Navitoclax + Ruxolitinib for Myelofibrosis

(TRANSFORM-2 Trial)

Recruiting at 336 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AbbVie

Must be taking: Ruxolitinib

Must not be taking: BH3-mimetics, BET inhibitors

Disqualifiers: Stem cell 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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 years

330 Participants Needed

Trial Summary

What is the purpose of this trial?

Myelofibrosis (MF) is a rare blood cancer, notable for scarring of the bone marrow (the spongy tissue inside bones) and the spleen becoming larger. The purpose of this study is to assess safety and change in spleen volume when navitoclax is given in combination with ruxolitinib, compared to best available therapy, for adult participants with MF. Navitoclax is an investigational drug (not yet approved) being developed for the treatment of MF. Participants in this study will be randomly selected (like picking numbers out of a hat) to be in 1 of 2 treatment arms. Neither participants nor the study doctor will be able to pick which treatment arm a participants enters. In Arm A, participants will receive navitoclax in combination with ruxolitinib. In Arm B, participants will receive the best available therapy (BAT) for MF. In Arm C, participants will receive navitoclax. Adult participants with a diagnosis of MF that came back or did not get better after earlier treatment will be enrolled. Approximately 330 participants will be enrolled in approximately 322 sites across the world. In Arm A, participants will receive navitoclax tablet by mouth once daily with by mouth ruxolitinib tablet twice daily. In Arm B, participants will receive the BAT available to the investigator. In Arm C, participants will receive navitoclax tablet by mouth once daily. Participants will receive the study drug until they experience no benefit (determined by the investigator), participants cannot tolerate the study drugs, or participants withdraw consent. The approximate treatment duration is about 3 years. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that interfere with blood clotting or platelet function, except for low-dose aspirin and certain blood thinners. You also cannot be on other cancer treatments unless they are part of the best available therapy group.

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

Ruxolitinib, a key component of the treatment, is a well-established drug for myelofibrosis, showing effectiveness in managing symptoms and improving quality of life. It is a Janus kinase (JAK) inhibitor, which helps reduce the overactive signaling that contributes to the disease. ^{1 2 3 4 5}

Is the combination of Navitoclax and Ruxolitinib safe for humans?

The combination of Navitoclax and Ruxolitinib has been studied for safety in patients with myelofibrosis, showing some benefits like reduced spleen size and symptoms. Ruxolitinib alone has a known safety profile as a treatment for myelofibrosis, but specific safety data for the combination with Navitoclax is limited in the provided research. ^{1 2 5 6 7}

How is the drug combination of Navitoclax and Ruxolitinib unique for treating myelofibrosis?

The combination of Navitoclax and Ruxolitinib is unique because it targets myelofibrosis by adding Navitoclax to ongoing Ruxolitinib treatment, which has shown to significantly reduce spleen size and symptoms in patients who no longer benefit from Ruxolitinib alone. ^{1 2 3 5 7}

Research Team

ABBVIE INC.

Principal Investigator

AbbVie

Eligibility Criteria

Adults with relapsed or refractory Myelofibrosis, a type of blood cancer that causes bone marrow scarring and spleen enlargement. Participants must have specific symptoms and spleen size criteria, be classified as intermediate-2 or high-risk by DIPSS+, and have been treated with ruxolitinib previously but not responded well.

Inclusion Criteria

My spleen has grown and can be felt at least 5 cm below my left rib cage since starting ruxolitinib.

My myelofibrosis is classified as intermediate-2 or high-risk.

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

Exclusion Criteria

I have previously been treated with specific cancer drugs or had a stem cell transplant.

I am not on blood thinners, except for low dose aspirin or LMWH.

I've completed my current cancer treatment at least a week ago, or it's been 30 days, whichever is shorter.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive navitoclax in combination with ruxolitinib or best available therapy for approximately 3 years

3 years

Regular visits at a hospital or clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Open-label extension (optional)

Continued access for navitoclax for participants from previous studies

Long-term

Treatment Details

Interventions

• Best Available Therapy (BAT)
• Navitoclax
• Ruxolitinib

Trial Overview The trial is testing the safety and effectiveness of an oral Navitoclax tablet in combination with Ruxolitinib versus Best Available Therapy (BAT) for reducing spleen volume in Myelofibrosis patients. It's a randomized study where neither participants nor doctors choose the treatment group.

Participant Groups

Group I: Arm C: Continued Access for Navitoclax Experimental Treatment 1 Intervention

Participants will receive navitoclax tablets once daily.

Group II: Arm A: Navitoclax + Ruxolitinib Experimental Treatment 2 Interventions

Participants will receive navitoclax tablets once daily and ruxolitinib tablets twice daily.

Group III: Arm B: Best Available Therapy (BAT) Active Control 1 Intervention

Participants will receive one of the BAT options, per the investigator's discretion.

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Findings from Research

In a phase 3 trial involving 156 patients with myelofibrosis who had previously been treated with ruxolitinib, momelotinib did not show superior efficacy compared to best available therapy (BAT) in reducing spleen size by at least 35%.

Both momelotinib and BAT had similar rates of severe adverse events, but momelotinib was associated with a higher incidence of peripheral neuropathy and serious adverse events, including deaths, indicating potential safety concerns with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Harrison, CN., Vannucchi, AM., Platzbecker, U., et al.[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 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]

Ruxolitinib is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

In a phase 2 trial involving 34 patients with myelofibrosis who were not responding well to ruxolitinib, the addition of navitoclax led to a significant reduction in spleen volume and improved symptoms, indicating its efficacy as a combination treatment.

Patients showing improvements in bone marrow fibrosis or a reduction in variant allele frequency had better overall survival, suggesting that navitoclax may modify the disease progression in myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Pemmaraju, N., Garcia, JS., Potluri, J., et al.[2022]

References

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

Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Oman pubmed.ncbi.nlm.nih.gov

Evaluation of Ruxolitinib versus Best Available Therapy in Treating Primary Myelofibrosis. [2022]

4. India pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. [2021]

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

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. [2022]

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

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. [2022]