| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Myelofibrosis and Janus-associated Kinase Inhibitor-Intolerant Myelofibrosis |
|
| 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 | 10028537 |
| E.1.2 | Term | 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b
To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232 in subjects with R/R MF
Phase 2
To determine the spleen response rate |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b
To characterize the PK profile of TL-895 and KRT-232 combination therapy
Phase 2
1.To determine the change in TSS
2.To determine the DoR-spleen
3.To determine the rate of conversion from RBC transfusion dependent to RBC transfusion independent at Week 24
4.To determine the rate of RBC transfusion independence at Week 24
5.To determine the OS
6.To determine the PFS
7.To determine spleen size reduction as measured by palpation
8.To determine the clinical response rate at Week 24
9.To determine the safety and tolerability
10.To characterize the PK profile of TL-895 and KRT-232 combination therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following criteria in order to be eligible for the study:
1. Adults ≥18 years of age and able to provide informed consent.
2. Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
3. Subjects with TP53 WT MF, defined as tumors that do not harbor deleterious alteration in TP53
4. Palpable spleen measuring ≥5 cm below the left lower costal margin or spleen volume of ≥450 cm3 by MRI or CT scan assessment
5. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
6. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) or DIPSS-PLUS
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 according to ECOG performance status criteria
8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 7 days [Phase 1b] or 28 days [Phase 2] prior to the first dose of study treatment)
a. Hematologic:
i. Absolute neutrophil count (ANC) ≥1.0×10^9/L (Note: ANC eligibility is based on values obtained in the absence of growth factors, ie, 7 days for granulocyte colony-stimulating factor (G-CSF) or 14 days for pegfilgrastim)
ii. Platelet count ≥50×10^9/L
iii. Peripheral blood blast count <10%
b. Hepatic:
i. Total bilirubin within normal limits if total bilirubin is >upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is ≤2.0×ULN, unless Gilbert's Syndrome
ii. Aspartate transaminase/serum glutamic oxaloacetic transaminase and alanine transaminase/serum glutamic pyruvic transaminase ≤2.5×ULN
c. Renal:
i. Estimated creatinine clearance (eCcr) ≥30 mL/min by Cockcroft Gault.
9. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use 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.
Must have R/R MF following JAK inhibitor treatment that meets either criterion (1) or (2) below:
1. Relapsed defined by one of the following:
a. Spleen volume increase by ≥25% by radiographic imaging from nadir
b. ≥100% increase in palpable distance below the left lower costal margin (LLCM), for Baseline splenomegaly of 5 to 10 cm
c. ≥50% increase in palpable distance below the LLCM, for Baseline splenomegaly of >10 cm
d. Regrowth after achieving complete response
2. Refractory defined by one of the following after receiving ≥12 weeks of JAK inhibitor treatment:
a. <10% spleen volume reduction by radiographic imaging
b. <30% decrease from Baseline in spleen size by palpation
|
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will not be eligible for the study:
1. Treatment with a JAK inhibitor within 21 days of the Screening MRI/CT
2. Prior MDM2 inhibitor therapy or TP53-directed therapy
3. Prior treatment with a BTK, BMX inhibitor
4. Major surgery, chemotherapy, immunomodulating therapy, biologic therapy, or radiation therapy within 28 days prior to the first dose of study treatment; hydroxyurea may be taken within 1 day prior to the first dose of study treatment
5. Participation in another interventional clinical study within the past 28 days of the first dose of study treatment (participation in observational studies is permitted)
6. Prior splenectomy
7. Splenic irradiation within 12 weeks prior to the first dose of study treatment
8. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation in the opinion of the Investigator; subjects that refuse a transplant are eligible for enrollment in this study.
9. Women who are pregnant or breastfeeding
10. History of major organ transplant
11. 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
12. Subjects with active hepatitis B virus or hepatitis C virus
13. Subjects with known history of human immunodeficiency virus (HIV)
14. 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.
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 National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] version 5.0 criteria)
17. Major hemorrhage or intracranial hemorrhage within 6 months prior to the first dose of study treatment
18. 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 TL-895 or KRT-232
19.Known hypersensitivity to or contraindications to the study drug or any of its excipients, or to required prophylaxis.
20.Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
1. Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids 3 days before Cycle 1 Day 1 are eligible for enrollment in this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
DLTs will be used to establish the MTD. The SRC will determine the RP2D based on safety data from the combination of TL-895 and KRT-232.
Phase 2
The proportion of subjects achieving a ≥35% spleen volume reduction from Baseline to Week 24, as assessed by MRI or CT scan by central review.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
The DLT evaluation period for Cohort 2 is 28 days starting from Cycle 1 Day 1 until Cycle 2 Day 1.
Phase 2
week 24 |
|
| E.5.2 | Secondary end point(s) |
Phase 1b
TL-895, KRT-232, and acyl glucuronide metabolite (M1) PK parameters, including but not limited to the following:
• Cmax
• tmax
• AUC
Phase 2
1.Proportion of subjects who have ≥50% reduction in the TSS from Baseline to Week 24, as measured by MFSAF v4.0.
2.Duration of a ≥35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT for applicable subjects).
3.The rate of conversion is defined as the proportion of subjects who convert from transfusion dependent to transfusion independent at Week 24.
4.The proportion of subjects with RBC transfusion independence at Week 24.
5.Median time to death (Kaplan-Meier estimate in months) and landmark OS rates (%) (OS defined as the interval from the first dose to death from any cause).
6.Median PFS (Kaplan-Meier estimate in months) among subjects who achieve a response (PFS defined as the interval from the first dose to the date of first documented progression of disease by spleen volume, leukemic transformation, or death) and landmark PFS rate (%).
7.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.
8.CR and PR defined according to IWG-MRT.
9.Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs.
10.TL-895, KRT-232, and acyl glucuronide metabolite (M1) PK parameters, including but not limited to the following:
• Cmax
• tmax
• AUC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
Cycle 2
Phase 2
Week24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 |
|
| 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 | 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 | 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 | 5 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| United States |
| Austria |
| France |
| Poland |
| Bulgaria |
| Spain |
| Germany |
| Italy |
| Hungary |
| Serbia |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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