Clinical trial NCT00273884: Amonafide in Combination With Cytarabine in Secondary AML
Official title: Phase 2 Open-Label Study of Amonafide L-Malate in Combination With Cytarabine in Subjects With Secondary Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
Secondary AML
Leukemia
Lead sponsor: Xanthus Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2006-01-09
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This protocol is designed to assess the safety and efficacy of amonafide in combination with cytarabine in subjects with previously untreated secondary AML.

Detailed description: This is a two-stage, open-label, phase 2, multicenter study of amonafide L-malate in combination with standard-dose cytarabine in subjects with secondary AML.

Amonafide is a DNA intercalating agent and inhibitor of topoisomerase II that has been extensively studied in patients with malignant solid tumors. Amonafide has also been studied in patients with AML. In three phase I clinical trials, amonafide demonstrated anti-leukemic activity, both as monotherapy and in combination with cytarabine. This protocol is designed to further assess the safety and efficacy of amonafide in combination with cytarabine in subjects with previously untreated secondary AML.

The duration of the study is approximately 42 months: enrollment approximately 18 months and subject duration up to 24 months

Eligibility criteria: Inclusion Criteria:

* Histologic diagnosis of AML (≥20% blasts of myeloid lineage in bone marrow), with FAB classification other than M3, secondary to either:

  1. Known and documented exposure to prior leukemogenic chemotherapy or radiotherapy, OR
  2. Diagnosis of MDS for ≥3 months prior to study entry (prior BM slides documenting MDS must be available for central pathology review).
* Age 18 years or older.
* ECOG performance status ≤2.
* No prior induction chemotherapy for AML; at least 4 weeks since completion of prior chemotherapy for MDS. (Subjects with rapidly rising blast count may be enrolled within 4 weeks of prior cytotoxic chemotherapy).
* Fertile and sexually active men and women must use effective contraception throughout study. Women of childbearing potential must have a negative pregnancy test.
* LVEF ≥50% by MUGA or ECHO.
* Adequate renal function: serum creatinine ≤1.5 x ULN.
* Adequate hepatic function: total serum bilirubin ≤1.5 x ULN as well as serum AST and ALT ≤1.5 x ULN.
* Subject must be able to participate fully in all aspects of the trial.
* Subject must give voluntary, written consent and HIPAA authorization (US only).

Exclusion Criteria:

* Histologic diagnosis of FAB M3 AML (acute promyelocytic leukemia).
* Clinically active CNS leukemia.
* Known to be HIV positive.
* Prior induction chemotherapy for AML.
* Known active hepatitis B or C or other active liver disease.
* Any major surgery or radiation therapy within 4 weeks prior to study entry.
* Prior cytotoxic chemotherapy within 4 weeks prior to study entry.(Subjects with rapidly rising blast count may be enrolled within 4 weeks of prior cytotoxic chemotherapy).
* Persistent chronic non-hematologic toxicity from prior chemotherapy (other than alopecia) that is \> than grade 1.
* Serious concomitant illness (e.g., active pulmonary infection, unstable angina or myocardial infarction within 3 months of study entry, congestive heart failure ≥AHA class 2, stroke within 3 months prior to study entry, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.).
* Women who are pregnant or lactating.
* History of clinically significant allergic reactions attributed to compounds similar to amonafide or cytarabine.
* Prior enrollment on this trial.
* Any other known condition (familial, sociological, or geographic) or behavior (including substance abuse, psychological or psychiatric illness), which in the investigator's opinion would make the subject a poor candidate for this trial.

Primary outcomes:
measure: - To determine the rate of complete remission with or without complete hematopoietic recovery (CR + CRi).
Secondary outcomes:
measure: Determine the median duration of complete remission with or without complete hematopoietic recovery (CR or CRi)
measure: Determine the proportion of subjects remaining in complete remission (CR +CRi) at 6 months, at 12 months and at 18 months
measure: Determine the median duration of overall survival (OS)
measure: Correlate clinical responses and duration of responses with specific cytogenetic abnormalities
measure: Define the population pharmacokinetic (PK) profile of amonafide and its metabolites when administered as an intravenous infusion daily x 5 days in combination with a standard-dose of cytarabine
measure: Define the safety profile and confirm the acceptability of amonafide and cytarabine
measure: Correlate PK exposure of amonafide and acetylation of amonafide with safety and efficacy assessments in individual subjects
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Comprehensive Cancer Center
state: Alabama
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Diego
country: United States
facility: Scripps Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center, Anschutz Cancer Center
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Health Science Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University, Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: St. Francis Cancer Research Foundation (formerly Indiana Oncology Hematology Consultants and American Health Network of Indiana LLC, Oncology Division)
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Charleston
country: United States
facility: MUSC - Hollings Cancer Center
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Morgantown
country: United States
facility: West Virginia University Medical Center
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: London
country: Canada
facility: London Regional Cancer Program, London Health Science Center
state: Ontario
Study officials:
affiliation: North Shore Hospital
name: Steven Allen, MD
role: PRINCIPAL_INVESTIGATOR
References: