Amrubicin + Cyclophosphamide in Advanced Solid Organ Malignancies

OUTLINE: This is a multi-center study.

This study will follow the 3+3 design with the following dose levels:

- Dose Level -1: Amrubicin 20mg/m2, Cyclophosphamide 500mg/m2

- Dose Level 1: Amrubicin 25mg/m2, Cyclophosphamide 500mg/m2

- Dose Level 2: Amrubicin 30mg/m2, Cyclophosphamide 500mg/m2

- Dose Level 3: Amrubicin 35mg/m2, Cyclophosphamide 500mg/m2

- Dose Level 4: Amrubicin 40mg/m2, Cyclophosphamide 500mg/m2

Dose escalation starts from dose level 1.

Amrubicin will be given as a slow IV push or infusion over approximately 5 minutes once
daily for 3 consecutive days starting on day 1 of each 21 day cycle.

Cyclophosphamide will be given at a fixed dose as an IV infusion over 30-60 minutes on day 1
of each 21 day cycle (following amrubicin).

ECOG Performance Status: 0-1

Life expectancy: not specified

Hematopoietic:

- Hemoglobin (Hgb) > 9 g/dL.

- Platelets > 100 K/mm3

- Absolute Neutrophil Count (ANC) > 1.5 K/mm3

Hepatic:

- Aspartate transaminase (AST) ≤ 2.5 x ULN

- Alanine transaminase (ALT) ≤ 2.5 x ULN

- Total bilirubin < 1.5 x ULN

Renal:

- Calculated creatinine clearance ≥ 60cc/min

Cardiovascular:

- Left Ventricular Ejection Fraction (LVEF) ≥ LLN for institution within 60 days prior to
registration for protocol therapy.

- No history of cardiomyopathy or uncontrolled heart arrhythmia.

Pulmonary:

- No suspected, diffuse idiopathic interstitial lung disease or history of pulmonary
fibrosis.

Inclusion Criteria:

- Histologically or cytologically confirmed advanced solid organ malignancy that is
refractory to currently available therapies or for which no effective therapy exists.

- Must have measurable or evaluable disease per RECIST as evaluated by imaging within
30 days prior to registration for protocol therapy.

- Must have completed chemotherapy at least 28 days prior to registration for protocol
therapy and recovered from the acute toxic effects.

- Prior radiation therapy is allowed to < 25% of the bone marrow. Patients must have
recovered from the acute toxic effects of radiation prior to registration for
protocol therapy.

- Must be willing to consent to the blood sample collection for SNP analysis.

- Females of childbearing potential and males must be willing to use an effective
method of contraception (hormonal or barrier method of birth control; abstinence)
from the time of consent until at least 30 days following completion of protocol
therapy.

- Females of childbearing potential must have a negative pregnancy test within 7 days
prior to registration for protocol therapy. Patients are considered not of child
bearing potential if they are surgically sterile (they have undergone a hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.

- Written informed consent and HIPAA authorization for release of personal health
information.

- Age > 18 years.

Exclusion Criteria:

- No prior therapy with cyclophosphamide or anthracyclines.

- No treatment with any investigational agent within 28 days prior to registration for
protocol therapy.

- No suspected, diffuse idiopathic interstitial lung disease or history of pulmonary
fibrosis.

- No evidence of severe or uncontrolled other systemic disease or any concurrent
condition which in the investigator's opinion makes it undesirable for the patient to
participate in the trial or which would jeopardize compliance with the protocol.

- No symptomatic brain metastases. Patients with treated brain metastasis must be off
steroids and must have completed radiation at least 21 days prior to registration for
protocol therapy.