Induction Therapy With Cytarabine, High-Dose Mitoxantrone and Dasatinib for Patients With Philadelphia-Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia

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Brief Title

Induction Therapy With Cytarabine, High-Dose Mitoxantrone and Dasatinib for Patients With Philadelphia-Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia

Official Title

Phase I Study of Induction Therapy With Cytarabine, High-Dose Mitoxantrone and Dasatinib for Patients With Philadelphia-Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL): ALL-6 Protocol

Brief Summary

      This research study is for people with a specific type of leukemia called Philadelphia
      chromosome positive acute lymphoblastic leukemia (the type the patients have). The
      investigators plan to give you combination of 3 drugs (dasatinib, mitoxantrone, cytarabine)
      for the first part of the chemotherapy (called Induction). The investigators have previously
      shown that the combination of mitoxantrone and cytarabine is very effective in your kind of
      leukemia. The purpose of this study is to establish a safe dose range of dasatinib in
      combination with this standard induction chemotherapy based on side effects. If possible, the
      trial will also give us an idea of how well this combination might work in treating your
      leukemia. Previous studies have shown that dasatinib can produce responses when given alone
      for your kind of leukemia. By using the dasatinib together with the chemotherapy, the
      investigators believe that we can kill even more leukemia cells than with either treatment
      alone. The investigators will initially treat patients with a low dose of dasatinib and
      monitor for side-effects. If the initial group of patients is able to tolerate this low-dose
      of dasatinib, then future patients will receive higher doses of dasatinib. Mitoxantrone and
      cytarabine chemotherapy is the standard therapy at the investigators' institution for the
      patient's leukemia and it is the combination of dasatinib with this chemotherapy that is new
      and investigational in this study.
    


Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

To determine the dose of dasatinib that can be safely administered with cytarabine, and high-dose mitoxantrone in patients with Ph+ ALL / lymphoid blast crisis of known chronic myelogenous leukemia.

Secondary Outcome

 To determine the toxicity of this combination in these patients.

Condition

Leukemia

Intervention

Dasatinib, Mitoxantrone, Cytarabine

Study Arms / Comparison Groups

 Chemotherapy
Description:  A phase I study designed to determine the dose of dasatinib that can be safely administered with cytarabine and high-dose mitoxantrone in Ph+ ALL / lymphoid blast crisis of known chronic myelogenous leukemia patients.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

7

Start Date

July 2009

Completion Date

April 2014

Primary Completion Date

April 2014

Eligibility Criteria

        Inclusion Criteria:

          -  Previously untreated and treated adult patients (> or = 18 years old) with a diagnosis
             of:

               -  Philadelphia-chromosome positive acute lymphoblastic leukemia

               -  Lymphoid blast crisis of known chronic myelogenous leukemia NOTE: Patients must
                  have evidence of a t(9;22) in leukemic cells based on chromosomal or molecular
                  analysis.

        NOTE: The diagnosis must be confirmed by the pathology department at MSKCC. NOTE: It is
        recognized that newly diagnosed patients may be started on therapy with cytarabine and
        high-dose mitoxantrone (which is the standard of care at our institution for treating adult
        ALL) prior to the identification of t(9;22) in leukemic cells. These patients will remain
        eligible for participation on study and will be evaluable for response if it is possible to
        start treatment with dasatinib within 30 days of receiving induction chemotherapy.

          -  Patients with adequate hepatic function (AST and ALT < or = 2.5 the institutional ULN,
             bilirubin < or = 2.0 mg/dl).

          -  Patients with adequate renal function (creatinine < or = 2.0 mg/dl or creatinine
             clearance > 50 ml/min).

          -  Patients with an LVEF > or = 50%.

          -  Karnofsky performance status > or = 20%.

          -  Ability to take oral medication (dasatinib must be swallowed whole).

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (sensitivity > or = 25IU HCG/L) within 72 hours prior to the start of study drug
             administration. Persons of reproductive potential must agree to use and utilize an
             adequate method of contraception throughout treatment and for at least 6 months after
             study drug is stopped. Prior to study enrollment, women of childbearing potential must
             be advised of the importance of avoiding pregnancy during trial participation and the
             potential risk factors for an unintentional pregnancy.

          -  concomitant Medications: Patient agrees to discontinue St. Johns Wort while receiving
             dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting
             dasatinib); Patient agrees that IV bisphosphonates will be withheld for the first 8
             weeks of dasatinib therapy due to risk of hypocalcemia.

          -  Signed informed consent, which indicates the investigational nature of this study,
             within 30 days of treatment initiation, is required.

        Exclusion Criteria:

          -  Female patients who are pregnant or lactating. Women and men of childbearing age
             should use effective contraception.

          -  Patients with uncontrolled active infections.

          -  Patients who are receiving other systemic chemotherapy. Patients must have been off
             prior antileukemic therapy for at least 2 weeks (hydroxyurea is considered
             acceptable).

        NOTE: Patients who had previously received combination therapy with cytarabine, high-dose
        mitoxantrone and dasatinib will be excluded from the trial. All other prior therapies will
        be allowed, including prior tyrosine kinase inhibitors usage. Prior dasatinib use will be
        allowed (as a single agent or in combination therapy, other than the combination therapy
        with cytarabine and high-dose mitoxantrone).

          -  Concomitant active secondary malignancy requiring treatment (other than squamous cell
             and basal cell carcinoma of skin).

          -  Concurrent medical condition which may increase the risk of toxicity, including: grade
             ≥ 2 pleural or pericardial effusion.

          -  Cardiac Symptoms; any of the following should be considered for exclusion:

               -  Uncontrolled angina, congestive heart failure or MI within (6 months).

               -  Diagnosed congenital long QT syndrome.

               -  Any history of clinically significant ventricular arrhythmias (such as
                  ventricular - tachycardia, ventricular fibrillation, or Torsades de pointes).

               -  Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec).

               -  Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to
                  dasatinib administration.

          -  History of significant bleeding disorder unrelated to cancer, including:

               -  Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).

               -  Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
                  VIII antibodies).

        Ongoing or recent (< or = 3 months) significant gastrointestinal bleeding

          -  Concomitant Medications, any of the following should be considered for exclusion:

               -  Category I drugs that are generally accepted to have a risk of causing Torsades
                  de Pointes including: (Patients must discontinue drug 7 days prior to starting
                  dasatinib)

               -  quinidine, procainamide, disopyramide amiodarone, sotalol, ibutilide, dofetilide
                  erythromycin, clarithromycin chlorpromazine, haloperidol, mesoridazine,
                  thioridazine, pimozide cisapride, bepridil, droperidol, methadone, arsenic,
                  chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,
                  lidoflazine.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Renier Brentjens, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00940524

Organization ID

09-046


Responsible Party

Sponsor

Study Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

 Bristol-Myers Squibb

Study Sponsor

Renier Brentjens, MD, PhD, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

April 2014