Navitoclax + Ruxolitinib for Myeloproliferative Disorders

Recruiting at 59 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AbbVie

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

Compensation: Varies

Number of Visits: Unknown

85 Participants Needed

Trial Summary

What is the purpose of this trial?

There are 5 parts to this study for which the primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of navitoclax when administered alone (Part 1) or when administered in combination with ruxolitinib (Part 2). In Part 2, participants must have been receiving a stable dose of ruxolitinib therapy for at least 12 weeks prior to study enrollment. In Part 3, all eligible participants will receive navitoclax, with the primary objective being to evaluate potential navitoclax effect on QTc prolongation. In Part 4, effect of navitoclax is evaluated on the PK, safety, and tolerability of a single dose of celecoxib. In Part 5, all eligible participants will receive ruxolitinib twice daily and navitoclax once daily for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib.

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.

What data supports the effectiveness of the drug Ruxolitinib for treating myeloproliferative disorders?

Ruxolitinib has been shown to be effective in controlling symptoms and improving outcomes in patients with polycythemia vera and myelofibrosis, especially for those who do not respond well to other treatments like hydroxyurea. Studies have demonstrated its ability to reduce spleen size, control blood cell counts, and improve overall symptoms. ^{1 2 3 4 5}

Is the combination of Navitoclax and Ruxolitinib safe for treating myeloproliferative disorders?

Ruxolitinib, used for conditions like polycythemia vera, is generally well tolerated but can cause mild to moderate anemia (low red blood cell count), thrombocytopenia (low platelet count), and lymphopenia (low white blood cell count). It may also increase the risk of infections and skin cancer. These side effects are usually manageable with dosage adjustments. ^{2 3 5 6 7}

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

The combination of Navitoclax and Ruxolitinib is unique because it targets both the JAK-STAT pathway, which is often overactive in myeloproliferative disorders, and the BCL-2 family of proteins, which are involved in cell survival. This dual approach may offer benefits over existing treatments that typically focus on a single pathway. ^{1 3 5 8 9}

Research Team

ABBVIE INC.

Principal Investigator

AbbVie

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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 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]

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 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]

References

1. France pubmed.ncbi.nlm.nih.gov

[Not Available]. [2021]

2. England 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. [2022]

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

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

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

Targeting the PI3K pathway in myeloproliferative neoplasms. [2022]

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

Ruxolitinib: A Review in Polycythaemia Vera. [2021]

6. Canada pubmed.ncbi.nlm.nih.gov

Unexpected Neurological Symptoms of Ruxolitinib: A Case Report. [2023]

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

Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Experience with ruxolitinib in the treatment of polycythaemia vera. [2021]

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

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