Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Telios Pharma, Inc.
Must not be taking: BTK inhibitors, JAKi, others
Disqualifiers: Splenectomy, Myeloproliferative disorder, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests TL-895, a strong oral medication that targets specific proteins to treat Myelofibrosis and Indolent Systemic Mastocytosis. It is for patients who haven't responded to other treatments or can't take certain therapies.
Will I have to stop taking my current medications?
The trial requires that you have not taken JAKi treatment within 28 days before starting the study. If you are currently on JAKi, you will need to stop it at least 28 days before joining the trial.
How does the drug TL-895 differ from other treatments for myelofibrosis?
The drug TL-895 is unique because it targets the ALK5 pathway, which is involved in the overproduction of collagen in myelofibrosis, unlike other treatments that primarily focus on the JAK2 pathway. This approach may offer a new way to address the fibrosis aspect of the disease.
12345Eligibility Criteria
This trial is for adults over 18 with Myelofibrosis who have a large spleen, are in fairly good health otherwise, and haven't responded well to or can't take JAK inhibitor treatments. They shouldn't have had certain other cancer treatments recently or any past spleen surgery.Inclusion Criteria
My spleen is enlarged, extending 5 cm below my ribcage or is larger than 450 cm³ on scans.
I can take care of myself but might not be able to do heavy physical work.
I have been diagnosed with a type of myelofibrosis according to WHO criteria.
+2 more
Exclusion Criteria
I have had my spleen removed or treated with radiation within the last 24 weeks.
I have not taken BTK or BMX inhibitors before.
I have (not) taken JAK inhibitors within the last 21 days.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive TL-895 or placebo orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle
24 weeks
Monthly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests TL-895, an oral drug designed to inhibit specific enzymes that may be involved in Myelofibrosis. It's aimed at patients whose disease has come back after treatment or who cannot tolerate current therapies.
13Treatment groups
Experimental Treatment
Placebo Group
Group I: Cohort 5d, Indolent Systemic MastocytosisExperimental Treatment1 Intervention
TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle in combination with BSC.
Group II: Cohort 5c, Indolent Systemic MastocytosisExperimental Treatment1 Intervention
TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle in combination with BSC.
Group III: Cohort 5b, Indolent Systemic MastocytosisExperimental Treatment1 Intervention
TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle in combination with BSC.
Group IV: Cohort 5a, Indolent Systemic MastocytosisExperimental Treatment1 Intervention
TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle in combination with best supportive care (BSC).
Group V: Cohort 3b, JAKi Ineligible Myelofibrosis with platelet count of ≥ 25 and < 50 × 109/LExperimental Treatment1 Intervention
300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle.
Group VI: Cohort 3a, JAKi Ineligible Myelofibrosis with platelet count of ≥ 25 and < 50 × 109/LExperimental Treatment1 Intervention
150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
Group VII: Cohort 2b, JAKi Intolerant MyelofibrosisExperimental Treatment1 Intervention
300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle.
Group VIII: Cohort 2a, JAKi Intolerant MyelofibrosisExperimental Treatment1 Intervention
150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
Group IX: Cohort 1d, Relapsed/Refractory MyelofibrosisExperimental Treatment1 Intervention
450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
Group X: Cohort 1c, Relapsed/Refractory MyelofibrosisExperimental Treatment1 Intervention
300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
Group XI: Cohort 1b, Relapsed/Refractory MyelofibrosisExperimental Treatment1 Intervention
300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle.
Group XII: Cohort 1a, Relapsed/Refractory MyelofibrosisExperimental Treatment1 Intervention
150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle.
Group XIII: Cohort 5e, Indolent Systemic MastocytosisPlacebo Group1 Intervention
Placebo to match TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle in combination with BSC.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic - RochesterRochester, MN
Revive Research Institute - Royal OakSouthfield, MI
Revive Research Institute - Sterling HeightsSterling Heights, MI
University of MarylandBaltimore, MD
More Trial Locations
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Who Is Running the Clinical Trial?
Telios Pharma, Inc.Lead Sponsor
References
Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT. [2012]Monitoring of minimal residual disease (MRD) after allogeneic (allo)-SCT for myelofibrosis (MF) allows recognizing the depth of remission and thus guides application of appropriate therapeutic interventions. MPL W515L/K mutations, which are detected in 5-10% of JAK2V617F-negative patients, may be useful for this purpose. Using a highly sensitive quantitative PCR method, we tested 90 patients with MF who underwent allo-SCT for the presence of MPL W515L/K mutations. Two patients with primary MF were found to harbor MPLW515L while no patient was positive for MPLW515K mutation. Both patients were JAK2V617F negative and cleared the mutation rapidly after allo-SCT and remained negative for a median follow-up of 19 months. The results of molecular monitoring correlated well with other remission parameters such as normalization of peripheral blood counts and morphology and complete donor chimerism. We conclude that MPLW515L can be cleared after allo-SCT and hence may be used as an MRD marker in a proportion of JAK2V617F-negative MF patients.
Efficacy of ALK5 inhibition in myelofibrosis. [2020]Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.
Momelotinib therapy for myelofibrosis: a 7-year follow-up. [2020]One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (
[Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. [2021]Since the identification of JAK2 V617F mutation in patients with BCR/ABL-negative myeloproliferative neoplasms in 2005, the molecular basis of these hematological disorders has been extensively studied. Consequently, various small molecular compounds including JAK2 inhibitors have been developed. The JAK2 inhibitor ruxolitinib improves survival as well as splenomegaly and the clinical symptomatic burden in intermediate-2 or high risk myelofibrosis patients. This agent also reduces the JAK2 V617F allele burden in some patients, suggesting that it also has a certain molecular effect. Based on the results of clinical studies, ruxolitinib has been approved for treatment of myelofibrosis in the United States and Europe. Clinical and preclinical studies of several other JAK2 inhibitors are currently ongoing. Other small molecular compounds including histone deacetylase inhibitors, mTOR inhibitors and telomerase inhibitors are currently being tested in clinical trials. We also discuss the possibility of combination therapies using JAK2 inhibitors and other agents.
Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. [2022]The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis-free survival (MFS) in WHO-defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3-4.9), male sex (2.1, 1.2-3.9), palpable splenomegaly (2.1, 1.2-3.9), CALR 1/1-like or MPL mutation (3.4, 1.9-6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6-10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: "high molecular risk" category included patients with JAK2V617F VAF >35%, CALR type 1/1-like or MPL mutations; all other driver mutation profiles were assigned to "low molecular risk" category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p