| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Janus associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib |
|
| 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 |
Phase 1b: To determine the recommended Phase 2 dose (RP2D) of TL-895 in combination with ruxolitinib.
Phase 2: To determine the spleen reduction volume (SVR) rate at Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
To determine:
the spleen volume reduction (SVR) rate at Week 24
the improvement in Total Symptom Score (TSS) at Week 24
spleen response
the duration of spleen response (DoR-spleen)
the rate of conversion from Red Blood Cell (RBC) transfusion dependent to independent
the clinical response rate: complete response (CR) and partial response (PR)
the overall survival (OS) rate
progression-free survival (PFS)
To characterize the pharmacokinetic (PK) profile of TL-895 and ruxolitinib
To determine the safety and tolerability of TL 895
Phase 2:
To determine the improvement in TSS at Week 24
To determine spleen response
To determine the DoR-spleen
To determine the rate of conversion from RBC transfusion dependent to independent
To determine the clinical response rate: CR and PR
To determine the OS rate
To determine PFS
To monitor the PK of TL 895 and ruxolitinib
To determine the safety and tolerability of TL 895 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1b and Phase 2 Cohort 2
1. Treatment with ruxolitinib for ≥ 12 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to Sponsor approval of the enrollment form
• A stable dose is defined as a ruxolitinib dose that has not required a treatment hold or dose adjustment
• Subjects must be taking a stable dose of ruxolitinib of at least 5 mg BID or 10 mg QD
Phase 1b and Phase 2 (both cohorts)
2. Subjects ≥ 18 years of age and able to provide informed consent.
3. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician 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. Palpable spleen measuring ≥ 5 cm below the left lower coastal margin (LLCM) or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment
6. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
8. Adequate hematological function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose, independent of growth factor support for at least 7 days, with the exception of pegylated Granulocyte Colony-Stimulating Factor (G CSF) which requires at least 14 days, defined as:
• Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
• Platelet count ≥ 50 × 109/L
9. Adequate hepatic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose of study treatment defined as:
• Total serum bilirubin ≤ 2.0 x upper limit of normal (ULN). Subjects with known Gilbert’s syndrome or disease-related hemolysis must have a total bilirubin ≤3.0 × ULN
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN, and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
10. Adequate renal function within 7 days (Phase 1b) or 28 days (Phase 2) defined as an estimated creatinine clearance ≥ 30 mL/min according to Cockcroft Gault.
11. 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 contraception for 1 month and 1 week and male subjects must continue to use contraception for 3 months and 1 week. A woman is considered of childbearing potential (i.e., fertile, following menarche and until becoming postmenopausal) unless permanently sterile (refer to Appendix 2 of the protocol for additional details).
Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the local prescribing guidelines must be followed for all concomitant drugs administered in this study. |
|
| E.4 | Principal exclusion criteria |
Phase 2 Cohort 1
1. Prior treatment with any JAKi
Phase 1b and Phase 2 Cohort 2
2. Documented disease progression while on ruxolitinib treatment, defined as any of the following:
• ≥100% increase in palpable distance, below the LLCM from nadir for baseline splenomegaly of 5 to 10 cm while on ruxolitinib, or
• ≥ 50% increase in palpable distance, below the LLCM from nadir, for baseline splenomegaly of >10 cm while on ruxolitinib, or
• ≥25% increase from nadir in spleen volume by radiographic imaging while on ruxolitinib treatment, or
• Regrowth after achieving complete response
Phase 1b and Phase 2 (both cohorts)
3. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
4. Prior treatment with a BTK or BMX inhibitor
5. Chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 28 days prior to first dose of study treatment. Subjects on hydroxyurea therapy may continue treatment until 1 day prior to the first dose of study drug.
6. Active participation in other therapeutic clinical trials including supportive care trials
7. Subjects with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 6 months prior to first dose of study treatment
8. Major surgery or planned major surgery within 28 days prior to first dose of study treatment.
9. History of major organ transplant
10. 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
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; ventricular arrhythmia; history of myocardial infarction within 3 months
12. Grade 2 or higher QTc prolongation (> 480 milliseconds [ms] per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
13. Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment.
14. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
15. Known infection with HIV
16. Known hypersensitivity or contraindications to the study drugs or any of their excipients.
17. History of another 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 non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection or superficial transitional cell bladder carcinoma
18. 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 first dose of study drug.
19. Women who are pregnant or breastfeeding.
20. Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (i.e., committed to an institution by judicial or administrative authority) that, in the Investigator's judgment, could jeopardize the subject's safety, or that could interfere with study objectives.
Phase 1b
21. Subjects receiving medications, herbal supplements, or food known to be strong inhibitors of CYP3A within 7 days prior to the first dose of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: Dose-limiting toxicities (DLTs) will be used to establish the maximum-tolerated dose (MTD) of TL-895 in combination with ruxolitinib. The safety review committee (SRC) will determine the RP2D based on safety and efficacy data of the combination of TL-895 and ruxolitinib.
Phase 2: The proportion of subjects achieving SVR of ≥35% at Week 24 by MRI or CT scan (central review)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: End of Phase
Phase 2: Week 24 |
|
| E.5.2 | Secondary end point(s) |
Phase 1b:
The proportion of subjects achieving ≥35% SVR at Week 24 by magnetic resonance imaging (MRI) or computed tomography (CT) scan (central review)
The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0
The proportion of subjects achieving ≥35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects)
Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression or death
The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria
OS is defined as the time from first dose to death from any cause
PFS is the time from first dose date to:
• Disease progression (≥25% increase in spleen volume)
or
• Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 10^9/L that lasts for at least 2 weeks)
or
• Death from any cause
TL-895 and ruxolitinib PK parameters, including but not limited to:
• Maximum observed concentration (Cmax)
• Area under the plasma concentration-time curve (AUC)
• Time of maximum plasma concentration (Tmax)
Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs
Phase 2:
The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by MFSAF v4.0
The proportion of subjects achieving ≥35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects)
Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression or death
The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to IWG-MRT and modified ELN criteria
OS is defined as the time from first dose to death from any cause
PFS is the time from first dose date to:
• Disease progression (≥25% increase in spleen volume)
or
• Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 10^9/L that lasts for at least 2 weeks)
or
• Death from any cause
TL-895 and ruxolitinib plasma concentrations monitored using sparse sampling.
Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: End of Phase
Phase 2: Week 24 |
|
| 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) | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Israel |
| United States |
| France |
| Hungary |
| Italy |
| Poland |
| United Kingdom |
| Spain |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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