Navitoclax + Ruxolitinib for Myelofibrosis

(REFINE Trial)

No longer recruiting at 191 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AbbVie

Must be taking: Ruxolitinib

Must not be taking: Coagulation inhibitors, CYP3A inhibitors

Disqualifiers: Splenectomy, Leukemic transformation, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of the drugs navitoclax and ruxolitinib (also known as Jakafi, Jakavi, or Opzelura), both individually and in combination, for treating myelofibrosis, a condition affecting the bone marrow and blood cells. The study aims to determine if these drugs can manage symptoms and improve patient outcomes. Individuals diagnosed with myelofibrosis who have tried other treatments, such as ruxolitinib, but still face issues like spleen problems or require frequent blood transfusions, might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

You may need to stop taking certain medications that interfere with blood clotting or are strong or moderate CYP3A inhibitors before starting the trial. However, you can continue taking low-dose aspirin and low-molecular-weight heparin.

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

Research shows that the combination of navitoclax and ruxolitinib is generally well-tolerated by patients with myelofibrosis. Previous studies found these drugs effective even when other treatments failed. However, some patients experienced side effects, with low platelet counts being a common issue. Doctors monitor this closely during treatment.

Navitoclax alone has also been studied and appears safe for most people. Most side effects are not severe and can be managed by adjusting the dose or using other treatments. While most patients taking navitoclax reported some side effects, no new safety concerns emerged. This suggests the treatment is relatively safe, but monitoring for potential issues remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Navitoclax and Ruxolitinib for treating myelofibrosis because it offers a fresh approach compared to existing therapies like JAK inhibitors. While most current treatments focus solely on inhibiting Janus Kinase (JAK) pathways to reduce symptoms, Navitoclax introduces the unique mechanism of targeting BCL-2 family proteins, which play a role in cell survival. This dual-action, combining JAK inhibition with apoptosis induction, could potentially lead to better control of the disease and improved patient outcomes. Additionally, Navitoclax's ability to be tailored based on individual platelet counts offers a personalized treatment approach, which is a step forward in managing myelofibrosis more effectively.

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

Research has shown that combining the drugs navitoclax and ruxolitinib may be promising for treating myelofibrosis, a type of bone marrow cancer. In this trial, participants in various treatment arms will receive different combinations of these drugs. Studies have found that adding navitoclax to ruxolitinib can significantly reduce spleen size by 35% or more. This combination also improves symptoms and overall health in patients who haven't responded well to previous treatments. While navitoclax alone, tested in a separate arm of this trial, offers some benefits, using it with ruxolitinib appears more effective. Overall, these treatments offer hope for patients with myelofibrosis by potentially slowing the disease's progression. ^{1 3 4 6 7}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

This trial is for people with myelofibrosis who've been treated with a JAK-2 inhibitor for at least 12 weeks and have significant symptoms or are considered intermediate-2/high-risk. They should be on a stable dose of ruxolitinib if currently taking it, not have had certain prior treatments, and must meet specific health criteria.

Inclusion Criteria

I have been diagnosed with a high-risk form of Myelofibrosis.

I cannot or do not want to have a stem cell transplant due to my age, health issues, or personal choice.

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

Exclusion Criteria

I haven't taken strong or moderate CYP3A inhibitors in the last 14 days.

I am not on blood thinners, except for low dose aspirin or low-molecular-weight heparin.

I have previously received treatment with a BH3 mimetic or had a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive navitoclax alone or in combination with ruxolitinib, with dose adjustments based on platelet count and treatment response

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 254 weeks

Open-label extension (optional)

Participants may continue treatment until end of clinical benefit or unacceptable toxicity

What Are the Treatments Tested in This Trial?

Interventions

• Navitoclax
• Ruxolitinib

Trial Overview The study tests the safety and effectiveness of Navitoclax alone or combined with Ruxolitinib in treating myelofibrosis. It's an open-label Phase 2 trial, meaning both researchers and participants know which treatment is being administered.

How Is the Trial Designed?

Group I: Navitoclax + ruxolitinib (Cohort 3) Experimental Treatment 2 Interventions

Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Group II: Navitoclax + ruxolitinib (Cohort 1b) Experimental Treatment 2 Interventions

Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Group III: Navitoclax + ruxolitinib (Cohort 1a) Experimental Treatment 2 Interventions

Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10\^9/L up to a maximum dose of navitoclax 300 mg QD. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Group IV: Navitoclax (Cohort 2) Experimental Treatment 1 Intervention

Participants must have received prior treatment with a Janus Kinase 2 (JAK-2) inhibitor. Those with Baseline platelet count \>150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 200 mg. Those with a Baseline platelet count ≤150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 100 mg, which could be increased to 200 mg once daily after 7 days provided the platelet count is ≥75 × 10\^9/L. Navitoclax didn't exceed 200 mg QD for the first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

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

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. news.abbvie.com news.abbvie.com/2022-06-10-AbbVie-Presents-Investigational-Navitoclax-Preliminary-Data-in-JAK-Inhibitor-Naive-Myelofibrosis-Patients

AbbVie Presents Investigational Navitoclax Preliminary ... Preliminary safety analysis identified no new safety signals. Thirty-one (97 percent) patients reported one or more adverse event (AE).1 The ...