Navitoclax + Ruxolitinib for Myelofibrosis

(TRANSFORM-2 Trial)

Not currently recruiting at 395 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine how a new drug combination can treat myelofibrosis (MF), a rare blood cancer that causes bone marrow scarring and an enlarged spleen. Participants will receive either a combination of navitoclax and ruxolitinib (also known as Jakafi, Jakavi, or Opzelura) or the best available therapy to assess which is more effective in reducing spleen size and improving safety. Suitable candidates for this trial should have myelofibrosis that hasn't improved after previous treatment and experience symptoms like an enlarged spleen that affect daily life. As a Phase 3 trial, this study is the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that combining navitoclax and ruxolitinib is generally safe for people with myelofibrosis. Thrombocytopenia, a common side effect, involves having fewer platelets in the blood than normal. However, this condition is usually temporary, and blood levels often return to normal with some treatment adjustments.

Studies indicate that navitoclax alone has a manageable safety profile. While side effects can occur, they are usually not severe and can be managed by doctors.

Adding navitoclax to ruxolitinib results in a safety profile similar to using ruxolitinib alone. This suggests that the combination does not significantly increase treatment risk compared to ruxolitinib alone. It is important to note that while side effects can occur, they are often expected and manageable by the healthcare team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for myelofibrosis because they offer new ways to tackle this challenging condition. Navitoclax, one of the drugs being studied, works by targeting and inhibiting proteins that help cancer cells survive, potentially leading to better outcomes. Ruxolitinib, on the other hand, is already used for myelofibrosis but combining it with Navitoclax could enhance its effectiveness by attacking the disease from multiple angles. Unlike the standard of care, which often involves just one line of treatment, this combination therapy could provide a more comprehensive strategy, potentially improving patient responses and quality of life.

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

Research has shown that using navitoclax with ruxolitinib, as studied in this trial's Arm A, can significantly reduce spleen size in people with myelofibrosis. Specifically, studies found that 63.2% of patients experienced a 35% decrease in spleen volume, leading to better symptoms and improved hemoglobin levels. While navitoclax alone, as provided in Arm C, offers some benefits, it proves much more effective when combined with ruxolitinib. The combination treatment has demonstrated lasting benefits over time. Participants in Arm B will receive the Best Available Therapy (BAT) as determined by the investigator. ^{1 3 4 6 7}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9113204/

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for ... CONCLUSION. The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, ...

2. ashpublications.org ashpublications.org/bloodneoplasia/article/2/1/100056/525855/Addition-of-navitoclax-to-ruxolitinib-for-patients

Addition of navitoclax to ruxolitinib for patients with ... Navitoclax plus ruxolitinib demonstrated clinically meaningful efficacy and symptom improvement in patients with R/R MF and suboptimal response ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03222609

NCT03222609 | A Study Evaluating Tolerability and ... This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with ...

4. onclive.com onclive.com/view/navitoclax-monotherapy-mirrors-safety-of-navitoclax-ruxolitinib-but-falls-short-in-efficacy-in-myelofibrosis

Navitoclax Monotherapy Mirrors Safety of ... Notably, at week 24, 7% of patients in cohort 2 achieved a spleen volume reduction of at least 35% (n = 2/29), 10% saw their TSS reduced by at ...

5. healthtree.org healthtree.org/myelofibrosis/community/articles/navitoclax-ruxcolitinib-treat-myelofibrosis

Navitoclax And Ruxolitinib to Treat Myelofibrosis ASH 2023 results reveal that a JAK inhibitor combined with navitoclax, a BCL-2 inhibitor showed success in myelofibrosis.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35180010/

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for ... TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia ...

7. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34986

New era for myelofibrosis treatment with novel agents beyond ... Patients who received navitoclax plus ruxolitinib demonstrated improved spleen volume: 26.5% of patients at week 24 achieved SVR35 (Table 3).