| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Or Secondary (Post-PV MF or Post-ET-MF) Myelofibrosis (MF) With Intermediate Or High-Risk TP53 Wild-Type (TP53 WT) Who Are Relapsed Or Refractory to Janus Kinase (JAK) - Inhibitor Treatment. |
|
| E.1.1.1 | Medical condition in easily understood language |
| A disorder of the bone marrow |
|
| 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 | 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) |
|
| 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) |
|
| 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) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A: to determine spleen response.
Part B: To compare the spleen volume reduction (SVR) at Week 24 between Arm 1 and Arm 2 |
|
| E.2.2 | Secondary objectives of the trial |
Part A:
To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48;
To determine the duration of spleen response (DoR-spleen);
To determine spleen size reduction as measured by palpation;
To determine RBC transfusion usage;
To determine the clinical response rate at Week 24;
To determine the overall survival (OS) rate;
To determine the safety and tolerability of KRT-232;
To determine the PK/PD profile of KRT-232
Part B:
To compare the improvement of TSS at Week 24 between Arm 1 and Arm 2;
To compare the OS between Arm 1 and Arm 2;
To compare the progression free survival (PFS) between Arm 1 and Arm 2;
To compare the overall SVR at any time in each study arm;
To evaluate the spleen response duration between Arm 1 and Arm2;
To compare the rate of conversion from RBC transfusion dependent to independent at Week 24 between Arm 1 and Arm 2;
To evaluate the safety between Arm 1 and Arm 2;
To monitor the PK of KRT-232 (Arm 1 only) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A:
1. Adults >18 years of age
2. Palpable spleen measuring ≥ 5 cm below the left lower costal margin or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment
3. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF according to the World Health Organization (WHO) criteria
4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
5. ECOG performance status of 0 to 2
6. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232)
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.
Subjects in Part A must meet the following JAK inhibitor treatment failure criteria in order to be eligible for the study:
JAK Inhibitor treatment failure in Part A must meet either criterion (a) or (b) below:
a) Either a lack of spleen response defined as receiving at least 12 weeks of JAK inhibitor treatment and having both of the following:
• Persistent splenomegaly, by physical exam, that is palpable ≥ 5 cm below the LLCM
• and TSS of >10 on the MPN-SAF TSS v.2.0 or patients with a single symptom score of >5 or two symptoms of >3, including only the
symptoms of left upper quadrant pain, bone pain, itching, or night sweats
b) Or progressive disease any time while on JAK inhibitor treatment as defined by any one of the following:
• Spleen volume increase by ≥ 25% from the nadir as assessed by MRI or CT
• Appearance of new splenomegaly that is palpable at least 5 cm below the LCM
• A ≥ 100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm
• A ≥ 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm
Part B:
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 (Appendix 3)
3. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) (Appendix 4)
4. Subjects with p53WT MF by central laboratory testing
5. Relapsed or refractory to prior treatment with an approved JAK inhibitor defined as:
Relapsed subjects are those with progressive disease after JAK inhibitor treatment, defined by one of the following:
• Increase in spleen volume by ≥25% by radiographic imaging from nadir
• ≥100% increase in palpable distance below LLCM for baseline splenomegaly of 5 to 10 cm
• ≥50% increase in palpable distance below LLCM for baseline splenomegaly of >10 cm
• Regrowth after achieving complete response
Refractory subjects are those with a lack of spleen response after ≥12 weeks of JAK inhibitor treatment, defined as <10% spleen volume reduction by radiographic imaging or <30% decrease from baseline in spleen size by palpation
6. A minimum of 2 symptoms with a score of at least 1 each on the MFSAF v4.0 TSS
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):
Hematologic function independent of growth factors support for 7 days or 14 days for pegylated G-CSF and darbepoetin
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, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study treatment (ie, KRT-232 or BAT) and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study treatment.
|
|
| E.4 | Principal exclusion criteria |
Part A:
1. Patients who are positive for p53 mutations
2. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted)
3. Major surgery within the first 28 days of KRT-232
4. Chemotherapy, immunomodulatory drug therapy within 14 days prior to first dose of KRT-232
5. Prior splenectomy
6. Splenic irradiation within 3 months prior to the first dose of KRT-232
7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation
8. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
9. Prior MDM2 inhibitor therapy or p53-directed therapy
10. Women who are pregnant or breastfeeding
11. History of major organ transplant
12. 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
13. 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.
14. 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
15. Grade 2 or higher QTc prolongation (>480 milliseconds per NCICTCAE criteria, version 5.0)
16. Growth factor treatment (e.g., erythropoeitin) within 14 days prior to first dose of KRT-232; no darbepoetin within 28 days prior to first dose of KRT-232
17. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
Part B:
1. Prior MDM2 inhibitor therapy or p53-directed therapy
2. Participation in an interventional clinical trial within 28 days before randomization (participation in observational studies is permitted)
3. Major surgery or radiotherapy within 21 days prior to randomization, or anticipation of needing such procedures while receiving study treatment
4. JAK-, PI3k-, SYK-, BTK-, BET- or MTOR inhibitor treatment within 28 days prior to the Screening MRI/CT scan
5. Treatment with any other anticancer agent including chemotherapy, immunotherapy or biologic therapy within 28 days prior to randomization. Hydroxyurea may be taken within 1 day prior to Cycle 1 Day 1
6. Prior splenectomy
7. Splenic irradiation within 12 weeks of randomization.
8. Prior allogeneic stem-cell transplantation or plans for allogeneic stem cell transplantation
9. Women who are pregnant, lactating, breastfeeding or intending to become pregnant during the study.
10. History of major organ transplant
11. 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 randomization. Patients with acute infections requiring systemic antibiotic use should complete antibiotic therapy at least 2 weeks prior to randomization
12. 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 psychiatric illness/social situations that would limit compliance with study requirements
13. 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
14. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
15. History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
16. History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment
17. History of severe hypersensitivity reaction to any component of KRT-232
18. History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: The proportion of subjects achieving a ≥35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan
Part B: The proportion of subjects in each arm achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: The Primary Endpoint will be assessed 24 weeks after each subject is enrolled.
Part B: Week 24 |
|
| E.5.2 | Secondary end point(s) |
Part A:
Proportion of subjects who have at least a 50% reduction from baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0.
Duration of a ≥35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT 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
• RBC transfusions (average number of RBC units per patient-month)
• RBC transfusion independence at Week 24 (proportion of patients who were transfusion-independent at Week 24, defined as absence of RBC transfusions and no hemoglobin <8 g/dL in the previous 12 weeks)
Complete remission (CR) and partial remission (PR) defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria
Overall survival is defined as the interval from randomization to death from any cause
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
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 concentrationtime curve (AUC), and terminal elimination half-life (t1/2z)
Part B:
The proportion of subjects in each arm with ≥ 50% reduction in TSS (MFSAF v4.0) at Week 24
Time from randomization to death from any cause in each arm
PFS is defined as the time from randomization to either the first occurrence of disease progression or death due to any cause. Disease progression is defined as any occurrence of the following:
• Spleen progression (≥25% increase in spleen volume from baseline)
• Leukemic transformation (bone marrow blast count of ≥20% or a peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1x109/L that lasts for at least 2 weeks)
• Transformation to accelerated phase (peripheral blood blasts ≥ 15% or peripheral blood blast ≥ 10% confirmed with a repeat assessment at least 3 days later)
• Leukocytosis (WBC ≥ 50x109/L (associated with at least 1% blasts and an increase in WBC of at least 1.5x from baseline)
The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
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
KRT-232 and acyl glucuronide metabolite (M1) plasma concentrations will be monitored in Cycles 1 and 2 with sparse sampling. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: Week 24, Week 48 and duration of study. Please refer to the protocol for full details.
Part B: Week 24, study duration, time from randomization to death from any cause, time from randomization to either the first occurrence of disease progression or death due to any cause, the first occurrence of disease progression. Please refer to the protocol for full details |
|
| 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 | 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) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| BAT: 1) hydroxyurea, 2) chemotherapy or 3) supportive care |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 128 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Israel |
| Mexico |
| Philippines |
| Thailand |
| United States |
| Russian Federation |
| Turkey |
| Bulgaria |
| Croatia |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Lithuania |
| Poland |
| Portugal |
| Romania |
| Spain |
| Hong Kong |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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