| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Phlebotomy-dependent polycythemia vera. Polycythemia Vera (PV) is classified as a myeloproliferative neoplasm (MPN). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Polycythemia vera is a slow-growing blood cancer in which your bone marrow makes too many red blood cells. These excess cells thicken your blood, slowing its flow. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036061 |
| E.1.2 | Term | Polycythemia vera |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <2 g/day for a minimum of 12 weeks, resulting in need for phlebotomy to maintain hematocrit <45% or platelet count >400 x109 /L and white blood cell (WBC) count >10 x 109 /L
HU intolerance is defined as:
• ANC <1.0 x109/L or platelet count <100 x109/L or hemoglobin <100 g/L (i.e., 10 g/dL) at the lowest dose of HU required to achieve a response (hematocrit <45% without phlebotomy and/or all 3 of a platelet count ≤ 400 x109/L, a WBC count ≤10 x109/L, and a nonpalpable spleen)
or
• Presence of leg ulcers or other unacceptable HU-related nonhematologic toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, or fever at any dose of HU), defined as:
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3–4 adverse event (AE) or
>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. 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. |
|
| E.4 | Principal 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 <30 mL/min by Cockcroft Gault)
b. Known history of hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease)
c. Total bilirubin ≥ 2 X upper limit of laboratory normal (ULN) unless Gilbert’s Syndrome
d. Alanine aminotransferase (ALT) > 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 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. Aspirin is permitted per treatment guidelines for PV unless medically contraindicated.
9. Absolute neutrophil count < 1.5 × 109/L prior to dosing on Cycle 1 Day 1
10. Platelet count ≤150 × 109/L prior to dosing on Cycle 1 Day 1
11. Splenic radiation within 3 months prior to first dose of KRT-232
12. Women who are pregnant or breastfeeding
13. History of major organ transplant
14. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; 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; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
15. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
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) |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Israel |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS which could be long term survival follow-up phone call |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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