XK469R in Treating Patients With Refractory Hematologic Cancer

PRIMARY OBJECTIVES:

I. Determine the dose-limiting toxicity, maximum tolerated dose, and recommended phase II dose of XK469R in patients with refractory hematologic malignancies.

II. Determine the pharmacokinetics of this drug in these patients.

SECONDARY OBJECTIVES:

I. Determine the presence of genetic variations potentially affecting XK469R disposition in patients treated with this drug.

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

Patients receive XK469R IV over 30-60 minutes on days 1, 3, and 5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of XK469R until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 2 of 6 patients experience dose-limiting toxicity. A total of 12 patients receive treatment at the MTD.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Inclusion criteria

• Diagnosis of 1 of the following relapsed or refractory hematologic malignancies for which all potentially curative therapy options have been exhausted:

• Acute myeloid leukemia* (AML) (non-M3)
• Acute lymphoblastic leukemia*
• Myelodysplastic syndromes*, including the following:

• Refractory anemia with excess blasts (RAEB)
• RAEB in transformation
• Chronic myelomonocytic leukemia in transformation* (CMML-t) with ≥ 10% peripheral blood/bone marrow blasts
• Chronic myelogenous leukemia in blast crisis* (CML-BC)
• Chronic lymphocytic leukemia

• Rai stage III-IV
• Failed prior fludarabine-based therapy and ≥ 1 other therapy

• Fludarabine failure defined as failure to achieve partial response or complete response (CR) to at least 1 fludarabine-containing regimen; disease progression while on fludarabine; or disease progression within 6 months of response to fludarabine
• Not a candidate for autologous or allogeneic stem cell transplantation (SCT)
• Patients with previously untreated AML, MDS, or CMML-t who are considered inappropriate candidates for, or refused, standard induction chemotherapy due to older age or concurrent medical conditions are eligible
• No known CNS disease
• Performance status - ECOG 0-2
• See Disease Characteristics
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT < 5 times ULN
• Creatinine < 1.5 times ULN
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to XK469R
• No other uncontrolled illness
• HIV-positive patients allowed provided CD4 counts are normal with no AIDS-defining disease
• No prior allogeneic SCT
• No concurrent prophylactic hematopoietic colony-stimulating factors
• More than 7 days since prior cytotoxic chemotherapy (except hydroxyurea)
• More than 7 days since prior radiotherapy
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anti-leukemia agents
• No other concurrent anticancer therapy