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Phase I Dose Escalation Trial of the Raf Kinase Inhibitor BAY 43-9006 (NSC #724772) as Single Agent for Adults With Relapsed and Refractory Acute Leukemias and Chronic Myeloid Leukemia in Blast Crisis


Phase 1
18 Years
N/A
Not Enrolling
Both
Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), 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 Del(5q), 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 Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia

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Trial Information

Phase I Dose Escalation Trial of the Raf Kinase Inhibitor BAY 43-9006 (NSC #724772) as Single Agent for Adults With Relapsed and Refractory Acute Leukemias and Chronic Myeloid Leukemia in Blast Crisis


PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity(s) (DLTs) and maximally tolerated dose (MTD) of
BAY 43-9006 given orally.

SECONDARY OBJECTIVES:

I. To obtain preliminary evidence of tumor response to BAY 43-9006 in patients. II. To
assess the pharmacokinetic profile of BAY 43-9006. III. To characterize the preliminary
profile of adverse events and changes in laboratory parameters in patients treated with BAY
43-9006.

IV. To assess effects of BAY 43-9006 on various cellular properties of leukemic blasts
exposed to drug in vivo and in vitro.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive oral sorafenib twice daily on days 1-14 or 1-21. Treatment repeats every 28
days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients achieving a complete remission (CR) may be considered for retreatment with
sorafenib for up to an additional 6 courses upon disease recurrence provided the duration of
CR is longer than 1 month.

Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that which 2 of 3 or 2 of
6 patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD.

After completion of study treatment, patients are followed monthly for up to 1 year.


Inclusion Criteria:



- Patients must have pathological confirmation (histologically or cytologically) of
relapsed or refractory acute myeloid leukemia (other than acute promyelocytic
leukemia), acute lymphocytic leukemia, or chronic myeloid leukemia in blast crisis

- The morphologic diagnosis of AML (non-APL), ALL, and CML in blast crisis will be made
independently by members of the hematologic pathology division; routine staining and
standard criteria as outlined by the Report of the NCI-Sponsored Workshop will be
followed

- All patients must have been refractory to or relapsed from their most recent therapy
AND are considered ineligible for potential curative approaches including allogeneic
stem cell transplant; in addition, patients must be at least:

- 3 weeks from last cytotoxic chemotherapy (excluding hydroxyurea)

- Hydroxyurea may be used for blast count control but must be discontinued within
48 hours of the initiation of BAY 43-9006

- 2 weeks from last radiation therapy

- 3 week from last biologic therapy (including myeloid growth factors)

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 2 months

- Multilineage bone marrow failure due to the subject's underlying leukemia

- Total blast count in the peripheral blood < 30,000

- Total bilirubin =< 2 mg/dl

- AST(SGOT)/ALT(SGPT) =< 5 X institutional upper limit of normal

- Serum creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- All 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; the effects of BAY 43-9006 on the developing
human fetus at the recommended therapeutic dose are unknown; however, kinase
inhibitors are known to be teratogenic; 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 with APL are not eligible for this clinical trial

- Patients who have not recovered from adverse events due to agents administered more
than 3 weeks earlier

- Patients with rapidly increasing peripheral blood blast counts (increase in the
absolute peripheral blast count > 50% within one week) or uncontrolled (absolute
blast count > 30,000) while on hydroxyurea will be excluded

- Patients with uncontrolled hypertension (i.e., persistent grade 3 while undergoing
treatment)

- Patients may not be actively receiving any other investigational agents

- Patients active and / or untreated CNS leukemia will not be eligible

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BAY 43-9006

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with BAY 43-9006

- Patients with immune deficiency are at increased risk of lethal infections when
treated with marrow suppressive therapy; therefore, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with BAY 43-9006; appropriate studies will be undertaken
in patients receiving combination anti-retroviral therapy when indicated

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

- Patients must not have any evidence of bleeding diathesis

- Patients must not be on therapeutic anticoagulation; prophylactic anticoagulation
(i.e. low dose warfarin) of venous or arterial access devices is allowed provided
that the requirements for PT, INR or PTT are met

- Patients must not be taking the cytochrome P450 enzyme-inducing antiepileptic drugs
(phenytoin, carbamazepine, or phenobarbital), rifampin or St. John's wort

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

DLT defined as non-hematologic > grade 3 or hematologic grade 4 marrow aplasia > 28 days (without leukemia clearance) as assessed by NCI-CTC version 3.0

Outcome Description:

Observed toxicities will be reported and summarized s with frequencies, type and grade in a descriptive manner. No formal statistical inference will be made on this dose-finding study.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

B. Smith

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03154

NCT ID:

NCT00131989

Start Date:

June 2005

Completion Date:

Related Keywords:

  • Adult Acute Basophilic Leukemia
  • Adult Acute Eosinophilic Leukemia
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • 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 Del(5q)
  • 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 Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • 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, Myelomonocytic, Chronic
  • Hypereosinophilic Syndrome

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205