Ruxolitinib + Chemotherapy for Acute Lymphoblastic Leukemia

Overseen By Clinical Trials Office

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must be taking: Intrathecal chemotherapy

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Second malignancy, Allergic reactions, Uncontrolled illness, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test if adding ruxolitinib to standard multi-drug chemotherapy regimen will be safe and tolerated in adolescents and young adults with newly diagnosed Ph-like acute lymphoblastic leukemia (ALL).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take any potent CYP3A4 inhibitors or inducers within 5 half-lives before starting the study drug. It's important to discuss your current medications with the study team to avoid any interactions.

What data supports the effectiveness of the drug Ruxolitinib for treating Acute Lymphoblastic Leukemia?

Research shows that Ruxolitinib, a drug that blocks certain proteins involved in cancer growth, has helped some patients with specific types of acute lymphoblastic leukemia (ALL) achieve remission, meaning their cancer symptoms improved or disappeared. It has been particularly effective in cases with certain genetic mutations that make the cancer more aggressive. ^{1 2 3 4 5}

Is Ruxolitinib generally safe for humans?

Ruxolitinib has been associated with some side effects, including infections (like viral, fungal, and mycobacterial infections), skin issues, and blood clotting problems. There have also been reports of rare skin reactions and virus reactivations. However, major heart problems were not significantly increased in reports. ^{2 5 6 7 8}

How does the drug Ruxolitinib combined with chemotherapy differ from other treatments for acute lymphoblastic leukemia?

Ruxolitinib, when combined with chemotherapy, offers a unique approach for treating acute lymphoblastic leukemia by targeting the JAK-STAT signaling pathway, which is often overactive in certain high-risk subtypes of the disease. This combination is particularly beneficial for patients with specific genetic mutations, such as JAK mutations, that make them less responsive to standard chemotherapy alone. ^{1 4 5 9 10}

Research Team

Wendy Stock, MD

Principal Investigator

University of Chicago

Eligibility Criteria

This trial is for adolescents and young adults aged 18-40 with newly diagnosed Ph-like acute lymphoblastic leukemia (ALL). Participants must have completed a specific chemotherapy regimen, have normal organ function, and agree to use contraception. Excluded are those with other active cancers, certain heart or psychiatric conditions, pregnant or breastfeeding women, and individuals on strong CYP3A4 inhibitors.

Inclusion Criteria

I have been newly diagnosed with a specific type of leukemia (B-precursor ALL).

My cancer has a 'Ph-like' signature.

Agreement to use adequate contraception for women of child-bearing potential and men

Exclusion Criteria

I haven't taken strong CYP3A4 inhibitors recently.

Down Syndrome

My leukemia was Ph+ at diagnosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants must have completed a 4-drug induction therapy regimen with intrathecal chemotherapy

4 weeks

Remission Consolidation Therapy

Participants receive remission consolidation therapy as part of the standard chemotherapy regimen

8 weeks

Interim Maintenance

Participants undergo interim maintenance therapy as part of the standard chemotherapy regimen

8 weeks

Delayed Intensification

Participants undergo delayed intensification therapy as part of the standard chemotherapy regimen

8 weeks

Maintenance Therapy

Participants receive maintenance therapy in 12-week courses/84-day cycles lasting 2-3 years

2-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Treatment Details

Interventions

• Ruxolitinib

Trial Overview The study tests the safety of adding ruxolitinib to a standard multi-drug chemotherapy regimen in treating Ph-like ALL. The goal is to determine if this combination improves outcomes for patients who fit the trial's criteria.

Participant Groups

Group I: Ruxolitinib Experimental Treatment 13 Interventions

Participants will receive ruxolitinib in addition to standard chemotherapy. Standard Chemotherapy Consists of: * Remission consolidation therapy (lasting 8 weeks) * Interim Maintenance (lasting 8 weeks) * Delayed Intensification (lasting 8 weeks * Maintenance Therapy (12 week courses/84 day cycles lasting 2-3 years) Prior to study entry, patients must have completed a 4-drug induction therapy regimen with intrathecal chemotherapy (modified Berlin-Frankfurt-Münster (aBFM) regimen or equivalent) as per the institution standard of care.

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

Ruxolitinib, a Janus kinase inhibitor, showed promising efficacy in treating Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), with 7 out of 12 patients achieving complete remission and 2 achieving partial remission after treatment.

The study highlights the potential of targeting the JAK-STAT signaling pathway in Ph-like ALL patients, particularly those with specific gene fusions affecting JAK2 and EPOR, suggesting that ruxolitinib could be a valuable addition to standard therapy for this high-risk leukemia subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. Kołodrubiec, J., Kozłowska, M., Irga-Jaworska, N., et al.[2022]

In a mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia, the combination of dasatinib (targeting BCR-ABL kinase) and ruxolitinib (targeting JAK2) led to prolonged survival.

This combined treatment approach also helped prevent resistance to therapy, suggesting a promising strategy for improving outcomes in patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BCR-ABL and JAK2 in Ph+ ALL. Hantschel, O.[2021]

The study demonstrates that targeting the IL-7R pathway with the JAK1/2 inhibitor ruxolitinib effectively induces cell death in T cell acute lymphoblastic leukemia (T-ALL) models, leading to reduced leukemia burden and extended survival in mice.

Combining ruxolitinib with the BCL-2 inhibitor venetoclax shows promise for enhanced therapeutic efficacy, suggesting a potential new treatment strategy for T-ALL that minimizes the toxicity associated with traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations. Senkevitch, E., Li, W., Hixon, JA., et al.[2019]

Ruxolitinib, a JAK inhibitor, showed potential efficacy in treating a patient with refractory T-cell acute lymphoblastic leukemia (T-ALL) that had a JAK3 mutation, indicating a promising new treatment avenue for this aggressive cancer.

This case highlights the importance of using molecular markers, like JAK3 mutations, to guide treatment decisions in T-ALL, as traditional chemotherapy alone has a low cure rate of only 25-45%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib is effective in the treatment of a patient with refractory T-ALL. Jaramillo, S., Hennemann, H., Horak, P., et al.[2022]

In a study of 8 pediatric B-ALL cases, the JAK inhibitor ruxolitinib significantly reduced peripheral and splenic blast counts, especially in samples with JAK-activating mutations, indicating its potential efficacy in treating high-risk Ph-like acute lymphoblastic leukemia.

The mTOR inhibitor rapamycin effectively controlled leukemia burden in all samples and significantly prolonged survival in xenograft models, suggesting it could be a valuable treatment option for this aggressive leukemia subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Maude, SL., Tasian, SK., Vincent, T., et al.[2022]

Ruxolitinib, a treatment for myelofibrosis, has been associated with a case of EBV reactivation leading to a severe lymphoproliferative disorder in a 57-year-old female patient, highlighting a potential risk of opportunistic infections.

This case emphasizes the need for close monitoring of patients on Ruxolitinib for signs of viral reactivations and opportunistic infections, as they may pose serious health risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib. Pálmason, R., Lindén, O., Richter, J.[2022]

A study analyzing 126,815 safety reports found that the JAK inhibitors ruxolitinib, tofacitinib, and baricitinib are associated with increased risks of infectious adverse events, particularly viral, fungal, and mycobacterial infections.

Tofacitinib specifically showed a significant association with gastrointestinal perforation events, while no significant increase in major cardiovascular events was observed, indicating a need for careful monitoring of these risks in patients using JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. Hoisnard, L., Lebrun-Vignes, B., Maury, S., et al.[2023]

Ruxolitinib, a JAK-2 inhibitor used for treating myeloproliferative neoplasms, is generally associated with very rare skin toxicity, but an unusual case of erythematous skin eruption with necrotic centers was observed in a patient with primary myelofibrosis.

This case highlights the need for increased awareness of potential skin side effects from ruxolitinib, especially as JAK-2 inhibitors may be used more widely in dermatological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. Dasanu, CA.[2021]

In a study of 53 myelofibrosis patients treated with a combination of hydroxyurea and ruxolitinib, significant reductions in white blood cell and platelet counts were observed after 48 weeks, indicating effective management of myeloproliferation.

The combination therapy also led to a notable decrease in spleen size, with the rate of spleen response increasing from 14% to 45%, while maintaining a safety profile similar to that of ruxolitinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Breccia, M., Luciano, L., Pugliese, N., et al.[2021]

The combination of ruxolitinib and venetoclax shows a dose-dependent effect on T cell acute lymphoblastic leukemia (T-ALL) but does not improve survival in a xenograft model, leading to increased leukemic infiltration in the central nervous system (CNS).

Adding the CXCR4 inhibitor plerixafor to the treatment regimen enhances survival and reduces clinical symptoms, suggesting that targeting the CXCR4-CXCL12 axis may be necessary for achieving better outcomes in T-ALL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. Walker, KL., Rinella, SP., Hess, NJ., et al.[2022]

References

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

Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. [2022]

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

Targeting BCR-ABL and JAK2 in Ph+ ALL. [2021]

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

Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations. [2019]

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

Ruxolitinib is effective in the treatment of a patient with refractory T-ALL. [2022]

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

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. [2022]

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

Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib. [2022]

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

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. [2023]

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

Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. [2021]

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

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. [2022]