Ruxolitinib + Chemotherapy for Acute Lymphoblastic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Breakthrough Therapy
Approved in 2 Jurisdictions
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.12345
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.25678
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.145910
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
See 7 more
Exclusion Criteria
I haven't taken strong CYP3A4 inhibitors recently.
Down Syndrome
My leukemia was Ph+ at diagnosis.
See 6 more
Trial 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 (Janus Kinase (JAK) Inhibitor)
Trial OverviewThe 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
1Treatment groups
Experimental Treatment
Group I: RuxolitinibExperimental Treatment13 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Chicago Medical CenterChicago, IL
Loading ...
Who Is Running the Clinical Trial?
University of ChicagoLead Sponsor
Incyte CorporationIndustry Sponsor
References
Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. [2022]Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk molecular subtype with a gene expression profile similar to Philadelphia-positive ALL, but not harboring the BCR-ABL1 gene fusion. We aimed to investigate the efficacy of target therapy with the Janus kinase inhibitor, ruxolitinib, in patients with Ph-like ALL and molecular signature of JAK-STAT signaling pathway. A systematic search of the literature was performed to identify reports concerning administration of ruxolitinib in Ph-like ALL patients. Additionally, Polish Pediatric ALL registries were searched for patients with Ph-like ALL treated with ruxolitinib. Extracted information included epidemiological background, somatic aberrations, treatment response, and patient outcome. After PubMed database search, twelve patients were identified, and one was identified in the Polish Pediatric ALL registry. In nine patients gene fusions affecting JAK2 (n = 7) and EPOR (n = 2) were detected. Surface overexpression of CRLF2 and IKZF1 deletions were observed in two and three patients, respectively. Induction failure occurred in all the patients. Therapy with ruxolitinib led to complete (n = 7) and partial (n = 2) remission, in three individuals no information was found. Based on the limited number of studies describing the efficacy of ruxolitinib as an additional compound administrated with standard ALL therapy, we conclude that this approach can be considered in patients with aberrations activating JAK-STAT pathway.
Targeting BCR-ABL and JAK2 in Ph+ ALL. [2021]In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively.
Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations. [2019]Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current chemotherapy is quite toxic in growing children and more directed therapeutics are being sought. The IL-7R pathway is a major driver of ALL and here we evaluate two drugs directed to that pathway using a model of T cell ALL. Mutant gain-of-function IL-7Rα was transduced into an IL-7-dependent murine thymocyte line conferring ligand-independent survival and growth. JAK1 is associated with IL-7Rα and mediates signaling from the mutant receptor. In vitro, treating the transformed cell line with the JAK1/2 inhibitor ruxolitinib inhibited ligand-independent signaling and induced cell death. Transfer of the transformed cell line into mice resulted in aggressive leukemia and untreated mice succumbed in about three weeks. Treatment with ruxolitinib incorporated into chow showed a potent therapeutic benefit with reduction in leukemic burden and extension of survival. BCL-2 is an anti-apoptotic downstream mediator of the IL-7R survival mechanism. Venetoclax, an inhibitor of BCL-2, showed activity against the transformed cell line in vitro and could be combined with ruxolitinib in vivo. These findings support the therapeutic potential of treating T-ALL by targeting the IL-7R pathway.
Ruxolitinib is effective in the treatment of a patient with refractory T-ALL. [2022]T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive T-cell malignancy. Chemotherapy alone cures only 25-45% of the cases, thus, novel treatment agents and strategies are urgently needed. We assessed the efficacy of ruxolitinib in a patient with a cutaneous relapse after allogeneic blood cell transplantation of a refractory T-ALL with a Janus kinase 3 (JAK3) mutation. In this case report, we were able to show the potential benefit of the JAK inhibitor ruxolitinib in JAK3-mutated refractory T-ALL and emphasize the importance of integrating molecular markers in current treatment decision making for patients with T-ALL.
Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. [2022]CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P
Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib. [2022]Ruxolitinib, a novel inhibitor of Janus kinases 1 and 2, was recently approved for the treatment of myelofibrosis but, recently, attention has been drawn to potential side effects and especially opportunistic infections and virus reactivations. EBV reactivation has not previously been reported to occur in association with Ruxolitinib.
Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. [2023]Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports [ICSRs] with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral [herpes and influenza], fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.
Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. [2021]Ruxolitinib is a small molecule JAK-2 inhibitor approved for the treatment of certain myeloproliferative neoplasms. Ruxolitinib-related skin toxicity is extremely rare. We report herein an unusual erythematous skin eruption with necrotic centers involving lower extremities in a patient with primary myelofibrosis treated with ruxolitinib. Awareness of this unusual skin toxicity with ruxolitinib becomes even more important as JAK-2 inhibition might soon find clinical applications in dermatology.
Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. [2021]Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.
CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. [2022]Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL in vitro. Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.