Navtemadlin + Ruxolitinib for Myelofibrosis

(POIESIS Trial)

Recruiting at 83 trial locations

Overseen By John Mei

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Kartos Therapeutics, Inc.

Must be taking: Ruxolitinib

Must not be taking: BCL-XL, BET, MDM2, others

Disqualifiers: Splenectomy, Bone Marrow Transplant, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

600 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical trial is evaluating whether addition of navtemadlin to ruxolitinib treatment will provide more clinical benefit than ruxolitinib alone for patients with Myelofibrosis who have a suboptimal response to ruxolitinib treatment alone. Subjects will start by receiving ruxolitinib alone in the run-in period. Those who demostrate a suboptimal response from ruxolitinib alone will then be randomized 2:1 to receive navtemadlin or navtemadlin placebo as add-on treatment to their ongoing ruxolitinib. Randomized means that subjects will be assigned to a group by chance, like a flip of a coin. The study is blinded, meaning the subjects, doctors, central endpoint assessors and sponsor will not know which add on treatment (navtemadlin or navtemadlin placebo) the subject is receiving.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be new to JAK-inhibitor treatments like ruxolitinib. You will continue taking ruxolitinib during the trial.

What is known about the safety of Navtemadlin and Ruxolitinib in humans?

Ruxolitinib, also known as Jakafi or Jakavi, has been studied extensively and is generally safe for treating myelofibrosis, though it can cause anemia (low red blood cell count) and thrombocytopenia (low platelet count), which are usually manageable. No new safety concerns have been identified in large studies, and these side effects rarely lead to stopping the treatment. ^{1 2 3 4 5}

How does the drug Ruxolitinib differ from other treatments for myelofibrosis?

Ruxolitinib is unique because it is an oral medication that specifically inhibits JAK1 and JAK2, which are proteins involved in the development of myelofibrosis. It is the first and only approved drug for this condition, providing significant benefits like reducing spleen size and improving symptoms and quality of life, with a survival advantage over previous therapies. ^{5 6 7 8 9}

What data supports the effectiveness of the drug combination Navtemadlin and Ruxolitinib for treating myelofibrosis?

Ruxolitinib, a part of the drug combination, has been shown to improve symptoms and quality of life in patients with myelofibrosis, as well as provide a long-term survival benefit. It is a well-established treatment for myelofibrosis, targeting key pathways involved in the disease. ^{7 10 11 12 13}

Are You a Good Fit for This Trial?

This trial is for patients with Myelofibrosis who haven't had a good enough response to Ruxolitinib. Participants should be new to JAK inhibitor treatments and meet specific health criteria not detailed here.

Inclusion Criteria

I have been diagnosed with a form of myelofibrosis according to WHO standards.

I have never been treated with JAK inhibitors.

High, Intermediate-1, Intermediate-2 risk category IPSS

Exclusion Criteria

I have had my spleen removed.

I have not had splenic irradiation in the last 3 months.

I have previously received treatments targeting specific cancer pathways or p53.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants receive ruxolitinib alone to assess response

4 weeks

Randomized Treatment

Participants receive either navtemadlin or placebo as add-on to ruxolitinib in 28-day cycles

24 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

What Are the Treatments Tested in This Trial?

Interventions

• Navtemadlin
• Ruxolitinib

Trial Overview The study tests if adding Navtemadlin to Ruxolitinib offers more benefits than Ruxolitinib alone in Myelofibrosis patients with poor responses. It's randomized and blinded, meaning treatment assignments are by chance and unknown to participants and researchers.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 2 Interventions

Navtemadlin administered orally once daily on Days 1-7, off treatment on Days 8-28, in 28-day treatment cycles. Ruxolitinib administered orally twice a day.

Group II: Arm 2 Active Control 2 Interventions

Navtemadlin placebo administered orally once daily on Days 1-7, off treatment on Days 8-28, in 28-day treatment cycles. Ruxolitinib administered orally twice a day.

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?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Published Research Related to This Trial

In a study of 219 patients with myelofibrosis, ruxolitinib significantly improved health-related quality of life (HRQoL) and reduced disease-related symptoms over 48 weeks compared to best available therapy (BAT).

Ruxolitinib treatment led to notable enhancements in physical functioning, fatigue, and appetite, with significant improvements observed as early as week 8 and continuing throughout the study, supporting its efficacy as a treatment for symptomatic myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Harrison, CN., Mesa, RA., Kiladjian, JJ., et al.[2021]

Ruxolitinib, an oral JAK1 and JAK2 inhibitor, has transformed the treatment of myelofibrosis (MF) since its approval, demonstrating significant clinical benefits in patients as shown in the phase 3 COMFORT-I/II trials.

Over the past 10 years, extensive research on ruxolitinib has enhanced the understanding of MF and its management, paving the way for future combination therapies to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy. Pemmaraju, N., Bose, P., Rampal, R., et al.[2023]

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 pooled analysis of 528 patients from the phase 3 COMFORT-I and -II trials, ruxolitinib significantly improved overall survival in patients with intermediate-2 or high-risk myelofibrosis, reducing the risk of death by 30% compared to control groups (median OS of 5.3 years vs 3.8 years).

The survival benefit of ruxolitinib was consistent across different patient subgroups, including those with varying anemia status and transfusion needs, indicating its efficacy as a treatment option regardless of these factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. Verstovsek, S., Gotlib, J., Mesa, RA., et al.[2021]

Ruxolitinib is the first drug approved in the U.S. for treating high- and intermediate-risk myelofibrosis, working by inhibiting JAK-1 and JAK-2 to reduce inflammation and control symptoms like splenomegaly.

Despite improving quality of life for many patients, over half discontinue ruxolitinib treatment within 2-3 years due to limited effectiveness in reversing bone marrow fibrosis and challenges in defining treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition and management of ruxolitinib treatment failure in myelofibrosis. Pardanani, A., Tefferi, A.[2021]

Ruxolitinib, a JAK1/JAK2 inhibitor, was evaluated in a large phase 3b study (N = 2233) for treating myelofibrosis, including patients with low platelet counts, showing significant reductions in spleen size and symptoms.

The safety profile of ruxolitinib was consistent with previous studies, with common adverse events like anemia and thrombocytopenia, but these rarely led to treatment discontinuation, indicating it is a viable option for patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Al-Ali, HK., Griesshammer, M., Foltz, L., et al.[2021]

In a phase 3 study involving 222 patients with polycythemia vera, ruxolitinib significantly outperformed standard therapy, achieving hematocrit control in 60% of patients and a 35% reduction in spleen volume in 38% of patients, compared to only 20% and 1% respectively in the standard therapy group.

Ruxolitinib also led to a higher rate of complete hematologic remission (24% vs. 9%) and a greater reduction in total symptom scores (49% vs. 5%), while maintaining a manageable safety profile with low rates of severe anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. Vannucchi, AM., Kiladjian, JJ., Griesshammer, M., et al.[2022]

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 an effective treatment for intermediate or high-risk myelofibrosis, significantly reducing spleen size and alleviating related symptoms, which improves patients' quality of life.

While ruxolitinib can cause dose-dependent anemia and thrombocytopenia, these side effects can be managed with dose adjustments and monitoring, allowing most patients to continue treatment without permanent discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. Mesa, RA., Cortes, J.[2021]

Ruxolitinib has been a key treatment for myelofibrosis for over a decade, but the emergence of new JAK inhibitors like fedratinib and pacritinib necessitates a clear understanding of what constitutes 'failure' of ruxolitinib therapy.

A consensus among experts suggests that in cases of ruxolitinib failure, either continuing ruxolitinib with an additional agent or switching to a different JAK inhibitor may be beneficial, highlighting the need for personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving beyond ruxolitinib failure in myelofibrosis: evolving strategies for second line therapy. Bose, P., Kuykendall, AT., Miller, C., et al.[2023]

Ruxolitinib is an effective oral treatment for myelofibrosis, showing significant and lasting improvements in symptoms and splenomegaly in patients from major clinical trials, including the phase III COMFORT-I and -II studies with a survival advantage for those treated with ruxolitinib.

While ruxolitinib can cause dose-related anemia and thrombocytopenia, these side effects are manageable and rarely lead to treatment discontinuation, highlighting the importance of monitoring and dosage adjustments for optimal patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a review of its use in patients with myelofibrosis. Plosker, GL.[2021]

Ruxolitinib, a JAK 1/2 inhibitor, has become the primary treatment for myelofibrosis (MF) due to its significant benefits in survival, spleen volume reduction, and symptom relief, but there are still unmet needs in MF treatment.

Ongoing research is exploring various novel therapies, including new JAK inhibitors with potentially fewer side effects, as well as first-in-class agents like sotatercept and imetelstat, to enhance treatment options for MF and related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developmental Therapeutics in Myeloproliferative Neoplasms. Bose, P., Verstovsek, S.[2023]

Citations

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

Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. [2021]

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

Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy. [2023]

3. India pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. [2021]

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

Definition and management of ruxolitinib treatment failure in myelofibrosis. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. [2021]

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

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. [2022]

8. United States 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. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Moving beyond ruxolitinib failure in myelofibrosis: evolving strategies for second line therapy. [2023]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a review of its use in patients with myelofibrosis. [2021]

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

Developmental Therapeutics in Myeloproliferative Neoplasms. [2023]