Ruxolitinib in Combination with Standard Chemotherapy in Treating Adolescents and Young Adults with Ph-Like Acute Lymphoblastic Leukemia
This phase I trial studies the best dose and side effects of ruxolitinib in combination with standard chemotherapy in treating adolescents and young adults with Philadelphia (Ph)-like acute lymphoblastic leukemia. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib and chemotherapy may work better in treating patients with h-like acute lymphoblastic leukemia.
- Newly diagnosed de novo B-precursor acute lymphoblastic leukemia (World Health Organization [WHO] criteria). Patients must have unequivocal diagnosis of precursor B ALL. This includes an institutional immunophenotyping report that is to assign B-lineage or T-lineage. Recommended immunophenotype markers should include myeloperoxidase or Sudan black B by routine techniques, CD19, CD20, CD22, CD10, cCD3 or CD3, CD2, CD7 and CD5, CD13 and CD33, CD34, CD52, and TdT (CD25 suggested).
- “Philadelphia chromosome (Ph)-like” signature, as determined by low density micro-array (LDA) card.
- JAK-targetable genetic signature as defined by any of the following: * Cytokine receptor-like factor 2 (CRLF2) rearranged (JAK2 mutant or wild-type). * JAK2 or EPOR fusions. * Other JAK pathway alterations at the discretion of the principle investigator including, but not limited to: ** SH2B3 deletions. ** IL7RA mutations.
- Prior to starting ruxolitinib, patients must have completed a 4-drug induction regimen with intrathecal chemotherapy (modified augmented Berlin-Frankfurt-Munster [aBFM] regimen or equivalent) as per the institutional standard of care.
- No additional prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys. When indicated, leukapheresis or exchange transfusion is recommended to reduce the white blood cell (WBC).
- Screening may occur at any point prior to or during induction therapy.
- Because this is specifically a study of the adolescent and young adult population and no adverse event data are currently available on the use of this pediatric-based chemotherapy regimen in patients ≥ 40 years of age, older adults are excluded from this study, but may be eligible for future trials.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%).
- Platelet count > 25,000/uL.
- Total bilirubin =< 2 mg/dL.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal.
- Creatinine within normal institutional limits OR
- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
- Because the therapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation.
- Ability to understand and the willingness to sign a written informed consent document.
- Patients who are receiving any other investigational agent.
- Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for >= 3 years.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib or other agents used in study.
- Use of any potent cytochrome P450 (CYP) 3A4 inhibitor or inducer within 5 half-lives before the first dose of the study drug. Potent inhibitors of CYP3A4 include systemic ketoconazole, posaconazole, voriconazole, clarithromycin, itraconazole, nefazodone, and telithromycin. At the fluconazole dose of 200mg daily used this regimen, there is minimal inhibition of CYP3A4  and therefore fluconazole is not prohibited on this trial and no dose modifications should be made in the presence of fluconazole. * Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list. Medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Pregnant women are excluded from this study because ruxolitinib is a class C agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib breastfeeding should be discontinued if the mother is treated with ruxolitinib. These potential risks may also apply to other agents used in this study.
- Down syndrome due to the likelihood of excessive toxicity resulting. These patients should be treated in consultation with a pediatric oncologist.
- Burkitt type leukemia (FAB L3; SIg positive; t(8;14) or variant, etc.)
- Ph+ ALL at time of diagnosis.
Locations & Contacts
Contact: Wendy Stock
Trial Objectives and Outline
I. Determine the maximum tolerated dose sequence of ruxolitinib when added to a standard-of-care pediatric-based chemotherapy regimen in adolescents and young adult patients with newly diagnosed Ph-like acute lymphoblastic leukemia (ALL) and JAK kinase-activating lesions.
I. Among patients who are MRD+ at the end of induction, describe rate of achieving minimal residual disease (MRD) negativity with the addition of ruxolitinib.
II. Describe 2 year event-free survival (EFS) and overall survival (OS) with the addition of ruxolitinib, relative to historic controls.
I. Assess ruxolitinib-induced target inhibition by JAK-STAT pathway analysis.
II. Among patients with detectable minimal residual disease (MRD) following induction, assess MRD following JAK inhibition.
OUTLINE: This is a dose escalation study of ruxolitinib.
REMISSION INDUCTION THERAPY (COURSE I): Patients receive cytarabine intrathecally (IT) on day 1, vincristine sulfate intravenously (IV) on days 1, 8, 15, and 22, dexamethasone orally (PO) or IV on days 1-7 and 15-21, daunorubicin hydrochloride IV on days 1, 8, 15, and 22, pegaspargase IV or intramuscularly (IM) on day 4, 5 or 6, and methotrexate IT on days 8 and 29. Patients with central nervous system (CNS)3 involvement also receive methotrexate IT on days 15 and 22. Patients with CD20+ ALL also receive rituximab IV on days 2 and 16 in the absence of disease progression or unacceptable toxicity.
REMISSION CONSOLIDATION THERAPY (COURSE II): Patients receive cyclophosphamide IV on days 1 and 29, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, vincristine sulfate IV on days 15, 22, 43, and 50, pegaspargase IM or IV on days 15 and 43, methotrexate IT on days 1, 8, 15, and 22, and ruxolitinib PO twice a day (BID) on days 1-14 and 29-43. Patients with CD20+ ALL also receive rituximab IV on days 1, 8, 29, and 36. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE (COURSE III): Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, pegaspargase IV on days 2 and 22, methotrexate IT on days 1 and 31, and ruxolitinib PO BID on days 1-14 and 29-43. Patients with CD20+ ALL also receive rituximab IV on days 1 and 11. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (COURSE IV): Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin hydrochloride IV on days 1, 8 and 15, pegaspargase IM or IV on day 4, 5, or 6 and 43, cyclophosphamide IV on day 29, cytarabine IV or SC on days 29-32 and 36-39, thioguanine PO on days 29-42, methotrexate IT on days 1, 29, and 36, and ruxolitinib PO BID on days 1-14 and 29-43. Patients with CD20+ ALL also receive rituximab IV on days 1 and 8. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE (COURSE V): Patients receive vincristine sulfate IV on days 1, 29, and 57, dexamethasone PO or IV BID on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years from the start of interim maintenance for females, and up to 3 years for males in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every month for 1 year, every 2 months for 1 year, every 3 months for 1 year, every 6 months for 2 years.
Trial Phase & Type
University of Chicago Comprehensive Cancer Center
Secondary IDs NCI-2018-02108
Clinicaltrials.gov ID NCT03571321