IRB Study Number 25-302
Status Recruiting
Phase Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Cohorts 1-4: Part A
Primary Objective
To determine the RP2D and schedule of TL-895 in each cohort
Secondary Objectives
To determine the SVR rate of each arm of Cohorts 1, 2 and 3 at Week 24
Improvement in total symptom score (TSS) in each arm of Cohorts 1, 2 and 3 at Week 24
To characterize the pharmacokinetic (PK) profile of TL-895
Cohorts 1-4: Part B
Primary Objective
Improvement in TSS at Week 24
Secondary Objectives
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
To determine the rate of conversion from RBC transfusion dependent to independent
To determine the rate of RBC transfusion independence at Week 24
To determine the duration of response (DOR)
To determine the progression-free survival (PFS)
To determine the OS
To evaluate safety and tolerability of TL-895
To monitor the PK of TL-895
Inclusion Criteria
Cohorts 1-4 Only:
Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
High-risk, intermediate-2 risk, or intermediate-1 risk, defined by DIPSS
Cohort 1 (R/R MF) (closed for enrollment) – Must have relapsed or refractory MF following JAKi treatment
Relapsed MF is defined as one 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) from nadir, 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 one of the following after receiving ≥ 12 weeks of JAKi treatment:
e. < 10% SVR by radiographic imaging
f. < 30% decrease from baseline in spleen size by palpation
- 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 two months)
b. Grade ≥ 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage
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 two platelet assessments performed at least one week apart, and without platelet transfusion in the two weeks prior to platelet assessments)
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 two platelet assessments performed at least one week apart)
MF symptoms as defined by having at least two symptoms with an average baseline (Day -7 to Day -1) score of at least one for each of the two symptoms per MFSAF v4.0
Cohort 5 Only:
Country-specific inclusion criteria are provided in Appendix 27.
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.
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.
Subject must have failed to achieve symptom control for one or more baseline symptoms measured by the ISM-TSAF, as determined by the Investigator, with at least one 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
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)
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
Cohort 6 Only:
- Confirmed diagnosis of MCAS as defined by Working Group diagnostic criteria (Valent 2012; Valent 2020), inclusive of the three following criteria:
a) Presence of typical clinical signs of severe, recurrent (episodic) systemic mast cell activation. Systemic is defined to mean involving at least two organ systems (see Appendix 26)
b) A documented increase in validated markers of mast cell activation during a severe symptomatic period consisting of either:
i) An increase in the serum tryptase level of 20% + 2 ng/mL above the individual’s baseline serum tryptase, or
ii) A 30% increase above the individual’s baseline in the urine metabolites prostaglandin D2, histamine, or leukotriene C4. At least two of the three metabolites must be increased to meet this criterion.
c) Response of symptoms (during a severe symptomatic period) to therapy with mast cell-stabilizing agents, drugs directed against mast cell mediator production, or drugs blocking mediator release or effects of mast cell-derived mediators
Moderate-to-severe chronic MCAS symptoms, as defined by a mean MCAS-TSAF TSS of ≥ 28 measured over the 14-day or 28-day eligibility screening period
Subject must have failed to achieve symptom control for one or more baseline chronic symptoms measured by the MCAS-TSAF, as determined by the Investigator, with at least one of the following symptomatic therapies administered for a minimum of 28 days before starting the MCAS-TSAF for determination of eligibility: H1 blockers, H2 blockers, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab
The subject’s symptomatic MCAS therapies (eg, H1 and H2 blockers) must be stable for ≥ 14 days before beginning the MCAS-TSAF TSS eligibility assessment (ie, no dosing changes and no new medications)
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 MCAS-TSAF TSS eligibility assessment.
All Cohorts (Cohorts 1-6, Unless Otherwise Noted)
Adults ≥ 18 years of age who can provide informed consent
ECOG performance status of ≤ 2
Adequate hematological function independent of myeloid growth factor support for at least 21 days, defined as:
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
Platelet count:
i. ≥ 50 × 109/L for Cohorts 1 and 2
ii. ≥ 25 and < 50 × 109/L for Cohort 3
iii. ≥ 15 and < 25 × 109/L for Cohort 4.
iv. ≥ 150 × 109/L for Cohort 5
v. ≥ 150 × 109/L for Cohort 6
Platelet count for Cohort 3 and Cohort 4 must be based on the average of 2 platelet assessments performed at least 1 week apart.
a. Hemoglobin:
i. ≥ 10 g/dL for Cohort 5
ii. ≥ 10 g/dL for Cohort 6
- Adequate hepatic function defined by:
Total bilirubin within normal limits (WNL); subjects with known Gilbert’s syndrome with total bilirubin above normal limit may be enrolled if direct bilirubin is WNL
a. AST and ALT:
i. ≤ 2.5 × ULN, for Cohorts 1-4
ii. WNL for Cohort 5
iii. WNL for Cohort 6
Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according Cockcroft Gault
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 one month and one week and male subjects must continue to use a highly effective method of contraception for three months and one week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal) unless permanently sterile (refer to Appendix 22 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:
Prior treatment with JAKi within 28 days prior to first study treatment
Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
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 one day prior to Cycle 1 Day 1. Subjects on a stable dose of erythroid growth factor support for at least three months prior to Cycle 1 Day 1 are eligible for the study.
b. Any investigational agent within 28 days or five 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 six months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within three months prior to first dose of study treatment
d. For Cohorts 3 and 4: Requiring or receiving anticoagulation within seven 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
Subjects with peripheral blood or bone marrow blast counts ≥ 10% within 28 days prior to first dose of study treatment
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:
- Prior therapy with:
a. Avapritinib, bezuclastinib, or BLU-263/elenestinib
b. Within 28 days prior to starting the ISM-TSAF for determination of eligibility, the following are excluded: any antineoplastic agent including chemotherapy, immunomodulating therapy, biologic therapy (eg, omalizumab), radiation therapy, any other antineoplastic agent, or herbal medications or herbal supplements
c. 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.
d. Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-TSAF for determination of eligibility
e. Any hematopoietic growth factor < 14 days before starting the ISM-TSAF for determination of eligibility
f. 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
- 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. Mast cell sarcoma
Subject has been diagnosed with another myeloproliferative disorder (eg, myelodysplastic syndrome, MPN)
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 mast cell infiltration in tissues
- Planned major surgery within 28 days prior to the pretreatment period, during the pretreatment period, or through Week 24 of the treatment period
Cohort 6 Only:
- Prior therapy with:
a. Any KIT inhibitor or KIT antibodies
b. Within 28 days prior to starting the MCAS-TSAF for determination of eligibility, the following are excluded: any antineoplastic agent including chemotherapy, immunomodulating therapy, biologic therapy (eg, omalizumab), radiation therapy, any other antineoplastic agent, or herbal medications or herbal supplements.
c. Any investigational agent within 28 days or five half-lives, whichever is longer, prior to starting the MCAS-TSAF for determination of eligibility. Participation in an observational study is permitted.
d. Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the MCAS-TSAF for determination of eligibility
e. Any major surgical procedure < 14 days before starting the MCAS-TSAF for determination of eligibility. Surgical procedures such as central venous catheter placement and BM biopsy are not considered major surgical procedures.
- A current diagnosis of cutaneous or systemic mastocytosis as defined by WHO criteria
All Cohorts (Cohorts 1-6):
Prior treatment with any BTK or BMX inhibitor
Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within six months prior to first dose of study treatment
Subjects with symptomatic ascites or subjects requiring paracentesis
Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant
Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural)
Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
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
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 arrhythmia; or psychiatric illness/ social situations that would limit compliance with study requirements
Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
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
Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
Subjects with known history of human immunodeficiency virus (HIV)
Other malignancy within the last three 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
Requires treatment with proton-pump inhibitors (eg, 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. For Cohorts 1-4, the proton-pump inhibitor must be discontinued at least three days prior to the first dose of study drug. For Cohort 5, the proton-pump inhibitor must be discontinued at the time of informed consent. For Cohort 6, the proton-pump inhibitor must be discontinued at the time of informed consent.
Women who are pregnant or breastfeeding
Subjects who have received a live vaccine within 28 days prior to Cycle 1 Day 1 or plan to receive one during the study
Known hypersensitivity to study drug or its excipients
Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
Any concurrent disease or condition that would make the subject unsuitable for participation in the study
Subjects with any open wound or ulcer
