TL-895 + Ruxolitinib for Myelofibrosis

Recruiting at 19 trial locations

Overseen By Nikki Stuart

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Telios Pharma, Inc.

Must be taking: Ruxolitinib

Must not be taking: JAKi, BTK, BMX inhibitors

Disqualifiers: Splenectomy, Splenic irradiation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for people with myelofibrosis, a type of bone marrow cancer. It examines how well TL-895, a new drug, works with ruxolitinib (also known as Jakafi, Jakavi, or Opzelura). The goal is to determine if this combination benefits those who have never tried JAK inhibitors or who haven't had satisfactory results with ruxolitinib alone. Eligible participants have myelofibrosis, have not used JAK inhibitors before, or are not achieving good results from their current ruxolitinib treatment. Participants must have noticeable spleen enlargement. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires participants with a suboptimal response to ruxolitinib to continue taking it at a stable dose before joining the study. The protocol does not specify if other medications need to be stopped.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ruxolitinib, a drug often used for myelofibrosis, has been studied for over ten years and is generally safe. However, it can sometimes cause anemia, which means a low red blood cell count. TL-895 is a newer drug still under investigation. Early studies are examining its safety, particularly in combination with ruxolitinib.

The safety review team closely monitors how these two drugs interact. They assess any side effects and determine the safest dose. As this research is still in the early stages, there may be limited safety information available. The goal of combining these two drugs is to improve treatment for people with myelofibrosis. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of TL-895 and ruxolitinib for treating myelofibrosis because it introduces a new approach to managing this condition. Unlike the standard treatment, which primarily involves JAK inhibitors like ruxolitinib alone, TL-895 is a BTK inhibitor that targets a different pathway, potentially enhancing the treatment's effectiveness. By combining these two mechanisms, this therapy aims to improve patient outcomes, especially for those who haven't responded optimally to JAK inhibitors. This dual-action strategy could offer new hope for better symptom control and disease management.

What evidence suggests that this trial's treatments could be effective for Myelofibrosis?

Research has shown that ruxolitinib has treated myelofibrosis for over ten years and is generally safe, though it can sometimes cause anemia, or a low red blood cell count. This trial studies TL-895 as a new treatment designed to work with ruxolitinib by targeting specific proteins that may help manage anemia and reduce inflammation. Early findings suggest that combining TL-895 with ruxolitinib could improve results by reducing spleen size and easing symptoms in myelofibrosis patients. This combination aims to disrupt harmful cells in the bone marrow, potentially leading to better overall outcomes. Initial data supports the idea that TL-895, when used with ruxolitinib, might provide better relief for those with myelofibrosis, especially if previous treatments have not worked well. Participants in this trial will receive different doses of TL-895 combined with their stable dose of ruxolitinib, or they will be treatment-naïve to JAK inhibitors. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with Myelofibrosis (MF) who are either new to JAK inhibitor treatments or haven't responded well to Ruxolitinib. They should have a confirmed MF diagnosis, a spleen enlarged by at least 5 cm or of a certain volume, and be in fair health as judged by their ability to perform daily activities.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My blood, liver, and kidney functions are all within normal ranges.

My condition is classified as high, intermediate-2, or intermediate-1 risk.

Exclusion Criteria

I have had my spleen removed or treated with radiation within the last 24 weeks.

I have never been treated with JAK inhibitors before.

My condition worsened while I was on ruxolitinib.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TL-895 and ruxolitinib in a 28-day cycle, with doses adjusted based on baseline platelet count and pre-study stable dose of ruxolitinib

24 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Ruxolitinib
• TL-895

Trial Overview The study tests TL-895 combined with Ruxolitinib on two groups: those who've never had JAK inhibitors and those whose condition didn't improve enough with just Ruxolitinib. It aims to see if this combination can better manage symptoms of MF.

How Is the Trial Designed?

Group I: Phase 2 - Cohort 2 suboptimal response to Ruxolitinib Experimental Treatment 2 Interventions

The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose schedule will be the stable ruxolitinib dose schedule as the subject is currently taking prior to entry into the study.

Group II: Phase 2 - Cohort 1 JAKi treatment-naïve MF Experimental Treatment 2 Interventions

The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose of ruxolitinib will be based on the subject's baseline platelet count.

Group III: Phase 1b - Dose Level 3 Experimental Treatment 2 Interventions

450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Group IV: Phase 1b - Dose Level 2 Experimental Treatment 2 Interventions

300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Group V: Phase 1b - Dose Level 1 Experimental Treatment 2 Interventions

150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Ruxolitinib is already approved in United States, European Union for the following indications:

Approved in United States as Jakafi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Vitiligo

Approved in European Union as Jakavi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Non-segmental vitiligo

Who Is Running the Clinical Trial?

Telios Pharma, Inc.

Lead Sponsor

Trials

11

Recruited

1,700+

Published Research Related to This Trial

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

In a phase 2 trial involving 51 patients with myelofibrosis who were intolerant to ruxolitinib, 43.2% of those treated with the novel JAK inhibitor jaktinib showed a significant reduction in spleen volume after 24 weeks.

Jaktinib also improved symptoms related to myelofibrosis, with 61.8% of patients experiencing a notable decrease in total symptom scores, although it was associated with some serious adverse events, including anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. Zhang, Y., Zhou, H., Duan, M., et al.[2023]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

Ruxolitinib is a selective oral inhibitor of JAK1 and JAK2 that effectively reduces spleen size and alleviates symptoms in patients with myelofibrosis, showing a 41.9% spleen-volume response rate compared to only 0.7% for placebo in a Phase III trial.

Patients taking ruxolitinib also experienced significant improvements in their overall quality of life and symptom scores, with 45.9% showing a ≥ 50% improvement compared to 5.3% for placebo, although the treatment was associated with thrombocytopenia as a dose-limiting toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Ostojic, A., Vrhovac, R., Verstovsek, S.[2021]

Ruxolitinib is a dual inhibitor of JAK1 and JAK2, which are crucial in the development of myelofibrosis (MF), and it has been FDA-approved since November 2011 for treating intermediate or high-risk MF.

The review discusses Ruxolitinib's current role in managing MF and explores its potential future applications in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. Malhotra, H.[2021]

In a study of 219 patients with myelofibrosis, ruxolitinib demonstrated a significant efficacy advantage over the best available therapy, with 28% of patients achieving at least a 35% reduction in spleen volume at 48 weeks, compared to 0% in the control group.

Ruxolitinib not only reduced spleen size but also improved overall quality of life and disease symptoms, with manageable side effects, primarily hematologic issues like thrombocytopenia and anemia, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. Harrison, C., Kiladjian, JJ., Al-Ali, HK., et al.[2022]

In a study of 53 myelofibrosis patients treated with a combination of hydroxyurea and ruxolitinib, significant reductions in white blood cell and platelet counts were observed after 48 weeks, indicating effective management of myeloproliferation.

The combination therapy also led to a notable decrease in spleen size, with the rate of spleen response increasing from 14% to 45%, while maintaining a safety profile similar to that of ruxolitinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Breccia, M., Luciano, L., Pugliese, N., et al.[2021]

Ruxolitinib is commonly used for managing myelofibrosis symptoms, but many patients experience treatment failure after 2-3 years, highlighting the need for alternative therapies like fedratinib.

Fedratinib has shown efficacy in reducing spleen volume and symptoms in patients with myelofibrosis, and ongoing trials are focused on understanding its long-term effects and managing potential gastrointestinal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. England, JT., Gupta, V.[2022]

Ruxolitinib, the first JAK2 inhibitor, has significantly improved symptoms, spleen size, and overall survival in patients with myelofibrosis compared to traditional chemotherapy, but about 50% of patients discontinue it after 3 years due to resistance or intolerance.

While second-generation tyrosine kinase inhibitors have been tested for patients who discontinue ruxolitinib, they have not shown significant effects on disease progression, highlighting the need for new treatments that target different pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors. Breccia, M., Assanto, GM., Laganà, A., et al.[2023]

Ruxolitinib, a JAK1/JAK2 inhibitor, significantly improves bone marrow (BM) fibrosis and spleen size in patients with advanced myelofibrosis (MF) over a treatment period of up to 66 months, compared to best available therapy (BAT).

Long-term treatment with ruxolitinib not only stabilizes or improves BM fibrosis but also suggests a potential disease-modifying effect, particularly in patients with advanced fibrosis, as indicated by changes in reticulin fibrosis grade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. Kvasnicka, HM., Thiele, J., Bueso-Ramos, CE., et al.[2023]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, effectively managed dose-dependent cytopenias in patients with intermediate- or high-risk myelofibrosis through dose adjustments, as demonstrated in the COMFORT-I trial with 309 participants.

Titrated doses of ruxolitinib of 10 mg BID or higher led to significant improvements in myelofibrosis-related symptoms and reductions in spleen volume by week 24, indicating its efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Verstovsek, S., Gotlib, J., Gupta, V., et al.[2021]

Citations

1. withpower.com withpower.com/trial/phase-2-myelofibrosis-post-et-9-2022-23e2e

TL-895 + Ruxolitinib for Myelofibrosis Ruxolitinib, used for myelofibrosis, has been studied for over a decade and is generally safe, though it can cause anemia (low red blood cell count) and ...

2. drugpatentwatch.com drugpatentwatch.com/p/drugs-in-development/drugname/TL-895?srsltid=AfmBOopyCOLe3U3kDPRT9MmU9PG7mY4REJsOFDKSifT8douej2Ttpq2u

TL-895 patents and clinical trials: Drug pipeline profiles for ... A1: TL-895's activity against additional targets such as IRAK1 and ACVR1 could improve anemia management and reduce inflammatory symptoms, ...

3. rarediseaseadvisor.com rarediseaseadvisor.com/therapies/myelofibrosis-experimental-therapies/

Myelofibrosis Experimental Therapies Preliminary findings suggest that pelabresib, when combined with Jakafi® (ruxolitinib), results in lasting improvements in spleen volume and ...

4. pvreporter-com.clinicaltrialconnect.com pvreporter-com.clinicaltrialconnect.com/trials/NCT05280509

Study of TL-895 Combined With Ruxolitinib in JAKi Treatment ... This study evaluates TL-895, a potent, orally-available and highly selective irreversible tyrosine kinase inhibitor for the treatment of Myelofibrosis.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10428783/

PB2198: TRIAL IN PROGRESS: AN OPEN-LABEL, ... We reasoned adding TL-895 to rux may enhance symptom response and potentiate pro-apoptotic effects on malignant MF cells by disrupting stromal ...

6. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/336356

Study of TL-895 Combined With Ruxolitinib in JAKi ... The safety review committee (SRC) will determine the RP2D based on safety and efficacy data of the combination of TL-895 and ruxolitinib. Time frame. 28 days.

7. drugpatentwatch.com drugpatentwatch.com/p/drugs-in-development/drugname/TL-895?srsltid=AfmBOoo7Q3ZAVjaW0w-Vl5rpRENY1cILbT00MA165Ea3Bn7Di_uHpLCD

TL-895 patents and clinical trials: Drug pipeline profiles for ... What is the drug development status for TL-895? TL-895 is an investigational drug. There have been 7 clinical trials for TL-895.