MRI or CT are eligible. 5. Previous treatment with hydroxyurea (HU) (Part A and B), or interferon (Part A only). If previously treated with HU, subject must be resistant to/intolerant of HU according to the following criteria: HU resistance is defined as a dose =2 g/day or a maximum tolerated dose 400 x109 /L and white blood cell (WBC) count >10 x 109 /L HU intolerance is defined as: • ANC 1 week of CTCAE version 5.0 grade 2 AE or Permanent discontinuation of HU or Interruption of HU until toxicity resolved or Hospitalization due to HU toxicity 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 7. Part B only: Subjects must be negative for HbsAg, negative for Hepatitis B core antibody, and negative for viral RNA if HCV antibody is positive. Subjects must be negative for Hepatitis B DNA, if either HbsAg or Hepatitis B core antibody is positive 8. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females 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; and (f) 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. Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirement
Exclusion criteria
Exclusion criteria: 1. Meets the criteria for post-PV myelofibrosis, as defined by the International Working Group- Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2. >10% blasts 3. Clinically significant thrombosis within 3 months of screening 4. Inadequate liver or renal function: a. Renal impairment (estimated creatinineclearance 2.5x ULN 5. Part B only: Previous treatment with a JAK inhibitor 6.Part B only: Patients with a history of progressive multifocal leukoencephalopathy (PML) 7. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors 8. Patients previously treated with MDM2 antagonist therapies, p53-directed therapies, or patients receiving interferon-alpha or anagrelide, within 28 days or approximately 5 half-lives, or hydroxyurea within 1 day, or patients receiving any other cytoreductive or investigational agents within 28 days or 5 half lives of initial KRT-232 dose. Patients receiving hydroxyurea during the screening period may continue hydroxyurea up to and including Study Day -1 (i.e., the day before therapy with KRT-232 is started). Patients being treated with ruxolitinib (or other JAK inhibitor) should be tapered and discontinued from ruxolitinib therapy prior to starting KRT-232 as per the tapering guidelines. Patients who are tapering ruxolitinib during the screening period may continue lowdose ruxolitinib (5 mg QD or 5 mg twice daily [BID]) until Study Day -1. Aspirin is permitted per treatment guidelines for PV unless medically contraindicated. 9. Absolute neutrophil count 480 milliseconds, per NCI CTCAE criteria, version 5.0)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A Primary Objectives -To determine the efficacy of KRT-232 in PV subjects with splenomegaly who are phlebotomy dependent -To determine the dose of KRT-232 in PV subjects with splenomegaly to be evaluated against ruxolitinib in Part B. Part B Primary Objectives To demonstrate superiority of KRT-232 vs. ruxolitinib in PV subjects with splenomegaly who are resistant/intolerant to hydroxyurea;Secondary Objective: Part A and Part B Secondary Objectives -To determine duration of response -To determine the response rate at Week 32 (PR + CR) -To determine spleen response at Week 32 -To determine duration of response, including percentage of subjects with durable response lasting 12 weeks and beyond -To determine KRT-232 safety and tolerability -To determine changes from baseline in patient-reported outcomes -To determine the pharmacokinetic/ pharmacodynamic (PK/PD) profile of KRT-232 ;Primary end point(s): Part A Proportion of subjects with splenomegaly achieving a response at Week 32, with response defined as having achieved both of the following: - The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring postrandomization and prior to the Week 8 visit - A reduction in spleen volume as assessed by MRI (or CT) = 35% from baseline at Week 32 Selection of KRT-232 dose in PV subjects with splenomegaly that has an overall response rate of >40% in Part A Part B Proportion of subjects with splenomegaly achieving a response at Week 32, with response defined as having achieved both of the following: • The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring postrandomization and prior to the Week 8 visit • A reduction in spleen volume as assessed by MRI (or CT) = 35% from baseline at Week 32;Timepoint(s) of evaluation of this end point: up to 32 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Duration of trial;Secondary end point(s): • To estimate the duration of both the absence of phlebotomy eligibility and reduction in spleen volume (for subjects with baseline splenomegaly) • To estimate the proportion of subjects achieving a durable phlebotomy independence • Response per Modified European Leukemia Network (ELN) Criteria • Time to disease progression per Modified European Leukemia Net (ELN) Criteria • Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), ECGs, vital signs • Changes from baseline in patient-reported outcomes •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), and terminal elimination half-life (t1/2z) | — |
Countries
Australia, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Israel, Poland, Spain, United Kingdom, United States
Contacts
Public ContactClinical Operations
Kartos Therapeutics, Inc.
Outcome results
None listed