Clinical trial NCT00933985: Obatoclax Mesylate, Vincristine Sulfate, Doxorubicin Hydrochloride, and Dexrazoxane Hydrochloride in Treating Young Patients With Relapsed or Refractory Solid Tumors, Lymphoma, or Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Leukemias of Ambiguous Lineage
Acute Undifferentiated Leukemia
Angioimmunoblastic T-cell Lymphoma
Blastic Phase Chronic Myelogenous Leukemia
Childhood Burkitt Lymphoma
Childhood Chronic Myelogenous Leukemia
Childhood Diffuse Large Cell Lymphoma
Childhood Immunoblastic Large Cell Lymphoma
Childhood Nasal Type Extranodal NK/T-cell Lymphoma
Cutaneous B-cell Non-Hodgkin Lymphoma
Hepatosplenic T-cell Lymphoma
Intraocular Lymphoma
Noncutaneous Extranodal Lymphoma
Peripheral T-cell Lymphoma
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Recurrent Childhood Anaplastic Large Cell Lymphoma
Recurrent Childhood Grade III Lymphomatoid Granulomatosis
Recurrent Childhood Large Cell Lymphoma
Recurrent Childhood Lymphoblastic Lymphoma
Recurrent Childhood Small Noncleaved Cell Lymphoma
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent/Refractory Childhood Hodgkin Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
Relapsing Chronic Myelogenous Leukemia
Small Intestine Lymphoma
Unspecified Childhood Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-07-08
Enrollment: 22
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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. 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.

Detailed description: PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase II dose of obatoclax (obatoclax mesylate) administered as a single agent on day 1 and in combination with vincristine ( vincristine sulfate), doxorubicin (doxorubicin hydrochloride), and dexrazoxane (dexrazoxane hydrochloride) at day 8 in children with refractory solid tumors.

II. To define and describe the toxicities of obatoclax administered on this schedule.

III. To characterize the pharmacokinetics of obatoclax in children with refractory solid tumors or relapsed leukemia.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of obatoclax in children with refractory or relapsed solid tumors and leukemias within the confines of a Phase I study.

II. To preliminarily assess leukemic blast characteristics associated with obatoclax activity.

III. To preliminarily assess the biological activity of obatoclax by investigating effects on cell death regulatory pathways.

OUTLINE: This is a dose-escalation study of obatoclax mesylate.

STRATUM 1 (dose-escalation): Patients receive obatoclax mesylate intravenously (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.

Eligibility criteria: Inclusion Criteria:

* Stratum 1 (solid tumors, including lymphomas): patients must have had histologic verification of malignancy at original diagnosis or relapse; patients with recurrent or refractory solid tumors are eligible, excluding primary central nervous system (CNS) tumors or patients with known CNS metastases
* Stratum 2 (mixed-lineage leukemia \[MLL\] + leukemia): patients with recurrent or refractory MLL+ leukemia are eligible excluding those patients with symptomatic CNS leukemia, CNS chloromas, or leptomeningeal leukemic involvement
* Stratum 3 (other leukemias): patients with non-MLL+ recurrent or refractory leukemia (acute lymphoblastic leukemia \[ALL\], acute myeloid leukemia \[AML\] or chronic myeloid leukemia \[CML\] in blast crisis) are eligible excluding those patients with symptomatic CNS leukemia, CNS chloromas, or leptomeningeal leukemic involvement
* Stratum 1: patients must have either measurable or evaluable disease
* Strata 2 and 3: patients with leukemia must have a \> 25% blasts on bone marrow aspirate to be eligible
* Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
* Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 for patients =\< 16 years of age
* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

  * Myelosuppressive chemotherapy: must not have received within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea); hydroxyurea may be administered prior to study enrollment; in such cases at least 24 hours must have elapsed between the last dose of hydroxyurea and the first dose of obatoclax
  * Hematopoietic growth factors: at least 7 days since the completion of therapy with a growth factor
  * Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  * Immunotherapy: at least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines
  * Monoclonal antibodies: at least 3 half-lives since prior therapy that includes a monoclonal antibody
  * Radiation therapy (XRT): \>= 2 weeks (wks) for local palliative XRT (small port); \>= 6 months must have elapsed if prior total-body irradiation (TBI), craniospinal XRT or if \>= 50% radiation of pelvis; \>= 6 wks must have elapsed if other substantial bone marrow (BM) radiation
  * Stem cell transplant or rescue without TBI: no evidence of active graft vs. host disease and \>= 3 months must have elapsed since transplant
* STRATUM 1: Peripheral absolute neutrophil count (ANC) \>= 1000/mm\^3
* STRATUS 1: Platelet count \>= 100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
* STRATUM 1: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions)
* STRATA 2 and 3: Platelet count \>= 20,000/mm\^3 (may receive platelet transfusions)
* STRATA 2 and 3: Hemoglobin \>= 8.0 g/dL (may receive RBC transfusions)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70ml/min/1.73 m\^2 OR a 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 + unconjugated) \>= 1.5 x upper limit of normal (ULN) for age
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \>= 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
* Serum albumin \>= 2 g/dL
* Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by gated radionuclide study
* Stable neurological examination for at least 2 weeks prior to study enrollment; no known \> grade 2 unresolved neurological toxicities
* All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

* Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
* Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment
* Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days
* Patients who are currently receiving another investigational drug are not eligible
* Patients who are currently receiving other anticancer agents, with the exception of hydroxyurea, are not eligible; patients with leukemia may receive intrathecal therapy as outlined
* Any anti-convulsant medications
* Patients who have an uncontrolled infection are not eligible
* Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
* Patients with a total lifetime cumulative anthracycline dose \> 750 mg/m2 (25 mg/kg if \< 1 year) doxorubicin or equivalent at the time of enrollment are not eligible

Primary outcomes:
measure: Maximum-tolerated dose of obatoclax mesylate in combination with vincristine sulfate, doxorubicin hydrochloride, and dexrazoxane hydrochloride, defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity
timeFrame: 28 days
measure: Incidence of adverse events characterized by grade, relationship to study therapy, and prior experience, assessed by NCI CTCAE v4.0
timeFrame: Up to 30 days
Secondary outcomes:
measure: Disease response assessed using Response Evaluation Criteria in Solid Tumors
timeFrame: Up to 30 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
Study officials:
affiliation: COG Phase I Consortium
name: Richard Aplenc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Urtishak KA, Edwards AY, Wang LS, Hudome A, Robinson BW, Barrett JS, Cao K, Cory L, Moore JS, Bantly AD, Yu QC, Chen IM, Atlas SR, Willman CL, Kundu M, Carroll AJ, Heerema NA, Devidas M, Hilden JM, Dreyer ZE, Hunger SP, Reaman GH, Felix CA. Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia. Blood. 2013 Apr 4;121(14):2689-703. doi: 10.1182/blood-2012-04-425033. Epub 2013 Feb 7.