Study for Patients with Myelofibrosis and Indolent Systemic Mastocytosis

The purpose of this study is to determine the safety and tolerability of TL-895. There are 2 parts planned for this study, Part A will test different doses of TL-895 to identify the recommended dose for Part B. Part B will continue to test if the recommended dose is a tolerable and effective treatment for myelofibrosis.

Inclusion Criteria

Cohorts 1-4 only:

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 Scoring System (DIPSS)
3. Cohort 1 (R/R MF) (closed for enrollment) – Must have relapsed or refractory MF following JAKi treatment. Relapsed MF is defined as 1 of the following:
   1. Spleen volume increase by ≥ 25% by radiographic imaging from nadir
   2. A ≥ 100% increase in palpable distance below the left lower costal margin (LLCM) from nadir, for baseline splenomegaly of 5 to 10 cm
   3. A ≥ 50% increase in palpable distance below the LLCM from nadir, for baseline splenomegaly of > 10 cm
   4. Regrowth after achieving complete response.
   5. Refractory MF is defined as 1 of the following after receiving ≥ 12 weeks of JAKi treatment:
      1. < 10% SVR by radiographic imaging
      2. < 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:
   1. RBC transfusion requirement (≥ 2 units per month for 2 months)
   2. Grade ≥ 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage
5. Cohort 3 (JAKi treatment ineligible MF) – Must be ineligible for JAKi treatment with 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:

1. 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.
2. 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.
3. 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:
   1. H1 blockers
   2. H2 blockers
   3. Leukotriene inhibitors
   4. Cromolyn sodium
   5. Corticosteroids
   6. Omalizumab
4. 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).
5. 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)
6. Adults ≥ 18 years of age who can provide informed consent.
7. ECOG performance status of ≤ 2.
8. Adequate hematological function independent of myeloid growth factor support for at least 21 days, defined as:
   1. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
   2. Platelet count:
      1. ≥ 50 × 109/L for Cohorts 1 and 2
      2. ≥ 25 and < 50 × 109/L for Cohort 3
      3. ≥ 15 and < 25 × 109/L for Cohort 4.
      4. ≥ 100 × 109/L for Cohort 5
9. Platelet count for Cohort 3 and Cohort 4 must be based on the average of 2 platelet assessments performed at least 1 week apart.
   1. Hemoglobin ≥ 10 g/dL for Cohort 5
10. Adequate hepatic function defined by:
    1. Total bilirubin 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.
    2. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
11. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according Cockcroft Gault
12. 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 (refer to Appendix 21 for additional details).
    Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including the required duration of contraception use. The contraception requirements in the local prescribing guidelines must be followed for all concomitant drugs administered in this study.

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:
   1. 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.
   2. 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.
   3. 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.
   4. 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. Subjects who are HSCT eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.

Cohort 5 only:

1. Prior therapy with:
   1. Avapritinib, bezuclastinib, or BLU-263/elenestinib.
   2. Any BTKi.
   3. 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.
   4. 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.
   5. Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-TSAF for determination of eligibility.
   6. Any hematopoietic growth factor < 14 days before starting the ISM-TSAF for determination of eligibility.
   7. 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.
2. Subject has a current diagnosis of any of the following WHO systemic mastocytosis subclassifications:
   1. Cutaneous mastocytosis (CM) only (ie, without documentation of systemic involvement).
   2. Smoldering systemic mastocytosis.
   3. Systemic mastocytosis with an associated hematologic neoplasm of non-mast cell lineage (SM-AHN). d. Aggressive systemic mastocytosis (ASM).
   4. Mast cell leukemia (MCL).
   5. MC sarcoma.
3. Subject has been diagnosed with another myeloproliferative disorder (eg, myelodysplastic syndrome, MPN).
4. Subject has any of the following organ damage C-findings (Valent 2017) attributable to SM:
   1. Hepatomegaly with ascites and impaired liver function, cirrhosis, or portal hypertension.
   2. Palpable splenomegaly with hypersplenism.
   3. Malabsorption with hypoalbuminemia and significant weight loss.
   4. Skeletal lesions: large osteolytic lesions with pathologic fractures.
   5. Life-threatening organ damage in other organ systems caused by MC infiltration in tissues.
5. 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):

1. Prior treatment with any BTK or BMX inhibitor
2. Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within 6 months prior to first dose of study treatment.
3. Subjects with symptomatic ascites or subjects requiring paracentesis.
4. Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant.
5. Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural)
6. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
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 bacterial, fungal, parasitic, tuberculosis (TB) or viral infection (including COVID-19). 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 provided the proton-pump inhibitor is discontinued at least 3 days prior to the first dose of study drug.
15. Women who are pregnant or breastfeeding.
16. Subjects who have received a live vaccine within 28 days prior to Cycle 1 Day 1 or plan to receive one during the study.
17. Known hypersensitivity to study drug or its excipients.
18. Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
19. Any concurrent disease or condition that would make the subject unsuitable for participation in the study.
20. Subjects with any open wound or ulcer.

This is a partial list of eligibility requirements. To inquire about your eligibility, please call the contact number provided. If you wish to inquire via email, please include the title of the study in your message.