TL-895 for Myelofibrosis

Recruiting at53 trial locations

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. ^{1 2 3 4 5}

Research Team

Eligibility 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.

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

Treatment Details

Interventions

• TL-895 (Tyrosine Kinase Inhibitor)

Trial Overview 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.

Participant Groups

Group I: Cohort 5d, Indolent Systemic Mastocytosis Experimental Treatment 1 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 Mastocytosis Experimental Treatment 1 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 Mastocytosis Experimental Treatment 1 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 Mastocytosis Experimental Treatment 1 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/L Experimental Treatment 1 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/L Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Myelofibrosis Experimental Treatment 1 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 Mastocytosis Placebo Group 1 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.

Who Is Running the Clinical Trial?

Telios Pharma, Inc.

Lead Sponsor

Trials

11

Recruited

1,700+

Findings from Research

In a study of 90 myelofibrosis patients who underwent allogeneic stem cell transplantation, MPL W515L mutations were identified in 2 patients, indicating its potential as a minimal residual disease (MRD) marker for monitoring remission.

Both patients with the MPL W515L mutation cleared it rapidly after transplantation and remained negative for a median follow-up of 19 months, suggesting that monitoring this mutation can effectively guide treatment decisions in JAK2V617F-negative myelofibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT. Alchalby, H., Badbaran, A., Bock, O., et al.[2012]

TGF-β1 is significantly overexpressed in myelofibrosis (MF) patients and contributes to excessive collagen production, which worsens the disease, indicating its role in MF pathogenesis.

The ALK5 inhibitor galunisertib showed promising results in improving MF symptoms in mouse models, suggesting that targeting the TGF-β pathway could be an effective therapeutic strategy for treating MF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of ALK5 inhibition in myelofibrosis. Yue, L., Bartenstein, M., Zhao, W., et al.[2020]

In a phase 1/2 trial involving 100 patients with high/intermediate-risk myelofibrosis, treatment with the JAK1/2 inhibitor momelotinib led to clinical improvement in 57% of patients, particularly in those without ASXL1 mutations and with low circulating blasts.

Despite some patients experiencing significant side effects, such as thrombocytopenia and peripheral neuropathy, the overall survival after discontinuation of momelotinib was similar to that of a comparable group of patients not receiving the treatment, suggesting that while momelotinib may provide some benefits, it does not significantly alter long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib therapy for myelofibrosis: a 7-year follow-up. Tefferi, A., Barraco, D., Lasho, TL., et al.[2020]

Ruxolitinib, a JAK2 inhibitor, has been shown to improve survival and reduce symptoms like splenomegaly in patients with intermediate-2 or high-risk myelofibrosis, indicating its efficacy in treating this condition.

The drug also decreases the JAK2 V617F allele burden in some patients, suggesting it has a beneficial molecular effect, and it has been approved for use in the United States and Europe based on clinical study results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. Nagai, T.[2021]

In a study of 1607 patients with essential thrombocythemia (ET), several clinical and molecular factors were identified as predictors of inferior myelofibrosis-free survival, including age over 60, male sex, palpable splenomegaly, and specific genetic mutations.

A new 'high molecular risk' category was established for patients with certain genetic profiles, showing significantly higher rates of fibrotic transformation over 10 and 20 years, indicating the need for closer monitoring and counseling for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. Loscocco, GG., Guglielmelli, P., Gangat, N., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT. [2012]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy of ALK5 inhibition in myelofibrosis. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Momelotinib therapy for myelofibrosis: a 7-year follow-up. [2020]

4. Japan pubmed.ncbi.nlm.nih.gov

[Small molecular compounds for BCR/ABL-negative myeloproliferative neoplasms]. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. [2022]