Phase 3 Open-Label Randomized Study of Amonafide L-Malate in Combination with Cytarabine Compared to Daunorubicin in Combination with Cytarabine in Patients with Secondary Acute Myeloid Leukemia (AML)

• Register: EUCTR
• Last refreshed on: 17 July 2012
• Main ID: EUCTR2007-004427-38-GR
• Date of registration: 29/10/2009
• Prospective Registration: No
• Primary sponsor: Antisoma Research Ltd.
• Public title: Phase 3 Open-Label Randomized Study of Amonafide L-Malate in Combination with Cytarabine Compared to Daunorubicin in Combination with Cytarabine in Patients with Secondary Acute Myeloid Leukemia (AML)
• Scientific title: Phase 3 Open-Label Randomized Study of Amonafide L-Malate in Combination with Cytarabine Compared to Daunorubicin in Combination with Cytarabine in Patients with Secondary Acute Myeloid Leukemia (AML)
• Date of first enrolment: 21/05/2009
• Target sample size: 420
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-004427-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Austria, Czech Republic, Estonia, France, Germany, Greece, Hungary, Italy, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
a.) Diagnosis of AML according to WHO diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with FAB classification other than M3 (Acute
Promyelocytic Leukemia), documented by bone marrow aspiration and biopsy
performed within 14 days prior to administration of 1st dose of remission induction
chemotherapy;

b.) Either
a. Known and documented exposure to specific leukemogenic therapy of a specified nature for a non-myeloid condition.
OR
b. Documented diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to WHO criteria for at least 3 months prior to study entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting MDS available to be submitted for subsequent central pathology review.

c.) Age 18 years or older;

d.) Eastern Cooperative Oncology Group (ECOG) performance score = 2;

e.) Fertile sexually active patients (men and women) must use an effective method of
contraception which must be continued throughout the study.

f.) Women of childbearing potential must have a negative serum pregnancy test. A
woman of childbearing potential is defined as one who is biologically capable of
becoming pregnant. This includes women who are using contraceptives or whose
sexual partners are either sterile or using contraceptives;

g.) Left Ventricular Ejection Fraction (LVEF) = 50%, as determined by multiple-gated
acquisition scan (MUGA) or echocardiogram (ECHO) within 14 days prior to
administration of 1st dose of remission induction chemotherapy;

h.) Adequate renal function as evidenced by the following laboratory test, obtained
within 14 days prior to administration of 1st dose of remission induction
chemotherapy:
•Serum creatinine = 1.5 x ULN;

i.) Adequate hepatic function as evidenced by the following laboratory tests, obtained within 14 days prior to administration of 1st dose of remission induction
chemotherapy (unless attributed to hepatic involvement with AML):
•Total serum bilirubin = 1.5 x ULN;
•Serum AST and ALT = 1.5 x ULN;

j.) Ability of the patient to participate fully in all aspects of this clinical trial;

k.) Written Informed Consent and HIPAA authorization (USA sites only) must be
obtained and documented.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
a.) Histologic diagnosis of FAB M3 Acute Promyelocytic Leukemia;

b.) Clinically active CNS leukemia;

c.) Prior induction therapy for AML;

d.) Known HIV positive;

e.) Known active hepatitis B or C, or any other active liver disease;

f.) Patients with parenchymal abnormality on screening chest x-ray must have no
evidence of pulmonary infection on chest tomography (CT) prior to starting remission
induction therapy.

g.) Any major surgery or radiation therapy within 4 weeks prior to study entry;

h.) Prior cytotoxic chemotherapy for MDS within 4 weeks prior to study entry (patients with rapidly rising blast count may be enrolled within 4 weeks of prior cytotoxic chemotherapy with waiver from the Medical Monitor);

i.) Persistent chronic non-hematologic toxicity (other than alopecia) greater than grade 1 from prior therapy for MDS;

j.) Serious concomitant illnesses (for example, pulmonary infiltrate, unstable angina or myocardial infarction or stroke within 3 months prior to study entry, congestive heart failure AHA class 2 or greater, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.), which in the investigator’s opinion would not make the patient a good candidate for the trial;

k.) Pregnant or breast feeding;

l.) History of clinically significant allergic reactions attributed to compounds of similar
chemical or biological composition to amonafide, cytarabine or daunorubicin;

m.) Prior enrollment in this trial;

n.) Any other known condition (e.g., familial, sociological, or geographical) or behavior
(including substance dependence or abuse, psychological or psychiatric illness), which in the investigator’s opinion would make the patient a poor candidate for the
trial.




Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

secondary acute myeloid leukemia
MedDRA version: 9.1 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia

Intervention(s)

Product Name: Amonafide L-malate
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Amonafide
CAS Number: 69408-81-7
Other descriptive name: Amonafide L-malate
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Trade Name: cytarabine
Product Name: cytarabine
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: cytarabine
CAS Number: 147-94-4
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal
Concentration number: 200-

Trade Name: daunorubicin
Product Name: daunorubicin
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: daunorubicin
CAS Number: 20830-81-3
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal
Concentration number: 45-

Primary Outcome(s)

Primary end point(s): The rate of confirmed CR + CRi (which includes CRc and CRd) will be determined
by assessing the proportion of patients who achieved confirmed CR or CRi among all
evaluable patients. Peripheral blood hematopoietic recovery in accord with a CR
may occur up to several months after resolution of leukemia, i.e., < 5% blasts in the
bone marrow.

Main Objective: The rate of confirmed complete remission with or without hematopoietic recovery [complete remission (CR) and complete remission with incomplete hematopoietic
recovery (CRi); this includes complete cytogenetic remission (CRc) and complete remission with persistent morphologic dysplasia (CRd)]. Confirmed CR or CRi is
defined as documentation of CR or CRi at least 30 days after initial determination of CR or CRi following remission induction therapy, or immediately prior to postremission
therapy if such therapy occurs within 30 days from the initial determination of CR or CRi.

Secondary Objective: - Rate of initial complete remission with or without hematopoietic recovery;
- Rate of CR + CRi within different clinical subsets;
- Rate of response overall and within different clinical subsets;
- Rate of response for each individual response category overall and within different clinical subsets;
- Median duration of remission;
- Median duration of disease free survival (DFS);
- Proportion of patients remaining in remission at 6 months, at 12 months, and at 18 months;
- Median duration of overall survival (OS) for all patients, for all patients in remission and for each individual response category;
- Correlation of clinical responses, duration of responses, DFS and OS with cytogenetic abnormalities;
- Correlation of clinical responses, duration of responses, DFS and OS with expression and function of Pgp;
- Correlation of PK exposure of amonafide and N-acetyl amonafide with both safety
and efficacy assessments.

Secondary ID(s)

2007-004427-38-DE

0001A3-300-GL