Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Patients Aged 40 Years or Older

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02494882

Collaborator

Incyte Corporation (Industry), Novartis Pharmaceuticals (Industry)

Enrollment

Location

Arm

95.1

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans.

This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Ruxolitinib Drug: Dasatinib Drug: Dexamethasone	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Trial Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Patients Aged 40 Years or Older.

Actual Study Start Date :

Jun 29, 2015

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Adding Ruxolitinib to Combination of Dasatinib + Dexamethasone Steroid Pre-Phase (Days -6 to 0) Prednisone 10 mg/m2/day uptitrated to 60/mg/m2/day oral over seven days (capped at 120 mg/day). Remission Induction (Days 1 to 84) Dasatinib 140 mg oral once daily. Days 1-84. Dexamethasone 10 mg/m2/day oral (capped at 20 mg/day). Days 1-24. Dexamethasone oral taper 10 mg/m2/day (capped at 20 mg/day) to off. Taper days 25-32. Off day 33. Ruxolitinib phase I cohort dose oral. Days 1-84. Delivered BID. Delivered per the phase I dose cohort. Methotrexate (MTX) 12 mg Intrathecal (IT) for 4 doses on days 22, 43, 64, 85; +/- 3 days. Post-Remission Induction Therapy (Starting Day 85) Allogeneic HSCT, at the discretion of the treating physician, at any point post-remission induction. Or, post-remission induction (consolidation) therapy to be determined per the treating physician	Drug: Ruxolitinib Drug: Dasatinib Drug: Dexamethasone

Arm

Intervention/Treatment

Experimental: Adding Ruxolitinib to Combination of Dasatinib + Dexamethasone

Steroid Pre-Phase (Days -6 to 0) Prednisone 10 mg/m2/day uptitrated to 60/mg/m2/day oral over seven days (capped at 120 mg/day). Remission Induction (Days 1 to 84) Dasatinib 140 mg oral once daily. Days 1-84. Dexamethasone 10 mg/m2/day oral (capped at 20 mg/day). Days 1-24. Dexamethasone oral taper 10 mg/m2/day (capped at 20 mg/day) to off. Taper days 25-32. Off day 33. Ruxolitinib phase I cohort dose oral. Days 1-84. Delivered BID. Delivered per the phase I dose cohort. Methotrexate (MTX) 12 mg Intrathecal (IT) for 4 doses on days 22, 43, 64, 85; +/- 3 days. Post-Remission Induction Therapy (Starting Day 85) Allogeneic HSCT, at the discretion of the treating physician, at any point post-remission induction. Or, post-remission induction (consolidation) therapy to be determined per the treating physician

Drug: Ruxolitinib

Drug: Dasatinib

Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

Clinical response [2 years]
is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria

Secondary Outcome Measures

Complete Molecular Remission (CMR) rate [2 years]
Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient able to give informed consent.
Patients >/= 18 years with the following disease will be eligible
Newly diagnosed Ph+ ALL, previously untreated, except for the below allowances
Previously received HpyerCVAD cycle 1A+/- cycle 1B
Previously received Induction Phase 1 +/- Induction Phase II of BFM-modeled (Pediatric of Pediatric-Inspired) ALL regimen
Previously received other representative (modified from HyperCVAD, BFM, or AML-like) ALL induction course, including ABL TKI plus corticosteroid.
If the patient has received any of the above prior therapy, they may be enrolled, regardless of remission status.
Relapsed PH+ ALL, with no prior exposure to dasatinib and without known ABL kinase mutations predited to be resistant to dasatibin (e.g. L248R, L248V, Q252H, E255K, V299L, T315A, T315I, F317C, F317L, F317S, F317V)
Relapsed or refractory Ph-like ALL without prior exposure to dasatibin and with mutations or rearrangements of genes conferring sensitivity to dasatibin (ABL, CSF1R, PDGFRB) or ruxolitinib (CRLF2, JAK3, EPOR, TSLP)
Newly diagnosed or relapsed CML in lymphoid blast crisis
Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/FISH) and/or molecular tests (BCR-ABL1 transcripts)
Acceptable end-organ function, except for documented exclusions for organ function compromise due to ALL itself
ECOG performance status ≤ 2
Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and for at least 4 months following treatment on study

Exclusion Criteria:

Ph-negative ALL
Patients with dominant leukemic clone bearing documented bcr-abl mutations enabling bcr-abl TKI resistance at diagnosis
Mature B-cell (Burkitt's) ALL
Serum creatinine > 1.5x ULN and calculated creatinine clearance, based on a 24-hour urine collection, < 30 mL/min--unless related to ALL/tumor lysis syndrome and able to be corrected
Direct Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration.
Pregnant women or women who are breast-feeding
Patients with HIV, Hepatitis B, or Hepatitis C
Pre-treatment QTcF > 480 msecs
A "washout" period of at least 14 days from last previous cytotoxic chemotherapy will be required prior to starting treatment on this protocol. No "washout" period will be required for previous bcr-abl TKI therapy given with the aforementioned previous chemotherapy cycles. Hydroxyurea and corticosteroids may be given as bridge therapy up until 24 hours prior to initiating protocol treatment.
Active malignancy requiring treatment other than ALL within two years prior to start of treatment, with the exception of basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate cancer, or DCIS or LCIS of the breast
Active, uncontrolled infection, any other concurrent disease, or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator
Unable to tolerate anti-viral and anti- Pneumocystis jirovecii prophylaxis while on pre-phase and remission induction therapy
Unable to tolerate gastrointestinal prophylaxis therapy with sucralfate while on pre-phase and remission induction therapy. Or severe pre-existing GI disorder that requires PPI or H2 receptor antagonist therapy be uninterrupted