Navitoclax + Ruxolitinib for Myeloproliferative Disorders

Not currently recruiting at 66 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AbbVie

Must be taking: Ruxolitinib

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Leukemic transformation, Active malignancy, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effects of two treatments, navitoclax and ruxolitinib, for individuals with specific blood disorders, including myelofibrosis, polycythemia vera, and essential thrombocythemia. The trial consists of several parts, with some participants receiving only navitoclax, while others receive a combination of navitoclax with either ruxolitinib (a JAK inhibitor) or celecoxib to observe drug interactions. Suitable candidates have been managing these conditions, particularly if previous treatments have failed or if they are not candidates for a stem cell transplant. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

If you are currently taking ruxolitinib, you may need to continue it at a stable dose for certain parts of the trial. However, you may need to stop medications that interfere with blood clotting, like warfarin, and certain other drugs that affect liver enzymes. It's best to discuss your specific medications with the study doctor.

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

Research has shown that navitoclax, whether used alone or with other treatments, is generally well-tolerated by patients. In one study, the most common side effect was a drop in platelet count, known as thrombocytopenia, but it did not lead to serious bleeding issues. This suggests that navitoclax is mostly safe, although some monitoring may be needed.

When combined with ruxolitinib, research has not identified any new safety concerns. This combination has proven effective without causing unexpected problems. Studies also indicate that using navitoclax with celecoxib, a pain reliever, does not significantly increase safety concerns. Overall, navitoclax has demonstrated a good safety profile in various situations, but discussing any concerns with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myeloproliferative disorders, which usually involve medications like hydroxyurea or interferon that target cell replication, navitoclax works by inhibiting proteins that prevent cancer cell death, specifically targeting BCL-2 family proteins. Researchers are excited about navitoclax's potential to enhance the effects of ruxolitinib, a JAK inhibitor that reduces abnormal blood cell production. This combination could offer a more comprehensive approach by not only inhibiting cell growth but also promoting cancer cell death, potentially leading to improved outcomes for patients.

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

Research shows that navitoclax, when combined with ruxolitinib, may help treat myelofibrosis, a type of blood cancer. In this trial, some participants will receive navitoclax with ruxolitinib, which studies have found can lead to long-lasting effects. Specifically, patients have experienced a noticeable decrease in spleen size and overall improvement. Some have also seen a reduction in bone marrow fibrosis, where the bone marrow tissue becomes stiff. Other participants will receive navitoclax alone, which has proven effective, but combining it with ruxolitinib seems to enhance the treatment's effectiveness. This evidence supports the potential of these treatments for certain blood disorders. ^{2 6 7 8 9}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

This trial is for adults with myeloproliferative disorders who've failed or can't tolerate standard treatments and aren't eligible for stem cell transplantation. They must have stable vital organ functions, an ECOG performance status of <=2 (<=1 in some parts), and specific blood values within range. People with active hepatitis B/C, HIV, recent use of certain drugs affecting coagulation or metabolism, leukemic transformation, or other malignancies within the last 2 years are excluded.

Inclusion Criteria

I am Japanese and considering Navitoclax treatment (Part 1 only).

I have been on ruxolitinib for at least 12 weeks and my dose hasn't changed recently.

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

Exclusion Criteria

Has a positive test result for HIV at screening.

I haven't taken strong CYP3A inducers in the last 10 days.

I have been treated with a BH3 mimetic or BET inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive navitoclax monotherapy to evaluate safety, tolerability, and pharmacokinetics

4 weeks

Treatment Part 2

Participants receive navitoclax in combination with ruxolitinib to evaluate safety, tolerability, and pharmacokinetics

4 weeks

Treatment Part 3

Participants receive navitoclax to evaluate potential effect on QTc prolongation

4 weeks

Treatment Part 4

Participants receive navitoclax and celecoxib to evaluate pharmacokinetics, safety, and tolerability

1 week

Treatment Part 5

Participants receive navitoclax and ruxolitinib for drug-drug interaction assessment

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Celecoxib
• Navitoclax
• Ruxolitinib

Trial Overview The study tests Navitoclax alone and combined with Ruxolitinib to assess safety and how the body processes these drugs in people with myeloproliferative neoplasms. It's divided into five parts: solo Navitoclax effects; its combination with ongoing Ruxolitinib treatment; impact on heart rhythm; interaction with Celecoxib; and a drug-drug interaction assessment followed by extended combination therapy.

How Is the Trial Designed?

Group I: Part 5: Navitoclax + Ruxolitinib Combination Therapy Experimental Treatment 2 Interventions

Participants will receive ruxolitinib BID and navitoclax QD for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib.

Group II: Part 4: Navitoclax + Celecoxib Experimental Treatment 2 Interventions

Participants will receive navitoclax once daily (QD) starting on Day 3. Participants will also receive celecoxib single dose on Day 1 and Day 7.

Group III: Part 3: Navitoclax Monotherapy Experimental Treatment 1 Intervention

Participants will receive navitoclax once daily (QD).

Group IV: Part 2: Navitoclax + Ruxolitinib Combination Therapy Experimental Treatment 2 Interventions

Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).

Group V: Part 1: Navitoclax Monotherapy Experimental Treatment 1 Intervention

Participants will receive various doses of navitoclax once daily (QD).

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 effective for controlling symptoms and reducing splenomegaly in myeloproliferative neoplasms, but most patients experience disease progression with long-term use.

Newer JAK inhibitors like fedratinib, momelotinib, and pacritinib are being evaluated, with fedratinib recently approved for both treatment-naive and previously treated patients, while pacritinib shows promise for patients with significant anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib. Patel, AA., Odenike, O.[2022]

Ruxolitinib is an effective treatment for patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea, as demonstrated in the phase 3 RESPONSE study, which showed improvements in hematocrit control, splenomegaly reduction, and alleviation of disease symptoms.

In patients with myelofibrosis (MF), ruxolitinib has been shown to reduce splenomegaly and improve symptoms and survival, based on the phase 3 COMFORT-I and COMFORT-II studies, although there are still unmet needs regarding cytopenias and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Soret, J., Kiladjian, JJ.[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]

Ruxolitinib is an effective treatment for patients with polycythaemia vera (PV) who do not respond well to hydroxyurea, showing superior results in reducing hematocrit and spleen size after 32 weeks in the phase III RESPONSE trial.

The drug is generally well tolerated, with manageable side effects like mild to moderate anemia and thrombocytopenia, making it a valuable option for PV patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: A Review in Polycythaemia Vera. McKeage, K.[2021]

Ruxolitinib, a Janus kinase inhibitor, has shown promise as a second or third-line treatment for patients with polycythaemia vera (PV) who are resistant or intolerant to standard therapies like hydroxycarbamide, based on findings from phase II trials.

Current therapies for PV, including low-dose aspirin and phlebotomy, primarily aim to manage hematocrit levels to reduce thrombotic risks, but there is limited evidence that they prevent transformation to more severe conditions like myelofibrosis or acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with ruxolitinib in the treatment of polycythaemia vera. Alimam, S., Harrison, C.[2021]

Ruxolitinib is an effective JAK2 inhibitor used to treat myelofibrosis and polycythemia vera, but it carries risks of immunosuppression and increased chances of skin cancer.

An 80-year-old woman treated with ruxolitinib experienced unusual neurological symptoms, including weakness and hypoesthesia in her right arm and leg, highlighting the need for monitoring neurological side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpected Neurological Symptoms of Ruxolitinib: A Case Report. Furia, F., Canevini, MP., Federici, AB., et al.[2023]

In the RESPONSE-2 study involving 149 patients with polycythaemia vera without splenomegaly, ruxolitinib was significantly more effective than best available therapy, achieving haematocrit control in 62% of patients compared to only 19% in the control group.

Ruxolitinib demonstrated a favorable safety profile, with fewer severe adverse events compared to best available therapy, suggesting it could be a standard second-line treatment for patients who are resistant or intolerant to hydroxyurea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Passamonti, F., Griesshammer, M., Palandri, F., et al.[2022]

The study highlights the potential of targeting the PI3K pathway alongside JAK inhibitors like ruxolitinib to address treatment resistance in myeloproliferative neoplasms (MPNs), particularly myelofibrosis.

Combining the PI3Kδ inhibitor parsaclisib with ruxolitinib may enhance treatment efficacy and improve outcomes for patients who do not respond adequately to JAK inhibitors, suggesting a promising new therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the PI3K pathway in myeloproliferative neoplasms. Gerds, AT., Bartalucci, N., Assad, A., et al.[2022]

Citations

1. 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 ... Adding navitoclax to ongoing ruxolitinib demonstrates durable responses and potential disease modification in relapsed/refractory MF.

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

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for ... This phase II trial investigated the efficacy and safety of adding BCL-X L /BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03222609?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BExpandedAccessNCTId%5DNCT03592576))&rank=3

A Study Evaluating Tolerability and Efficacy of Navitoclax ... 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/interpreting-data-from-the-refine-study-ruxolitinib-navitoclax-in-myelofibrosis

Interpreting Data From the REFINE Study: Ruxolitinib ... This group of patients is showing a very nice spleen size reduction overall, and symptom burden improvement, but also starting to correlate with ...

5. mpn-hub.com mpn-hub.com/medical-information/navitoclax-add-on-to-ruxolitinib-in-patients-with-myelofibrosis-latest-data-from-the-phase-ii-refine-trial

Navitoclax add-on to ruxolitinib in patients with myelofibrosis Below, we provide a visual abstract summarizing key efficacy and safety results from the REFINE trial, which were recently published in the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04041050

NCT04041050 | A Study Evaluating Safety and Tolerability, ... There are 5 parts to this study for which the primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of navitoclax when ...

7. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M19-753

M19-753 A study evaluating safety and tolerability, and pharmacokinetics of Navitoclax monotherapy and in combination with Ruxolitinib in participants with ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000566

Addition of navitoclax to ruxolitinib for patients with ... No new safety signals were observed. The most common adverse event was thrombocytopenia without clinically significant bleeding. NAV+RUX was tolerable and ...

9. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2020.1845332

Full article: Safety and efficacy of navitoclax, a BCL-2 and ... Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid ...