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:

  1. Males or females, aged 18-65 years;
  2. Histological or cytological diagnosis of solid malignancy for which no acceptable standard therapy exists or for which approved standard therapy has failed;
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
  4. Life expectancy greater than 3 months;
  5. 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;
  6. 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;
  7. 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;
  8. 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;
  9. Serum potassium, magnesium and corrected calcium that is within institutional normal range at screening;

  10. 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:

  1. Hypersensitivity to amrubicin or related compounds;
  2. 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;
  3. 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);
  4. Left ventricular ejection fraction (LVEF) <50%;
  5. Recent history (within 3 months of screening visit) of pericarditis and pericardial effusion;

  6. 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;
  7. Family history of long QT syndrome;
  8. Use of implantable pacemaker or implantable cardioverter defibrillator;
  9. Clinically significant bradycardia (<50 beats per minute);
  10. Systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg;
  11. Previous treatment with an investigational agent or any anticancer therapy within 4 weeks prior to the 'off-drug' visit;
  12. 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;
  13. 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;
  14. Previous treatment with any anthracycline;
  15. Any condition that would put the patient at undue risk or discomfort as a result of adherence to study procedures;
  16. Women who are pregnant or nursing;
  17. Uncontrolled intercurrent illness such as myelosuppression, renal impairment, hepatic impairment, infection and uncontrolled diabetes;
  18. 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;
  19. Suspected, diffuse idiopathic interstitial lung disease or pulmonary fibrosis not related to prior treatment;
  20. 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;
  21. Positive urine drug screen for undeclared concomitant medications and/or illegal drug use at screening.