Obatoclax Mesylate, Vincristine Sulfate, Doxorubicin Hydrochloride, and Dexrazoxane Hydrochloride in Treating Young Patients With Relapsed or Refractory Solid Tumors, Lymphoma, or Leukemia

OBJECTIVES:

Primary

- Estimate the maximum-tolerated dose and/or recommended phase II dose of obatoclax
mesylate in combination with vincristine sulfate, doxorubicin hydrochloride, and
dexrazoxane hydrochloride in pediatric patients with refractory solid tumors.

- Define and describe the toxicities of obatoclax mesylate in these patients.

Secondary

- Preliminarily define the antitumor activity of obatoclax hydrochloride in patients with
refractory or relapsed solid tumors or leukemias within the confines of a phase I
study.

OUTLINE: This is a multicenter, dose-escalation study of obatoclax mesylate. Patients are
stratified according to disease type (solid tumor or lymphoma [stratum 1] vs multilineage
leukemia (MLL) [stratum 2] vs non-MLL leukemia [stratum 3]) and treated according to
stratum.

- Stratum 1 (dose-escalation): Patients receive obatoclax mesylate IV over 3 hours on
days 1 and 8 and vincristine sulfate IV, doxorubicin hydrochloride IV, and dexrazoxane
hydrochloride IV on day 8 of course 1 (28 days). Drugs are administered on day 1 of
subsequent courses and repeat every 21 days for up to 1 year in the absence of disease
progression or unacceptable toxicity.

- Stratum 2: Patients receive obatoclax mesylate (at starting dose in stratum 1),
vincristine sulfate, doxorubicin hydrochloride, and dexrazoxane hydrochloride as in
stratum 1.

- Stratum 3: Patients receive obatoclax mesylate (at the MTD determined in stratum 1),
vincristine sulfate, doxorubicin hydrochloride, and dexrazoxane hydrochloride as in
stratum 1.

After completion of study therapy, patients are followed up for 30 days.

DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following:

- Histologically confirmed refractory or relapsed solid tumor or lymphoma (stratum
1)

- Measurable or evaluable disease

- No primary CNS tumors

- No known CNS metastases

- Recurrent or refractory mixed-lineage leukemia (MLL) leukemia (stratum 2)

- More than 25% blasts on bone marrow aspirate

- No symptomatic CNS leukemia, CNS chloromas, or leptomeningeal leukemic
involvement

- Recurrent or refractory non-MLL leukemia (stratum 3)

- Acute lymphoblastic leukemia, acute myeloid leukemia, or chronic myeloid
leukemia in blast crisis

- More than 25% blasts on bone marrow aspirate

- No symptomatic CNS leukemia, CNS chloromas, or leptomeningeal leukemic
involvement

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life

PATIENT CHARACTERISTICS:

- Karnofsky performance status 50-100% (> 16 years of age)

- Lansky performance status 50-100% (≤ 16 years of age)

- ANC ≥ 1,000/mm^3 (stratum 1)

- Platelet count ≥ 100,000/mm^3 (transfusion independent defined as ≥ 7 days since
prior transfusion)(stratum 1)

- Platelet count ≥ 20,000/mm^3 (may receive platelet transfusion) (stratum 2 and 3)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusion)

- Creatinine clearance OR radioisotope GFR ≥ 70 mL/min OR serum creatinine based on
age/gender as follows:

- 0.5 mg/dL (6 months to < 1 year of age)

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)

- Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal

- ALT ≤ 110 U/L

- Serum albumin ≥ 2 g/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Adequate cardiac function defined as 1 of the following:

- Shortening fraction ≥ 27% by echocardiogram

- Ejection fraction ≥ 50% by gated radionuclide study

- Central nervous system function defined as:

- Stable neurological examination ≥ 2 weeks prior to study

- No known unresolved neurological toxicities > grade 2

- No uncontrolled infection

- Must be able to comply with the safety-monitoring requirements of the study according
to the primary investigator's opinion

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

- At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)

- At least 24 hours since prior hydroxyurea

- At least 7 days since prior hematopoietic growth factor

- At least 7 days since prior biologic therapy

- Time must be extended for other biological agents known to have adverse events
beyond 7 days, at the discretion of the primary investigator

- At least 6 weeks since prior immunotherapy (e.g., tumor vaccine)

- At least 3 half-lives since prior monoclonal antibody therapy

- Prior radiotherapy allowed according to the following criteria:

- At least 2 weeks since prior palliative radiotherapy (small port)

- At least 6 months since prior total-body irradiation (TBI), craniospinal
radiotherapy, or ≥ 50% radiation of the pelvis

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

- At least 3 months since prior stem cell transplantation or rescue without TBI and no
evidence of active graft-vs-host disease

- More than 7 days since prior growth factor that supports platelet or white cell
number or function

- Stable or decreasing dose of corticosteroid in the past 7 days

- No concurrent investigational drugs

- No other concurrent anticancer agents (including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy) except for hydroxyurea

- Patients with leukemia may receive concurrent anticancer agents (methotrexate,
hydrocortisone, cytarabine) intrathecally, if necessary

- No concurrent anticonvulsants

- No prior total lifetime cumulative anthracycline dose > 750 mg/m^2 (25 mg/kg if
patient < 1 year) of doxorubicin hydrochloride or equivalent (e.g., daunorubicin
hydrochloride, idarubicin, or mitoxantrone hydrochloride)