| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary, post-polycythemia vera (PV), or post-essential thrombocythemia (ET) myelofibrosis (MF), who are treatment naïve to any JAK inhibitor. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10074691 |
| E.1.2 | Term | Post polycythaemia vera myelofibrosis |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 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 |
| To assess the spleen response rate of each arm at Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the change in total symptom score (TSS) for each arm.
- Spleen response duration.
- To determine the rate of conversion from RBC transfusion dependent to RBC transfusion independent at Week 24 for each arm.
- Overall survival (OS).
- Progression free survival (PFS).
- Safety and tolerability to treatment in each arm.
- Characterize the pharmacokinetic profile of KRT-232 (Arm 1) or TL-895 (Arms 2,3 and 4).
- To evaluate patient reported outcomes including quality of life, fatigue, and impression of change.
- To evaluate KRT-232 pharmacodynamic markers (Arm 1).
- To evaluate TL-895 pharmacodynamic markers (Arms 2,3 and 4).
- To determine changes in bone marrow. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults ≥18 years of age able to provide informed consent
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. Palpable spleen measuring ≥5 cm below the left lower costal margin or spleen volume of ≥450 cm3 by magnetic resonance imaging (MRI) or computed tomography (CT) scan assessment.
4. Two symptoms with a score of at least 3 for each symptom, according to Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
5. High-risk, or intermediate-1 and 2 risk, defined by Dynamic International Prognostic System (DIPSS).
6. ECOG performance status of 0 to 1.
7. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of study treatment).
8. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly 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. A woman is considered of childbearing potential (ie fertile, following menarche and until becoming post-menopausal) unless permanently sterile. |
|
| E.4 | Principal exclusion criteria |
1. Arm 1 (KRT-232)
a. Subjects who are positive for p53 mutations.
b. Prior MDM2 inhibitor therapy or p53-directed therapy.
2. 2. Arms 2,3 and 4(TL-895)
a. Prior treatment with any BTK, BMX inhibitor.
b. Require treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study provided the proton pump inhibitor is discontinued at least 3 days prior to first dose of study treatment.
c. Require receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of the first dose of study treatment.
3. Prior treatment with any JAK inhibitor.
4. Major surgery or planned major surgery within 28 days prior to the first dose of study treatment.
5. Chemotherapy, immunomodulating therapy, biologic therapy, or radiation therapy within 14 days prior to the first dose of study treatment. Hydroxyurea must be discontinued at least 14 days prior to the first dose of study treatment.
6. Participation in another interventional clinical trial within the past 4 weeks of the first dose of study treatment (participation in observational studies is permitted).
7. Prior splenectomy.
8. Splenic irradiation within 24 weeks prior to the first dose of study treatment.
9. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for hematopoietic stem cell transplantation per the opinion of the investigator, but who refuse transplant, are eligible for the study.
10. Women who are pregnant or breastfeeding.
11. History of major organ transplant.
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; unstable ventricular arrhythmia; or psychiatric illness/ social situations that would limit compliance with study requirements.
13. Subjects with known active hepatitis B virus (HBV) or hepatitis C virus (HCV).
14. Subjects with known history of HIV.
15. Subjects with clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection, including but not limited to hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Subjects must have completed IV antibiotics at least 2 weeks prior to the first dose of study treatment.
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 National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] criteria, version 5.0).
18. Major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment.
19. Having 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.
20. Known hypersensitivity to or contraindications to the study drug, any of its excipients, or to required prophylaxis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects achieving ≥35% SVR at Week 24 by MRI/CT (central review). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
2. Time from initial SVR of ≥35% by MRI/CT (central review) until progression, defined as 25% increase from baseline in spleen volume, or leukemic transformation (bone marrow blast count of ≥20% or a peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1x10 9/L that lasts for at least 2 weeks).
3. The rate of conversion is defined as the proportion of subjects who convert from transfusion dependent to transfusion independent at Week 24.
4. Time from first dose to death from any cause.
5. Time from first dose to progression (25% increase in spleen volume, or leukemic transformation [bone marrow blast count of ≥20% or a peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1x10 9 /L that lasts for at least 2 weeks]) or death from any cause.
6. Physical exam, laboratory tests, AEs, SAEs, ECGs, vital signs.
7. KRT-232 and acyl glucuronide metabolite (M1) or TL-895 PK
parameters, including but not limited to:
• Maximum observed concentration (Cmax)
• Time of maximum observed concentration (Tmax)area
under the plasma concentration-time curve (AUC)
• Concentration at 2 hours (C2h) (Stage 2 only)
8.
• EORTC QLQ-C30 Questionnaire
• PROMIS Fatigue Questionnaire
• Patient Global Impression of Change Question |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 24 weeks
2. Undefined
3. 24 weeks
4. Undefined
5. Undefined
6. Per schedule of events
7. Per protocol
8. Per schedule of events
|
|
| 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 | 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) | 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 | 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 | 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 | 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 | 10 |
| 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 |
| Brazil |
| Mexico |
| Peru |
| South Africa |
| United States |
| Poland |
| Bulgaria |
| Belarus |
| Georgia |
| Russian Federation |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
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