| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Myelofibrosis, Janus Kinase Inhibitor Intolerant Myelofibrosis, Janus Kinase Inhibitor Treatment Ineligible Myelofibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelofibrosis is an uncommon type of bone marrow cancer that disrupts the body's normal production of blood cells. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A: To determine the recommended phase 2 dose and schedule of TL-895 in each cohort.
Part B: To determine the spleen volume reduction rate of Cohorts 1, 2 and 3 at Week 24 |
|
| E.2.2 | Secondary objectives of the trial |
Part A:
To determine the spleen volume reduction rate of each arm of Cohorts 1, 2 and 3 at Week 24
Improvement in Total Symptom Score in each arm of Cohorts 1, 2 and 3 at Week 24
To evaluate the effect of TL-895 on BTK/BMX occupancy in peripheral blood mononuclear cells of subjects in Cohorts 1, 2 and 3
To characterize the pharmacokinetic profile of TL-895
Part B:
Improvement in Total Symptom Score at Week 24
To determine the rate of conversion from red blood cell transfusion dependent to independent
To determine the rate of red blood cell transfusion independence at Week 24
To determine the duration of response
To determine the progression-free survival
To determine the overall survival
To evaluate safety and tolerability of TL-895
To evaluate the effect of TL-895 on BTK/BMX occupancy in peripheral blood mononuclear cells of subjects
To monitor the pharmacokinetics of TL 895 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The inclusion criteria mentioned below are applicable to all cohorts unless otherwise specified.
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. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
4. Cohort 1 (relapsed/refractory MF) - Must have relapsed or refractory MF following JAKi treatment.
Relapsed MF is defined as 1 of the following:
a. Spleen volume increase by ≥25% by radiographic imaging from nadir
b. A ≥100% increase in palpable distance below the left lower coastal margin (LLCM), for baseline splenomegaly of 5 to 10 cm
c. A ≥50% increase in palpable distance below the LLCM, for baseline splenomegaly of >10 cm
d. Regrowth after achieving complete response
Refractory MF is defined as 1 of the following after receiving ≥12 weeks of JAKi treatment:
e. <10% spleen volume reduction by radiographic imaging
f. <30% decrease from baseline in spleen size by palpation
5. Cohort 2 (JAKi intolerant MF) - Must have received JAKi treatment for at least 28 days complicated by one of the following criteria while receiving treatment:
a. RBC transfusion requirement (≥2 units per month for 2 months)
b. Grade ≥ 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage
6. Cohort 3 (JAKi treatment ineligible MF) - Must be ineligible for JAKi treatment defined by a platelet count of ≤50 x 109/L
7. Palpable spleen measuring ≥5 cm below the LLCM or spleen volume of ≥450 cm3 by MRI or CT scan assessment
8. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
10. Adequate hematological function independent of growth factor support for at least 7 days with the exception of pegylated granulocyte colony-stimulating factor (G-CSF) and darbepoetin which require at least 21 days, defined as:
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L
b. Platelet count ≥50 × 109/L for Cohorts 1 and 2, and ≥25 × 109/L for Cohort 3
11. Adequate hepatic function defined by:
a. Total bilirubin level within normal limits (WNL); if total bilirubin is > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is ≤2.0 x ULN
b. Aspartate aminotransferase (AST) ≤2.5 × ULN, and alanine aminotransferase (ALT) ≤2.5 × ULN.
12. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according Cockcroft Gault
13. 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 and continue to use contraception for 60 days after the last dose of study drug. Effective birth control for males is the use of condoms. Effective birth control for females includes (a) combined, estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion/ligation; (e) vasectomized partner; (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. Prior treatment with any BTK, BMX, BCR-ABL, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET) or spleen tyrosine kinase (Syk) inhibitors
2. Cohorts 1 and 2 - Prior treatment with JAKi within 21 days of the Screening MRI/CT scan.
3. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
4. Prior therapy with:
a. Anticancer treatment with chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or with any other anticancer therapy within 28 days prior to first dose of study treatment (except for JAKi [see exclusion #2]). Hydroxyurea may be taken within 1 day of the first dose of study treatment.
b. Any investigational agent within 28 days or 5 half-lives, whichever is longer, prior to first dose of study treatment. Participation in observational study is permitted.
c. Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within 3 months prior to first dose of study treatment
5. Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within 6 months prior to first dose of study treatment.
6. Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant
7. 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
8. 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
9. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
10. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of screening.
11. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
12. Subjects with known history of human immunodeficiency virus (HIV)
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. Requires treatment with proton-pump inhibitors (e.g., 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.
15. Women who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: The safety review committee (SRC) will determine the RP2D and schedule for Cohorts 1, 2 and 3 based on safety and tolerability data obtained from each arm of that cohort
Part B: The proportion of subjects achieving ≥35% spleen volume reduction at Week 24 by MRI or CT scan (central review) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: End of Cohort
Part B: Week 24 |
|
| E.5.2 | Secondary end point(s) |
Part A:
The proportion of subjects achieving ≥35% spleen volume reduction at Week 24 by magnetic resonance imaging or computed tomography scan (central review)
The proportion of subjects achieving ≥50% reduction in Total Symptom Score at Week 24 by Myelofibrosis Symptom Assessment Form
BTK/BMX occupancy in peripheral blood mononuclear cells
TL-895 pharmacokinetic parameters (including but not limited to, predose concentration, Observed concentration 2 hours post dose, Cmax, Tmax, AUC)
Part B:
The proportion of subjects achieving ≥50% reduction in Total Symptom Score at Week 24 by Myelofibrosis Symptom Assessment Form
The proportion of RBC dependent subjects achieving red blood cell transfusion independence at Week 24
The proportion of subjects with red blood cell transfusion independence at Week 24
Time from initial response to progression
Time from the first dose to progression or death from any cause
Time from the first dose to death from any cause
Analyses of the safety and tolerability endpoints will include the following measurements or assessments - Incidence, nature, the severity of treatment-emergent adverse events and deaths, including the cause of death, from Screening up to the End of Treatment visit. Clinical laboratory measurements, electrocardiogram measures, vital signs, Eastern Cooperative Oncology Group performance status from Screening up to the End of Treatment visit.
BTK/BMX occupancy in peripheral blood mononuclear cells
TL-895 pharmacokinetics will be monitored with sparse samples collected on Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose and 2 hours post-dose
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 24 or End of Treatment visit |
|
| 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 | No |
| 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.8.3 |
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 | 40 |
| 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 |
| Belgium |
| Brazil |
| Bulgaria |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Romania |
| Spain |
| United Kingdom |
| United States |
| France |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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