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



Status:Recruiting
Conditions:Cancer, Blood Cancer, Lymphoma, Leukemia
Therapuetic Areas:Oncology
Healthy:No
Age Range:Any
Updated:11/18/2012
Start Date:June 2009

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A Phase I Study of Obatoclax (Pan Anti-Apoptotic BCL-2 Family Small Molecule Inhibitor), in Combination With Vincristine/Doxorubicin/Dexrazoxane, in Children With Relapsed/Refractory Solid Tumors or Leukemia


RATIONALE: Obatoclax mesylate may stop the growth of cancer cells by blocking some of the
proteins needed for cell growth and causing the cells to self-destruct. Drugs used in
chemotherapy, such as vincristine sulfate, doxorubicin hydrochloride, and dexrazoxane
hydrochloride, work in different ways to stop the growth of cancer cells, either by killing
the cells or by stopping them from dividing. Giving obatoclax mesylate together with
combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of obatoclax mesylate
when given together with 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)
We found this trial at
18
sites
660 S Euclid Ave #8100
Saint Louis, Missouri 63110
(314) 362-5196
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis The Alvin J. Siteman Cancer Center...
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Saint Louis, MO
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1540 East Hospital Drive
Ann Arbor, Michigan 48109
734-936-4000
C.S. Mott Children's Hospital at University of Michigan Medical Center Behind the doors of C.S....
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Ann Arbor, MI
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1802 6th Avenue South
Birmingham, Alabama 35294
(205) 934-4011
UAB Comprehensive Cancer Center One of the nation’s leading cancer research and treatment centers, the...
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Birmingham, AL
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450 Brookline Ave
Boston, Massachusetts 2215
(617) 632-3000
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute Founded in 1997, Dana-Farber/Harvard Cancer Center (DF/HCC) was...
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Boston, MA
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3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
 1-513-636-4200 
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
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Cincinnati, OH
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Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas From its...
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Dallas, TX
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262 Danny Thomas Pl
Memphis, Tennessee 38105
(901) 495-3300
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
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Memphis, TN
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425 E River Pkwy # 754
Minneapolis, Minnesota 55455
612-624-2620
Masonic Cancer Center at University of Minnesota The Masonic Cancer Center was founded in 1991....
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Minneapolis, MN
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701 West 168th Street
New York, New York 10032
(212) 851-4680
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center The Herbert Irving Comprehensive Cancer...
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New York, NY
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1201 W La Veta Ave
Orange, California 92868
(714) 997-3000
Children's Hospital of Orange County For more than 45 years, CHOC Children’s has been steadfastly...
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Orange, CA
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South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
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Philadelphia, PA
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4401 Penn Avenue
Pittsburgh, Pennsylvania 15224
412-692-5325
Children's Hospital of Pittsburgh of UPMC UPMC is one of the leading nonprofit health systems...
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Pittsburgh, PA
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3181 SW Sam Jackson Park Rd
Portland, Oregon 97239
(503) 494-5058
Knight Cancer Institute at Oregon Health and Science University Cancer takes many forms. Although cancer...
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Portland, OR
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4800 Sand Point Way Northeast
Seattle, Washington 98105
(206) 987-2000
Children's Hospital and Regional Medical Center - Seattle Seattle Children
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Seattle, WA
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2515 N Clark St
Chicago, Illinois 60614
(312) 227-6060
Children's Memorial Hospital, Chicago Ann & Robert H. Lurie Children
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Chicago, IL
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One Baylor Plaza
Houston, Texas 77030
(713) 798-4951
Baylor University Medical Center - Houston Baylor University Medical Center in Dallas began in 1903...
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Houston, TX
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705 Riley Hospital Drive
Indianapolis, Indiana 46202
317.944.2060
Riley's Children Cancer Center at Riley Hospital for Children The Riley Hospital for Children Cancer...
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Indianapolis, IN
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111 Michigan Ave NW
Washington, District of Columbia
(202) 476-5000
Childrens National Medical Center As the nation’s children’s hospital, the mission of Children’s National Medical...
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Washington,
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