E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post-ET-MF) |
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E.1.1.1 | Medical condition in easily understood language |
Patients with Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post-ET-MF) |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074689 |
E.1.2 | Term | Post polycythemia vera myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074690 |
E.1.2 | Term | Post essential thrombocythemia myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10074691 |
E.1.2 | Term | Post polycythaemia vera myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074692 |
E.1.2 | Term | Post essential thrombocythaemia myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077161 |
E.1.2 | Term | Primary myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
• To determine the recommended phase 2 dose (RP2D) of KRT-232 in combination with ruxolitinib |
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E.2.2 | Secondary objectives of the trial |
• To determine spleen response • To determine the change in Total Symptom Score (TSS) based on Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) • To determine the duration of spleen response (DoR-spleen) • To determine spleen size reduction as measured by palpation • To determine red blood cell (RBC) transfusion usage • To determine the clinical response rate: complete response (CR) and partial response (PR) • To determine the overall survival (OS) rate • To determine progression-free survival (PFS) • To determine the leukemia-free survival rate • To determine the safety and tolerability of KRT-232 • To monitor the PK of KRT-232, KRT-232 glucuronide and ruxolitinib
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adults >18 years of age. 2. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF, as assessed by treating physician according to the World Health Organization (WHO) criteria. 3. Treatment with ruxolitinib for ≥ 18 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to Sponsor approval of the enrollment form. 4. Spleen ≥ 5 cm palpable below the LLCM or ≥450 cm3 by MRI or CT 5. Patients must have at least 2 symptoms with a score of at least 1 on the MFSAF v4.0 6. An MRI or CT scan for spleen volume must be performed no more than 14 days prior to the first dose of KRT-232. 7. ECOG performance status of 0 to 2. 8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232). 9. 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, both male and female subjects must continue to use contraception for 6 months after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
1. Patients who are positive for TP53 mutations. 2. Documented disease progression or clinical deterioration any time while on ruxolitinib treatment. 3. Patients who have had a documented spleen response to ruxolitinib. 4. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted). 5. Other JAK inhibitors, except for ruxolitinib treatment; other recent/concurrent treatment such as a major surgery, chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks or approximately 5 half-lives before the first dose of KRT-232, whichever is shorter. Hydroxyurea is permitted up until the day prior to study Day 1 of study treatment with KRT-232. 6. Prior splenectomy. 7. Splenic irradiation within 3 months prior to the first dose of KRT-232. 8. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation 9. Prior MDM2 inhibitor therapy or p53-directed therapy 10. Women who are pregnant or breastfeeding 11. History of major organ transplant 12. Subjects must be negative for HIV-1 antibody, 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. 13. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before screening/enrollment. Subjects with acute infections requiring systemic antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. 14. Patients with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or patients with psychiatric illness/social situations that would limit compliance with study requirements; or patients who have been committed to an institution by judicial or administrative authority. 15. 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. 16. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0). 17. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232.
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose-limiting toxicity (DLTs) will be used to establish the maximum tolerated dose (MTD) of KRT-232 in combination with ruxolitinib. The SRC will determine the recommended phase 2 dose (RP2D) based on safety and efficacy data of the combination of KRT-232 and ruxolitinib. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose-limiting toxicity (DLT) evaluation period is the first cycle (i.e., the first 28 days). All AEs should be considered for DLTs unless reported as unrelated to the study drugs. Specific DLT criteria for nonhematologic toxicity, neutropenia, and thrombocytopenia can be referred from Clinical Protocol. |
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E.5.2 | Secondary end point(s) |
- The proportion of subjects achieving ≥ 35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects). - The percentage change in TSS as measured by the MFSAF v4.0 at any time point from Baseline while on study. - Duration of a ≥ 35% reduction in SVR from Baseline as measured by MRI (or by CT scan for applicable subjects). - Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a ≥ 50% decrease in spleen size - Red blood cell (RBC) transfusion usage: • Rate of RBC transfusion usage (average number of RBC units per patient-month) • Rate of change from RBC transfusion dependent to transfusion independent - The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment(IWG-MRT) and modified European Leukemia Net (ELN) criteria - OS is defined as the interval from randomization to death from any cause - PFS is the interval from Cycle 1 Day 1 to: • Disease progression (≥ 25% increase in spleen volume) or • Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥ 20% associated with an absolute blast count of at least 1 x 109/L that lasts for at least 2 weeks) or • Death from any cause - Leukemia-free survival is defined as the interval from Cycle 1 Day 1 to the date of first documented transformation to leukemia (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 109/L that lasts for at least 2 weeks). - Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs - KRT-232, acyl glucuronide metabolite (M1) and ruxolitinib PK parameters will be determined, including but not limited to: • Maximum observed concentration (Cmax) • Minimum observed concentration (Cmin) • Area under the plasma concentration-time curve (AUC) • Time of maximum plasma concentration
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bone marrow aspirate and biopsy: At Screening visit and at Week 24. Palpation of Spleen Size: Performed at Screening and at each physical exam till end of treatment period MRI (or CT) of abdomen and Volumetric Measurement of Spleen: Week 12, Week 24, and every 12 weeks, and anytime splenic progression is suspected (this may be at an unscheduled imaging visit) Response assessment per IWG-MRT: At Week 24, and every 24 weeks PRO MFSAF TSS v4.0 Questionnaire: Daily until End of Treatment Transfusion dependence: At Screening and on Day 1 of every cycle Hematology: Cycle 1, 2, and 3 (Days 1, 8, 15, 22); Cycle 4 and beyond on Day 1 of each cycle AEs: Every visit Biomarkers: Subjects will have a blood sample collected and stored at the time points indicated in Table-3 of protocol. |
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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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
To determine MTD of KRT-232 in combination with ruxolitinib in a 3+3 dose-escalation design |
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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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Safety and Efficacy of KRT-232 with Ruxolitinib in Patients with PMF, Post–PV-MF, Post-ET-MF |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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 |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
United States |
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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
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The study will be considered complete 2 years after the last subject is enrolled, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |