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Phase I and Pharmacodynamic Study of SB-715992 in Acute Leukemias


Phase 1
18 Years
N/A
Not Enrolling
Both
Acute Undifferentiated Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Acute Promyelocytic Leukemia (M3), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Blastic Phase Chronic Myelogenous Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

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Trial Information

Phase I and Pharmacodynamic Study of SB-715992 in Acute Leukemias


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of SB-715992 given as a daily x 3 infusion
in patients with acute leukemia.

II. To obtain pharmacokinetic studies of SB-715992 given on a 3 consecutive day schedule
every 3 weeks.

III. To describe treatment-related and dose-limiting toxicities of SB-715992 in patients
with acute leukemia.

IV. To describe the anti-leukemia activity of SB-715992. V. To correlate treatment-related
toxicities with pharmacokinetic studies of SB-715992.

SECONDARY OBJECTIVES:

I. To validate KSP as the major target of SB-715992 by determining the impact of drug
treatment on cytoskeletal morphology in peripheral blood mononuclear cells and circulating
leukemic blasts.

II. To determine the expression of tubulin isoforms and KSP in leukemic blasts and explore
possible relationships between gene expression and response to SB-715992.

OUTLINE: This is a dose-escalation, multicenter study.

Induction chemotherapy: Patients receive SB-715992 IV over 1 hour on days 1-3. Treatment
repeats every 21 days for up to 3 courses in the absence of disease progression or
unacceptable toxicity.

Consolidation chemotherapy: Patients achieving complete response (CR), partial response
(PR), or stable disease (SD) after induction chemotherapy receive up to 4 additional courses
of SB-715992 beyond CR, PR, or SD.

Cohorts of 3-6 patients receive SB-715992 until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients
experience dose-limiting toxicity. At least 9 patients are treated at the MTD.

Patients are followed for 6 weeks.

PROJECTED ACCRUAL: Approximately 15-30 patients will be accrued for this study within 7.5-15
months.


Inclusion Criteria:



- Patients must have acute myelogenous or acute lymphoblastic leukemia refractory to
primary standard induction therapy; relapsed/refractory acute leukemia; chronic
myelogenous leukemia in blast crisis are eligible at diagnosis or after failing
aggressive induction chemotherapy (providing they are refractory to imatinib); acute
leukemia secondary to preexisting hematologic condition or prior chemotherapy are
eligible at diagnosis or after failing aggressive induction chemotherapy, advanced
myelodysplastic syndrome (RAEB or RAEB-2 providing they are neutropenic or
transfusion dependent); patients with de-novo acute leukemia who are not eligible for
aggressive standard induction chemotherapy due to advanced age or serious comorbid
medical or psychiatric conditions, patients above age 60 with de-novo AML and
unfavorable cytogenetics

- At least 2 weeks must have elapsed between completion of most recent cytotoxic
chemotherapy, or biologic therapy except for hydroxyurea or corticosteroids or
Imatinib (24 hours); patients who have previously received an autologous stem cell
transplant are allowed providing a minimum of 3 months has elapsed from transplant
(T0) and patient has recovered from transplant associated toxicities; patients who
have had prior allogeneic stem cell transplant are not eligible; a minimum of five
days must have elapsed since administration of granulocyte or granulocyte-macrophage
colony-stimulating factor and a minimum of 2 weeks if Neulasta; minimum of 2 weeks
since administration of gemtuzumab, ozogamicin (Mylotarg), minimum of 4 weeks for
prior investigational agents

- ECOG performance status =< 2 (Karnofsky >= 50%)

- Life expectancy of at least 4 weeks

- Direct serum bilirubin =< 1.5 mg/dl

- AST(SGOT)/ALT(SGPT) < 3 X institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal

- The effects of SB-715992 on the developing human fetus are unknown; for this reason
and because mitotic inhibitors are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients may not have received any other investigational agents within 28 days of
study entry

- Patients may not receive any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement) while on this study

- Prohibited medications: SB-715992 is a moderate to significant in vitro inhibitor of
CYP3A4; the following lists of medications/substances are moderate to significant
inhibitors/inducers of CYP3A4 that, if administered concomitantly with SB-715992, may
alter study drug exposure; the use of these medications/substances within 14 days (>=
6 months for amiodarone) prior to the administration of the first dose of SB-715992
through discontinuation from the study is prohibited

- Inhibitors of CYP3A4:

- Antibiotics: clarithromycin, erythromycin, troleandomycin

- Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200 mg/day),
voriconazole

- Antidepressants: nefazodone, fluvoxamine

- Calcium channel blockers: verapamil, diltiazem

- Miscellaneous: amiodarone*, grapefruit juice, bitter orange; *use of amiodarone
within 6 months prior to the administration of the first dose of SB-715992 is
prohibited

- Inducers of CYP3A4:

- Anticonvulsants: phenytoin, carbamazepine, phenobarbital, oxcarbazepine

- Antibiotics: rifampin, rifabutin, rifapentine

- Miscellaneous: St. John's wort, modafinil

- Patients with suspected or proven CNS leukemia (diagnostic lumbar puncture not
required before enrollment)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to SB-715992

- Uncontrolled intercurrent illness including, but not limited to ongoing or active or
poorly controlled infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric
illness/social situations that would limit compliance with study requirements

- Patients with pre-existing neuropathy of grade 2 or higher are not eligible to
participate

- Pregnant women are excluded from this study because SB-715992 is a mitotic inhibitor
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with SB-715992, breastfeeding should be discontinued if the
mother is treated with SB-715992

- Patients with immune deficiency are at increased risk of lethal infections when
treated with marrow-suppressive therapy; therefore, HIV-positive patients are
excluded from this study

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of ispinesib, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0

Outcome Time Frame:

Up to day 28

Safety Issue:

Yes

Principal Investigator

Brenda Cooper

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Western Reserve University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03127

NCT ID:

NCT00098826

Start Date:

December 2004

Completion Date:

Related Keywords:

  • Acute Undifferentiated Leukemia
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Acute Promyelocytic Leukemia (M3)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Blastic Phase Chronic Myelogenous Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Excess Blasts in Transformation
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Blast Crisis
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Chronic
  • Anemia, Aplastic

Name

Location

Case Western Reserve UniversityCleveland, Ohio  44106