| 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: Improvement in Total Symptom Score 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 characterize the pharmacokinetic profile of TL-895
Part B:
To determine the platelet response rate
To determine the duration of platelet response
To determine the incidence of platelet transfusion
To determine the incidence of bleeding events
To determine the spleen volume reduction rate 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 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 who are 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. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
4. Cohort 1 (relapsed/refractory MF) (closed for enrolment) - 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 from nadir, 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) (closed for enrollment after approval of Amendment 4) - 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 - Must be ineligible for JAKi treatment defined by a platelet count of ≥ 25 and < 50 x 109/L (based on the average of 2 platelet assessments performed at least 1 week apart, and without platelet transfusion in the 2 weeks prior to platelet assessments).
7. Cohort 4 (JAKi treatment ineligible MF) - Must be ineligible for JAKi treatment with a platelet count of ≥ 15 and < 25 x 109/L (based on the average of 2 platelet assessments performed at least 1 week apart).
8. MF symptoms as defined by having at least 2 symptoms with an average baseline (Day -7 to Day -1) score of at least 1 for each of the 2 symptoms per MFSAF v4.0
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
10. Adequate hematological function independent of myeloid 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, ≥ 25 and < 50 × 109/L for Cohort 3, and ≥ 15 and < 25 × 109/L for Cohort 4. Platelet count for Cohort 3 and Cohort 4 must be based on the average of 2 platelet assessments performed at least 1 week apart.
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 a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week and male subjects must continue to use a highly effective method of contraception for 3 months and 1 week. 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. Prior treatment with any BTK or BMX inhibitors
2. Prior treatment with JAKi within 28 days prior to first study treatment.
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 with the exception of prednisone. Prednisone 5 mg QD may be administered from Day 28 until 1 day prior to Cycle 1 Day 1. Subjects on a stable dose of erythroid growth factor support for at least 3 months prior to Cycle 1 Day 1 are eligible for the study.
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
d. For Cohorts 3 and 4: Requiring or receiving anticoagulation within 7 days of first dose of study treatment. Subjects on anti-platelet therapy can be allowed on study after discussion with and approval by the medical monitor.
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. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural)
8. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
9. 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
10. 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
11. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
12. Subjects with uncontrolled bacterial, fungal, parasitic, tuberculosis
(TB), 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.
13. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
14. Subjects with known history of human immunodeficiency virus (HIV)
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. 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. provided the proton-pump inhibitor is discontinued at least 3 days prior to the first dose of study drug.
17. Women who are pregnant or breastfeeding.
18. Subjects with peripheral blood or bone marrow blast counts ≥10% within 28 days prior to first dose of study treatment.
19. Subjects who are eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) per the opinion of the investigator and have a donor. Subjects who are HSCT eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
20. Subjects who have received a live vaccine within 28 days prior to
Cycle 1 Day 1 or plan to receive one during the study.
21. Known hypersensitivity to study drug or its excipients.
22. Persons committed to an institution by virtue of an order issued
either by the judicial or the administrative authorities |
|
| 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
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 a platelet response defined as per modified International Working Group – Myeloproliferative Neoplasms
Research and Treatment (IWG-MRT 2006) criteria (≥ 50% increase in platelet count with an absolute platelet count of ≥ 50 x 109/L, both lasting for at least 8 weeks, independent of any platelet transfusion)
The proportion of subjects achieving a platelet response defined as per IWG-MRT 2006 criteria (≥ 100% increase in platelet count with an absolute platelet count of ≥ 50 x 109/L, both lasting for at least 8 weeks, independent of any platelet transfusion; Tefferi 2006)
The duration of platelet response in subjects achieving a platelet response defined as per the IWG-MRT 2006 and modified IWG-MRT 2006 criteria
The proportion of subjects receiving platelet transfusions while on study treatment
The proportion of subjects with major bleeding events (ie, any hemorrhagic event that was an SAE, grade 3 or higher in severity, or that was a central nervous system hemorrhage of any severity grade)
The proportion of subjects achieving ≥35% SVR at Week 24 by MRI or CT scan (central review)
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.
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 | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Taiwan |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Spain |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| 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 | 4 |
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