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A Phase I Study of BMS-354825 (Dasatinib) in Children With Recurrent/Refractory Solid Tumors or Imatinib Resistant Ph+ Leukemia (BMS Trial CA180038)


Phase 1
1 Year
21 Years
Not Enrolling
Both
Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Childhood Chronic Myelogenous Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Meningeal Chronic Myelogenous Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Relapsing Chronic Myelogenous Leukemia, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of BMS-354825 (Dasatinib) in Children With Recurrent/Refractory Solid Tumors or Imatinib Resistant Ph+ Leukemia (BMS Trial CA180038)


PRIMARY OBJECTIVES:

I. Determine the toxicities and estimate the maximum tolerated dose or the recommended phase
2 dose of dasatinib in pediatric patients with refractory solid tumors.

II. Determine the toxicities of dasatinib in pediatric patients with imatinib
mesylate-resistant Philadelphia chromosome-positive (Ph+) leukemia.

III. Characterize the pharmacokinetics of dasatinib in pediatric patients with refractory
solid tumors or imatinib-resistant Ph+ leukemia.

SECONDARY OBJECTIVES:

I. Preliminarily define the antitumor activity of dasatinib in pediatric patients with
refractory solid tumors within the confines of a phase I study.

II. Obtain pilot data on the activity of dasatinib administered in pediatric patients with
Ph+ leukemia.

III. Assess the biologic activity of dasatinib on tumor cells when available. IV. Determine
the phosphotyrosine state of SRC and ABL substrates and correlate this with dasatinib dosage
and antitumor activity (pharmacodynamics study).

OUTLINE: This is a multicenter, dose-escalation study. Patients are stratified according to
disease (solid tumors vs leukemia).

Stratum 1 (solid tumors): Patients receive oral dasatinib twice daily on days 1-28.
Treatment repeats every 28 days for up to 24 courses in the absence of disease progression
or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of dasatinib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which ≥ 2 of 6
patients experience dose-limiting toxicity (DLT).

Stratum 2 (leukemia): Patients receive dasatinib as in stratum 1. Cohorts of 3-12 patients
receive escalating or de-escalating doses of dasatinib. The MTD is defined as the dose
preceding that at which 7 of 12 patients experience DLT.

After completing study treatment, patients are followed for 1 month.


Inclusion Criteria:



- Histologically confirmed diagnosis of 1 of the following:

- Malignant extracranial solid tumor

- Recurrent or refractory disease

- Known bone marrow metastases* allowed

- Imatinib mesylate-resistant Philadelphia chromosome-positive (Ph+) acute
lymphoblastic leukemia (ALL), defined as M3 bone marrow in a patient who
previously received imatinib mesylate-containing treatment regimen

- Imatinib mesylate-resistant Ph+ chronic myelogenous leukemia (CML), as defined
by any of the following:

- Increasing WBC or platelet count while on imatinib mesylate therapy

- Lack of any cytogenetic response after an adequate duration of imatinib
mesylate therapy, as defined by 1 of the following:

- Failed to achieve a complete hematologic response after completion of
3 months of imatinib mesylate treatment

- Failed to achieve a partial or complete cytogenetic response (i.e., ≤
35% Ph+ cells) after 6 months of imatinib mesylate treatment

- Appearance of accelerated or blastic feature while on imatinib mesylate
therapy

- Reappearance of Ph+ clones after an initial complete cytogenetic response
to imatinib mesylate

- More than 30% increase in Ph+ cells in peripheral blood or bone marrow
cytogenetics while on imatinib mesylate therapy

- Imatinib mesylate intolerance, as defined by development of adverse effects
requiring discontinuation of imatinib mesylate therapy

- Measurable disease (for patients with CML or ALL)

- Determined by hematologic, cytogenetic, and molecular studies for CML

- Determined by bone marrow blast percentage for ALL

- Measurable or evaluable disease (for patients with solid tumors)

- No known curative therapy or survival-prolonging therapy with an acceptable quality
of life

- No CNS solid tumors

- CNS-positive leukemia allowed

- Karnofsky performance status (PS) ≥ 50% (for patients > 10 years of age)

- Lansky PS ≥ 50% (for patients ≤ 10 years of age)

- No evidence of graft-vs-host disease

- Solid tumors:

- Absolute neutrophil count ≥ 1,000/mm^3 (750/mm^3 if bone marrow infiltration)

- Platelet count ≥ 100,000/mm^3 (transfusion independent) (50,000/mm^3 if bone
marrow infiltration)

- Hemoglobin ≥ 8.0 g/dL (red blood cell [RBC] transfusions allowed)

- ALL/CML:

- Platelet count ≥ 20,000/mm^3 (platelet transfusions allowed)

- Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
creatinine based on age, as follows:

- No greater than 0.6 mg/dL (1-23 months of age)

- No greater than 0.8 mg/dL (2- 5 years of age)

- No greater than 1.0 mg/dL (6-9 years of age)

- No greater than 1.2 mg/dL (10-12 years of age)

- No greater than 1.4 mg/dL (13 years of age and over [female])

- No greater than 1.5 mg/dL (13-15 years of age [male])

- No greater than 1.7 mg/dL (16 years of age and over [male])

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 110 U/L

- Albumin ≥ 2 g/dL

- Normal 12-lead EKG with corrected QTc < 450 msec AND meets 1 of the following
criteria:

- Shortening fraction normal

- Ejection fraction normal

- No evidence of dyspnea at rest

- No exercise intolerance

- Pulse oximetry > 94% if there is a clinical indication for determination

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infection

- No swallowing dysfunction that would prevent taking an oral or liquid medication

- See Disease Characteristics

- Recovered from prior chemotherapy, immunotherapy, or radiotherapy

- No myelosuppressive chemotherapy within the past 3 weeks (6 weeks for nitrosoureas)

- At least 7 days since prior growth factors

- At least 14 days since prior pegfilgrastim

- At least 7 days since prior biologic agents

- At least 2 weeks since prior local small-port palliative radiotherapy

- At least 3 months since prior total-body irradiation, craniospinal radiation, or
radiation to ≥ 50% of the pelvis

- At least 6 weeks since other prior substantial bone marrow radiation

- At least 3 months since prior stem cell transplantation

- Hydroxyurea cytoreduction for Ph+ leukemia allowed provided it is discontinued 24
hours before first dose of dasatinib

- Prior intrathecal (IT) therapy allowed (for patients with CNS-positive leukemia)

- Concurrent IT therapy comprising hydrocortisone, cytarabine, methotrexate, or
cytarabine (liposomal) allowed (for patients with CNS-positive leukemia)

- No other concurrent investigational drugs

- No other concurrent anticancer agents, including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy

- No concurrent enzyme-inducing anticonvulsants, including any of the following:

- Phenytoin

- Phenobarbital

- Carbamazepine

- Felbamate

- Primdone

- Oxcarbazepine

- No concurrent antithrombotic or antiplatelet agents, including any of the following:

- Warfarin

- Heparin

- Low-molecular weight heparin

- Aspirin

- Ibuprofen

- Other nonsteroidal anti-inflammatory drugs

- No concurrent CYP3A4 inhibitors, including itraconazole, ketoconazole, and
voriconazole

- No concurrent highly active antiretroviral treatment for HIV-positive patients

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose defined as the maximum dose at which fewer than 1/3 patients experience dose-limiting toxicities (DLT) graded according to CTCAE

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Richard Aplenc

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01824

NCT ID:

NCT00316953

Start Date:

March 2006

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Blastic Phase Chronic Myelogenous Leukemia
  • Childhood Chronic Myelogenous Leukemia
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Meningeal Chronic Myelogenous Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Philadelphia Chromosome
  • Neoplasms

Name

Location

Children's Oncology GroupArcadia, California  91006-3776