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Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)

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ClinicalTrials.gov Identifier: NCT02420717
Recruitment Status : Recruiting
First Posted : April 20, 2015
Last Update Posted : August 21, 2017
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
The goal of this clinical research study is to learn if ruxolitinib or dasatinib in combination with chemotherapy can help to control Philadelphia Chromosome (Ph)-like acute lymphoblastic leukemia (ALL). The safety of these drug combinations will also be studied.

Condition or disease Intervention/treatment Phase
Leukemia Drug: Ruxolitinib Drug: Dasatinib Drug: Rituximab Drug: G-CSF Drug: Pegfilgrastim Drug: Methotrexate Drug: Cytarabine Drug: Cyclophosphamide Drug: Mesna Drug: Doxorubicin Drug: Vincristine Drug: Dexamethasone Drug: Solumedrol Drug: 6-mercaptopurine Drug: Prednisone Drug: Leucovorin Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of the Combination of Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)
Actual Study Start Date : July 2015
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023


Arm Intervention/treatment
Experimental: Ruxolitinib + Chemotherapy
Based on the molecular profile, participants stratified into 2 cohorts. For patients who fail to respond to a single agent ruxolitinib by 3 weeks (earlier if evidence of progressive disease), Hyper-CVAD chemotherapy added. Single-agent ruxolitinib cycle is cycle 0. Hyper-CVAD intensive cycles labelled cycles 1-8. The hyper-CVAD regimen consists of an intensive phase comprised of 8 cycles of chemotherapy alternating courses of hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) with courses of high-dose methotrexate and cytarabine every 21 days. Maintenance phase chemotherapy with POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) commences after the completion of the intensive phase of chemotherapy. Ruxolitinib given continuously concurrently with the intensive and maintenance phases.
Drug: Ruxolitinib
Starting dose of Ruxolitinib: 15 mg by mouth twice daily.
Other Names:
  • Jakafi
  • INCB018424
  • INC424
Drug: Rituximab
375 mg/m2 days 1 and 11 for cycles 1 and 3, and days 1 and 8 for cycles 2 and 4.
Other Name: Rituxan
Drug: G-CSF
5 mcg/kg/day within 72 ± 48 hours after completion of chemotherapy until neutrophil recovery 1 x 109/L or higher for Hyper-CVAD chemotherapy all courses.
Other Names:
  • Filgrastim
  • Neupogen
Drug: Pegfilgrastim
6 mg subcutaneously for one dose approximately 24 hours after completion of the chemotherapy may be substituted for G-CSF at the discretion of the treating physician for Hyper-CVAD chemotherapy all courses.
Other Names:
  • Neulasta
  • PEG-G-CSF
Drug: Methotrexate

12 mg (6 mg via Ommaya reservoir) day 2 of each of the first 4 cycles of Hyper-CVAD chemotherapy.

200 mg/m2 by vein over 2 hours followed by 800 mg/m2 by vein over 22 hours day 1 of Hyper-CVAD chemotherapy Courses 2, 4, 6, 8.

20 mg/m2 by mouth weekly for maintenance phase chemotherapy (POMP maintenance). Treatment cycle is 28 days.

Drug: Cytarabine

100 mg day 7 of each of the first 4 cycles of Hyper-CVAD chemotherapy during cycles 1 and 3 of Hyper-CVAD Courses 1, 3, 5, 7.

3 gm/m2 by vein over 2 hours every 12 hours for 4 doses on days 2, 3 for Hyper-CVAD Courses 2, 4, 6, 8.

Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine arabinosine hydrochloride
Drug: Cyclophosphamide
300 mg/m2 by vein over 3 hours every 12 hours for 6 doses days 1, 2, 3 (total dose 1800 mg/m2) for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Names:
  • Cytoxan
  • Neosar
Drug: Mesna
600 mg/m2/d by vein continuous infusion daily for 24 hours days 1 - 3 for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Name: Mesnex
Drug: Doxorubicin
50 mg/m2 by vein over 24 hours on day 4, after last dose of Cyclophosphamide given for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Names:
  • Doxorubicin hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex
Drug: Vincristine

2 mg by vein on day 4 and day 11 for Hyper-CVAD (Courses 1, 3, 5, 7).

2 mg by vein approximately every 28 days for maintenance phase chemotherapy (POMP maintenance).

Drug: Dexamethasone
40 mg by vein or mouth daily days 1 - 4 and days 11 - 14 for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Name: Decadron
Drug: Solumedrol
50 mg by vein over 2 hours approximately every 12 hours for 6 doses days 1 - 3 for Hyper-CVAD chemotherapy Courses 2, 4, 6, 8.
Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Solu-Medrol
Drug: 6-mercaptopurine
50 mg tablets by mouth 3 times daily for maintenance phase chemotherapy (POMP maintenance). Treatment cycle is 28 days.
Other Names:
  • Mercaptopurine
  • 6-MP
  • Purinethol
Drug: Prednisone
200 mg by mouth daily days 1 to 5 approximately every 28 days, starting with vincristine (if given) for maintenance phase chemotherapy (POMP maintenance).
Experimental: Dasatinib + Chemotherapy
Based on the molecular profile, participants stratified into 2 cohorts. For patients who fail to respond to a single agent dasatinib by 3 weeks (earlier if evidence of progressive disease), Hyper-CVAD chemotherapy added. Single-agent dasatinib cycle is cycle 0. Hyper-CVAD intensive cycles labelled cycles 1-8. The hyper-CVAD regimen consists of an intensive phase comprised of 8 cycles of chemotherapy alternating courses of hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) with courses of high-dose methotrexate and cytarabine every 21 days. Maintenance phase chemotherapy with POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) commences after the completion of the intensive phase of chemotherapy. Dasatinib given continuously concurrently with the intensive and maintenance phases.
Drug: Dasatinib
Starting dose of Dasatinib: 100 mg by mouth once daily.
Other Names:
  • BMS-354825
  • Sprycel
Drug: Rituximab
375 mg/m2 days 1 and 11 for cycles 1 and 3, and days 1 and 8 for cycles 2 and 4.
Other Name: Rituxan
Drug: G-CSF
5 mcg/kg/day within 72 ± 48 hours after completion of chemotherapy until neutrophil recovery 1 x 109/L or higher for Hyper-CVAD chemotherapy all courses.
Other Names:
  • Filgrastim
  • Neupogen
Drug: Pegfilgrastim
6 mg subcutaneously for one dose approximately 24 hours after completion of the chemotherapy may be substituted for G-CSF at the discretion of the treating physician for Hyper-CVAD chemotherapy all courses.
Other Names:
  • Neulasta
  • PEG-G-CSF
Drug: Methotrexate

12 mg (6 mg via Ommaya reservoir) day 2 of each of the first 4 cycles of Hyper-CVAD chemotherapy.

200 mg/m2 by vein over 2 hours followed by 800 mg/m2 by vein over 22 hours day 1 of Hyper-CVAD chemotherapy Courses 2, 4, 6, 8.

20 mg/m2 by mouth weekly for maintenance phase chemotherapy (POMP maintenance). Treatment cycle is 28 days.

Drug: Cytarabine

100 mg day 7 of each of the first 4 cycles of Hyper-CVAD chemotherapy during cycles 1 and 3 of Hyper-CVAD Courses 1, 3, 5, 7.

3 gm/m2 by vein over 2 hours every 12 hours for 4 doses on days 2, 3 for Hyper-CVAD Courses 2, 4, 6, 8.

Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine arabinosine hydrochloride
Drug: Cyclophosphamide
300 mg/m2 by vein over 3 hours every 12 hours for 6 doses days 1, 2, 3 (total dose 1800 mg/m2) for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Names:
  • Cytoxan
  • Neosar
Drug: Mesna
600 mg/m2/d by vein continuous infusion daily for 24 hours days 1 - 3 for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Name: Mesnex
Drug: Doxorubicin
50 mg/m2 by vein over 24 hours on day 4, after last dose of Cyclophosphamide given for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Names:
  • Doxorubicin hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex
Drug: Vincristine

2 mg by vein on day 4 and day 11 for Hyper-CVAD (Courses 1, 3, 5, 7).

2 mg by vein approximately every 28 days for maintenance phase chemotherapy (POMP maintenance).

Drug: Dexamethasone
40 mg by vein or mouth daily days 1 - 4 and days 11 - 14 for Hyper-CVAD (Courses 1, 3, 5, 7).
Other Name: Decadron
Drug: Solumedrol
50 mg by vein over 2 hours approximately every 12 hours for 6 doses days 1 - 3 for Hyper-CVAD chemotherapy Courses 2, 4, 6, 8.
Other Names:
  • Methylprednisolone
  • Depo-Medrol
  • Medrol
  • Solu-Medrol
Drug: 6-mercaptopurine
50 mg tablets by mouth 3 times daily for maintenance phase chemotherapy (POMP maintenance). Treatment cycle is 28 days.
Other Names:
  • Mercaptopurine
  • 6-MP
  • Purinethol
Drug: Prednisone
200 mg by mouth daily days 1 to 5 approximately every 28 days, starting with vincristine (if given) for maintenance phase chemotherapy (POMP maintenance).
Drug: Leucovorin
50 mg by vein followed by 15 mg by vein every 6 hours for 8 doses (or until MTX cleared) beginning 12 hours post MTX completion for courses 2, 4, 6, 8.
Other Names:
  • Citrovorum
  • Wellcovorin



Primary Outcome Measures :
  1. Response Rate (CR/CRi) of Ruxolitinib or Dasatinib in Combination With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL) [ Time Frame: 42 days ]

    The Optimum two-stage design proposed by Simon implemented in each of the cohorts separately. For each cohort, a target CR/CRi of 25% assumed and a CR/CRi of 10% or lower considered as not desirable.

    Complete Response (CR): Disappearance of all clinical and/or radiologic evidence of disease, Neutrophil count ≥ 1.0 x 109/L, Platelet count ≥ 100 x 109/L, Normal bone marrow differential (≤ 5% blasts), No extra-medullary leukemia.

    Complete Remission without Incomplete Blood Count Recovery (CRi): CR except for ANC < 1.0 x 109/L and/or platelets < 100 x 109/L.




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Ages Eligible for Study:   10 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with previously treated B-cell ALL (relapsed and/or refractory after prior therapy)
  2. Bone marrow involvement with >/= 5% lymphoblasts
  3. Age >/= 10 years
  4. Documented genetic lesion(s) known to confer susceptibility to inhibition by either ruxolitinib or dasatinib or CRLF2 positivity by flow cytometry (for the Ruxolitinib cohort)
  5. Eastern Cooperative Oncology Group (ECOG) performance status </= 2
  6. Adequate organ function (total bilirubin < 2.0 mg/dL, SGPT or SGOT < 3 x upper limit of normal [ULN], creatinine < 2 mg/dL)
  7. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (Beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Females of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Appropriate methods of birth control include the following: -- Any 2 of the following methods used together: --Birth control implants, injections, or pills (except for progesterone only pills), --Intrauterine device (IUD), --Vasectomy, --Tubal Ligation, --Barrier method (female or male condom with spermicide, cervical cap with spermicide, diaphragm with spermicide); --Male condom with spermicide and diaphragm; Male condom with spermicide and cervical cap
  8. (Continuation of #7) Unacceptable methods of birth control include using no birth control, withdrawal, rhythm method, vaginal sponge, any barrier method that does not use spermicide, progesterone only pills, and using male and female condoms at the same time.
  9. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
  10. Patients or their legally authorized representative must provide written informed consent

Exclusion Criteria:

  1. Burkitt's Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma
  2. Patients having undergone prior allogeneic stem cell transplant within 3 months or having active graft versus host disease
  3. Patient is pregnant or breastfeeding
  4. Patients with uncontrolled active infections (Fever >/= 38 degree C, Septic shock)
  5. Isolated extramedullary relapse (i.e. testicular, central nervous system)
  6. Current or chronic hepatitis B or C infection, or known seropositivity for HIV
  7. Concurrent chemotherapy (except intrathecal chemotherapy)
  8. Major surgery within 4 weeks prior to first study dose
  9. Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and steroids) prior to starting therapy. For patients receiving ALL maintenance with 6-mercaptopurine, methotrexate, vincristine, and steroids - these agents should be discontinued at least 48 hours prior to start of study drugs. For patients on oral targeted therapies (such as imatinib, dasatinib, ponatinib), - these agents should be discontinued at least 48 hours prior to start of study drugs.
  10. Patients must have recovered from acute non hematologic toxicity (to </= grade 1) of all previous therapy prior to enrollment
  11. Known active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within the prior 28 days, symptomatic CNS leukemia (i.e., cranial nerve palsies or other significant neurologic dysfunction) within 28 days. Patients may have history of CNS leukemic involvement if definitively treated with prior therapy and no evidence of active disease (defined as >/= 2 consecutive spinal fluid assessments with no evidence of disease) at the time of registration. Prophylactic intrathecal chemotherapy is not a criterion for exclusion.
  12. Patients with active heart disease (NYHA class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)
  13. Patients with a cardiac ejection fraction (as measured by either Multi-gated Acquisition (MUGA) scan or echocardiogram) < 40%. (Note: Patients who have had prior anthracycline exposure of >250 mg/m2 may be eligible after discussion with the PI).
  14. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix or the breast, unless they are successfully treated with curative intent for more than 2 years before entering the study
  15. Malabsorption syndrome or other conditions that preclude enteral route of administration
  16. Patients requiring strong CYP3A4 inhibitors. (Complete list of inhibitors can be found at: http://medicine.iupui.edu/clinpharm/ddis/table.aspx)
  17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02420717


Contacts
Contact: Nitin Jain, MBBS 713-745-6080

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Incyte Corporation
Investigators
Principal Investigator: Nitin Jain, MBBS M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02420717     History of Changes
Other Study ID Numbers: 2014-0521
NCI-2015-00779 ( Registry Identifier: NCI CTRP )
First Posted: April 20, 2015    Key Record Dates
Last Update Posted: August 21, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Leukemia
Acute Lymphoblastic Leukemia
ALL
Philadelphia Chromosome (Ph)-Like
Relapsed
Refractory
6-mercaptopurine
Mercaptopurine
6-MP
Purinethol
Ruxolitinib
Jakafi
INCB018424
INC424
Dasatinib
BMS-354825
Sprycel
Rituximab
Rituxan
G-CSF
Filgrastim
Neupogen
Pegfilgrastim
Neulasta
PEG-G-CSF
Methotrexate
Cytarabine
Ara-C
Cytosar
DepoCyt

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Dexamethasone acetate
Prednisolone acetate
Methylprednisolone acetate
Dexamethasone
Prednisone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Liposomal doxorubicin
Cyclophosphamide
Rituximab
Doxorubicin
Methotrexate
Cytarabine
Vincristine