Use of Nanoparticle Paclitaxel (ABI-007) for the Prevention of In-Stent Restenosis

A Phase I/II Safety Trial of Intracoronary Administration of Systemic Nanoparticle Paclitaxel (ABI-007) for the Prevention of In-Stent Restenosis

The purpose of this study was to investigate the use of systemic intracoronary administration of albumin-bound paclitaxel, ABI-007, for the prevention and reduction of restenosis following de novo stenting or following angioplasty for in-stent restenosis.

This study consisted of a Phase I non-randomized dose escalation phase to determine the maximum tolerated dose and a randomized Phase II component to assess preliminary efficacy. Nanoparticle paclitaxel was administered by intracoronary catheter following either successful and uncomplicated stenting of de novo lesions in native coronary arteries or following successful and uncomplicated balloon angioplasty of instent restenosis (ISR) lesions.

Inclusion Criteria:

• Male or non-pregnant and non-lactating female, and ≥ 18 years of age.
• Diagnosis of angina pectoris or unstable angina pectoris or patients with documented silent ischemia.
• Left ventricular ejection fraction ≥30%
• Patient has undergone successful and uncomplicated stenting of up to 2 de novo lesions in native coronary arteries OR patient has undergone successful and uncomplicated balloon angioplasty of up to 2 in-stent restenosis (ISR) lesions in native coronary arteries, but not both.
• Thrombolysis In Myocardial Infarction (TIMI) 3 coronary flow post-stenting for de novo lesions or post balloon angioplasty for ISR lesions.
• No angiographic evidence of thrombus post-procedure.
• Target vessel ≥2.5 mm diameter (by angiography).
• Each de novo lesion is such that it is stented with ≤ 25 mm of single continuous stent.
• Each in-stent restenosis (ISR) lesion is ≤ 25 mm in length.
• There is at least 5 mm of non-diseased vessel on either side of target lesion(s).
• By intravascular ultrasound (IVUS), stent is fully opposed and has a minimum diameter of 2.5 mm or an in-stent luminal area ≥ 5.0 mm^2
• Patient or guardian has provided a signed written informed consent to participate in the study and in all follow-up assessments using a form that is approved by the local Institutional Review Board (IRB)/Ethics Committee of the investigative site.

Exclusion Criteria:

• Target de novo lesion was treated with a drug-eluting stent

• Target ISR lesion requires any treatment other than balloon angioplasty

• Patient has both a de novo lesion and an ISR lesion.

• If more than 2 lesions are treated with percutaneous coronary intervention (PCI), or it is anticipated that additional lesions will require treatment within 2 months.

• Previous PCI within preceding two months.

• Intended surgical intervention within 6 months of enrollment in the study.

• Unprotected left main disease with >50% stenosis

• Malapposition, dissection, or unmasking of a significant narrowing in the inflow or outflow area of the implanted stent.

• Women who are pregnant and women of child bearing potential who do not use adequate contraception

• Previous participation in another study with any investigational drug or device within the past 30 days or current enrollment in any other clinical protocol or investigational drug or device trial.

• Patient has a life expectancy of less than 12 months or there are factors making clinical and/or angiographic follow-up difficult

• Any significant medical condition which, in the investigator's opinion, may interfere with the patient's optimal participation in the study

• Heart transplant candidate or recipient

• Patient is immunosuppressed or is HIV positive.

• Patient has experienced a Q wave or a non Q wave myocardial infarction (MI) with documented total creatine kinase (CK) ≥2 times normal within the preceding 24 hours and the CK and creatine kinase-MB fraction (CK-MB) enzymes remain above normal at the time of the procedure.

• Cardiogenic shock: sustained systolic blood pressure (SBP) less than 80 mmHg, with no response to fluids or SBP less than 100 mmHg with vasopressors (in absence of bradycardia)

• Any individual who may refuse a blood transfusion

• Documented major gastro-intestinal bleeding within 3 months

• The following lab values at baseline are exclusionary:

  • Serum creatinine > 2.5 mg/dl;
  • Platelet count < 150,000 cells/mm^3;
  • Absolute neutrophil count (ANC) < 2000 cells/mm^3;
  • Hemoglobin (HGB) <9 g/dl;
  • Total bilirubin >1.5 mg/dl;
  • Alanine Aminotransferase (SGPT) > 2.5 x upper limit of normal range (ULN);
  • Aspartate Aminotransferase (SGOT) > 2.5 x ULN;
  • Alkaline phosphatase > 2.5 x ULN.

• Known allergy/hypersensitivity/contraindication to the study drug; to any taxanes; or to any required study treatment: aspirin, clopidogrel bisulfate, stent materials

• Pre-existing peripheral neuropathy of National Cancer Institute (NCI) Toxicity Grade > 1.