A Phase I Study to Assess the Safety, Pharmacokinetics, and Potential Effects of Amrubicin on the QT/QTc Interval in Cancer Patients With Advanced Solid Tumors.

Inclusion criteria

• Patients meeting all of the following criteria will be considered for enrollment into the study:

• Males or females, aged 18-65 years;
• Histological or cytological diagnosis of solid malignancy for which no acceptable standard therapy exists or for which approved standard therapy has failed;
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
• Life expectancy greater than 3 months;
• Nonsmoker or not smoked or used tobacco products for at least 3 months before the screening visit and agree to abstain from smoking/using tobacco products throughout the formal study and until the End of Study visit;
• Capable of giving informed consent, has signed the informed consent form, and is willing to comply with scheduled visits, dose administration, and other study procedures;
• Women of childbearing potential may participate, providing they have a negative serum pregnancy test (β-HCG) at screening, and a negative urine pregnancy test prior to dosing on Day 1 of each cycle;
• Males and females of childbearing potential must agree to the use of at least 2 effective contraceptive methods until at least 28 days following the last dose of study drug;
• Serum potassium, magnesium and corrected calcium that is within institutional normal range at screening;
• Adequate organ function including the following:

• Adequate bone marrow reserve: absolute neutrophil count (segmented and bands) (ANC) ≥1.5 x 109/L, platelet count ≥100 x 109/L, and hemoglobin ≥90 g/L,
• Hepatic: bilirubin ≤1.5 x the upper limit of normal (ULN), ALT and AST ≤2.0 x ULN,
• Renal: serum creatinine ≤1.5 x ULN or calculated creatinine clearance >80 mL/min.

Exclusion criteria

• Patients meeting any of the following criteria will be excluded from the study:

• Hypersensitivity to amrubicin or related compounds;
• Radiotherapy with curative intent to a primary disease complex ≤ 28 days before first dose; cranial radiotherapy ≤ 21 days before first dose; radiotherapy to all other areas ≤ 7 days before first dose of amrubicin;
• History or presence of clinically significant abnormal 12-lead ECG or triplicate ECGs with a mean QT interval corrected for heart rate (HR) using Fridericia's method (QTcF) of >450 msec (males) or >470 msec (females), a PR interval >240 msec or a QRS interval >110 msec (within 3 months of screening visit);
• Left ventricular ejection fraction (LVEF) <50%;
• Recent history (within 3 months of screening visit) of pericarditis and pericardial effusion;
• History within 6 months of the screening visit of one of the following:

• cardiac disease including congenital long-QT syndrome,
• angina, congestive heart failure,
• myocardial ischemia or infarction,
• myocarditis, chest pain or dyspnea on exertion of cardiac origin,,
• idiopathic or hypertrophic cardiomyopathy,
• sarcoidosis,
• syncope,
• epilepsy,
• or other clinically significant cardiac disease;
• Family history of long QT syndrome;
• Use of implantable pacemaker or implantable cardioverter defibrillator;
• Clinically significant bradycardia (<50 beats per minute);
• Systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg;
• Previous treatment with an investigational agent or any anticancer therapy within 4 weeks prior to the 'off-drug' visit;
• Previous treatment with anticancer therapy and has not fully recovered (Common Terminology Criteria Adverse Event [CTCAE] Grade 1, except alopecia) from the toxic effects of that treatment;
• Treatment with any medication known to produce QT prolongation enzyme-inducing anticonvulsants, non-prescription medications including topical medications, all vitamins, minerals, herbs or dietary supplements/remedies (e.g., Saint John's Wort or Milk Thistle) for at least 7 days before the start of the off-drug visit;
• Previous treatment with any anthracycline;
• Any condition that would put the patient at undue risk or discomfort as a result of adherence to study procedures;
• Women who are pregnant or nursing;
• Uncontrolled intercurrent illness such as myelosuppression, renal impairment, hepatic impairment, infection and uncontrolled diabetes;
• Symptomatic central nervous system metastases. Patients with asymptomatic brain metastases are allowed. The patient must be stable for ≥ 2 weeks after radiotherapy, if the patient is on corticosteroids, the dose of corticosteroids must have been stable for ≥ 2 weeks prior to the first dose of study treatment, or be in the process of being tapered;
• Suspected, diffuse idiopathic interstitial lung disease or pulmonary fibrosis not related to prior treatment;
• History of seropositive HIV or patients who are receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the investigator, increase the risk of serious neutropenic complications;
• Positive urine drug screen for undeclared concomitant medications and/or illegal drug use at screening.