| 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, Indolent Systemic Mastocytosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelofibrosis is an uncommon disorder that disrupts the body's normal production of blood cells. Indolent Systemic Mastocytosis is a rare disorder where certain type of cells gather in the body. |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10056452 |
| E.1.2 | Term | Indolent systemic mastocytosis |
| 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: Cohorts 1-4: To determine the recommended phase 2 dose and schedule of TL-895 in each cohort.
Part B: Cohort 5: To determine the recommended phase 2 dose and schedule of TL-895.
Part B: Cohorts 1-4: Improvement in Total Symptom Score at Week 24 |
|
| E.2.2 | Secondary objectives of the trial |
Part A Cohorts 1-4:
To determine the Spleen Volume Reduction (SVR) rate of each arm of Cohorts 1-3 at Week 24
Improvement in Total Symptom Score (TSS) in each arm of Cohorts 1-3 at Week 24
To characterize the pharmacokinetic (PK) profile of TL-895
Part A Cohort 5:
To assess changes in ISM symptoms after treatment with TL-895 vs placebo
To compare time to reduction in TSS after treatment with TL-895 vs placebo
To compare reduction in TSS after treatment with TL-895 vs placebo
To determine the effects of TL-895 on quality of life
To characterize the PK profile of TL-895 in ISM
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 SVR rate at Week 24
For the other Part B secondary objectives, please refer to the study protocol.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohorts 1-4:
1. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
2. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
3. 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 costal 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
4. Cohort 2 (JAKi intolerant MF) (closed for enrollment) - 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
5. 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).
6. 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).
7. 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
Cohort 5 only:
8. Confirmed diagnosis of ISM as defined by WHO diagnostic criteria. Eligibility must be confirmed based on review of past bone marrow pathology report results. If the pathology report is not available, or if a biopsy was never completed, a local biopsy must be completed, and the pathology results evaluated to confirm subject eligibility.
9. Subject must have moderate-to-severe symptoms based on minimum mean ISM-TSAF v1.0 TSS over the 14-day eligibility screening period for assessment of TSS. Minimum TSS for eligibility is ≥ 28.
10. Subject must have failed to achieve symptom control for 1 or more baseline symptoms measured by the ISM-TSAF, as determined by the Investigator, with at least 1 of the following symptomatic therapies administered for a minimum of 28 days before starting the ISM-TSAF for determination of eligibility:
a. H1 blockers
b. H2 blockers
c. Leukotriene inhibitors
d. Cromolyn sodium
e. Corticosteroids
f. Omalizumab
11. The subject’s symptomatic ISM therapies (eg, H1 and H2 blockers) must be stable (same dose, no new medications ≥14 days before beginning the 14-day ISM-TSAF TSS eligibility assessment).
12. For subjects receiving corticosteroids, the dose must be ≤ 20 mg/day prednisone or equivalent, and the dose must be stable for ≥ 14 days before starting the 14-day ISM-TSAF TSS eligibility assessment.
All Cohorts (Cohorts 1-5, unless otherwise noted)
13. Adults ≥ 18 years of age who can provide informed consent.
14. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
15. Adequate hematological function independent of myeloid growth factor support for 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, ≥ 15 and < 25 × 109/L for Cohort 4, > 100 x109/L for Cohort 5. Platelet count for Cohort 3 and Cohort 4 must be based on the average of 2 platelet assessments performed at least 1 week apart.
c. Hemoglobin ≥ 10 g/dL for Cohort 5
16.. 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.
17. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according Cockcroft Gault
18. 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, as described in the protocol. |
|
| E.4 | Principal exclusion criteria |
Cohorts 1-4 only:
1. Prior treatment with JAKi within 28 days prior to first study treatment.
2. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
3. 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.
4. Subjects with peripheral blood or bone marrow blast counts ≥ 10% within 28 days prior to first dose of study treatment.
5. Subjects who are eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) per the opinion of the investigator and have a donor.
Cohort 5 only:
6. Prior therapy with a.Avapritinib, bezuclastinib, or BLU-263/elenestinib. b. Any BTKi. c.Any antineoplastic agent including chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, any other antineoplastic agent, or herbal medications or herbal supplements within 28 days prior to starting the ISM-TSAF for determination of eligibility. d. Any investigational agent within 28 days or five half-lives, whichever is longer, prior to starting the ISM-TSAF for determination of eligibility. Participation in an observational study is permitted. e. Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-TSAF for determination of eligibility. f. Any hematopoietic growth factor < 14 days before starting the ISM-TSAF for determination of eligibility. g. Any major surgical procedure (minor surgical procedures such as central venous catheter placement and BM biopsy are not considered major surgical procedures) < 14 days before starting the ISM-TSAF for determination of eligibility.
7. Subject has a current diagnosis of any of the following WHO systemic mastocytosis subclassifications: a. CM only (ie, without documentation of systemic involvement). b. Smoldering systemic mastocytosis. c. SM-AHN. d. ASM. e. MCL. f. MC sarcoma.
8. Subject has been diagnosed with another myeloproliferative disorder (eg, myelodysplastic syndrome, MPN).
9. Subject has any of the following organ damage C-findings (Valent 2017) attributable to SM: a. Hepatomegaly with ascites and impaired liver function, cirrhosis, or portal hypertension. b. Palpable splenomegaly with hypersplenism. c. Malabsorption with hypoalbuminemia and significant weight loss. d. Skeletal lesions: large osteolytic lesions with pathologic fractures. e. Life-threatening organ damage in other organ systems caused by MC infiltration in tissues.
10. Planned major surgery within 28 days prior to the pretreatment period, during the pretreatment period, or through Week 24 of the treatment period.
All Cohorts (Cohorts 1-5):
11. Prior treatment with any BTK or BMX inhibitor
12. Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within 6 months prior to first dose of study treatment.
13. Subjects with symptomatic ascites or subjects requiring paracentesis.
14. Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant.
15. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural)
16. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
17. 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.
Further exclusion criteria are listed in the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A Cohorts 1-4: 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 A Cohorts 5: The RP2D for Cohort 5 will be determined based on safety, efficacy, and tolerability data
Part B: The proportion of subjects achieving ≥50% reduction in Total Symptom Score at Week 24 by Myelofibrosis Symptom Assessment Form |
|
| 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 (Cohort 1-4:
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 A (Cohort 5):
Mean change and percent change in ISM-TSAF TSS from Baseline to Week 12, and from Baseline to Week 24
Changes in ISM-TSAF targeted symptoms from Baseline to Week 12, and from Baseline to Week 24
Changes in ISM-TSAF individual symptom scores from Baseline to Week 12, and from Baseline to Week 24
Proportion of subjects with targeted percent reduction by ISM-TSAF from Baseline to Week 12, and from Baseline to Week 24
Changes in most severe symptom (ie, individual symptom with highest score at baseline in each subject) in ISM-TSAF from Baseline to Week 12, and from Baseline to Week 24
Time to targeted percent reduction by ISM-TSAF score
Change in BSC concomitant medication usage from Baseline to Week 12, and from Baseline to Week 24
Change in:
• Supplemental Indolent Systemic Mastocytosis Targeted Symptom Assessment Form (SISM-TSAF)
• Mastocytosis Quality of Life Questionnaire (MC-QoL)
• Patients’ Global Impression of Severity (PGIS)
• Patients’ Global Impression of Change (PGIC)
• 5 Level 5 Dimension Euro QoL Questionnaire (EQ-5D-5L)
• Twelve-item Short Form Health Survey (SF-12)
TL-895 PK parameters, including but not limited to: C0h, C2h, Cmax, Tmax, AUC.
Part B (Cohorts 1-4 only):
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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 15 |
| 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 | 5 |
| 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 |
| Brazil |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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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