title: Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study.
abstract: BACKGROUND
  Combining the Bcl-2 down-regulator oblimersen with cytotoxic treatment leads to synergistic antitumor effects in preclinical trials. This multicentric phase I study was carried out to evaluate maximum tolerated dose (MTD), safety and preliminary efficacy of oblimersen in combination with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment (NST) in primary breast cancer (PBC).
  
  
  METHODS
  Previously untreated patients with PBC T2-4a-c N0-3 M0 received one cycle of docetaxel 75 mg/m(2), adriamycin 50 mg/m(2) and cyclophosphamide 500 mg/m(2) administered on day 5 combined with escalating doses of oblimersen as a 24-h continuous infusion on days 1-7 followed by five cycles of combination of docetaxel, adriamycin and cyclophosphamide (TAC) without oblimersen every 3 weeks. Prophylactic antibiotic therapy and granulocyte colony-stimulating factor administration were used in all six cycles. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis.
  
  
  RESULTS
  Twenty-eight patients were enrolled (median age, 50 years; ductal-invasive histology, 68%; tumorsize 2-5 cm, 61%; grade 3, 43%; hormone receptor negative, 36%; Her2 positive 18%) and received oblimersen in a dose of 3 mg/kg/day (cohort I, nine patients), 5 mg/kg/day (cohort II, nine patients) and 7 mg/kg/day (cohort III, 10 patients) respectively. No dose-limiting toxicity occurred. Following oblimersen combined with TAC, the most severe toxicity was neutropenia [National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grades 1-2/3/4] which developed in 0/0/56% of patients (cohort I), 11/0/56% of patients (cohort II) and 20/20/50% of patients (cohort III). No febrile neutropenia occurred. Most common adverse events (all NCI-CTC grade < or = 2) were fatigue, nausea, alopecia, headache and flue-like symptoms observed in 78% (cohort I), 89% (cohort II) and 90% (cohort III) of patients. With increasing dose of oblimersen, a higher incidence of grade IV leukopenia and neutropenia was noted. At the MTD of 7 mg/kg/day of oblimersen, serious adverse events occurred in 40% of the patients.
  
  
  CONCLUSIONS
  Oblimersen up to a dose of 7 mg/kg/day administered as a 24-h infusion on days 1-7 can be safely administered in combination with standard TAC on day 5 as NST in patients with PBC. The safety and preliminary efficacy warrants further evaluation of oblimersen in combination with every cycle of the TAC regimen in a randomized trial.
authors.affiliation: Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany. joachim.rom@med.uni-heidelberg.de
authors.forename: J
authors.initials: J
authors.lastname: Rom
authors.forename: G
authors.initials: G
authors.lastname: von Minckwitz
authors.forename: W
authors.initials: W
authors.lastname: Eiermann
authors.forename: M
authors.initials: M
authors.lastname: Sievert
authors.forename: B
authors.initials: B
authors.lastname: Schlehe
authors.forename: F
authors.initials: F
authors.lastname: Marmé
authors.forename: F
authors.initials: F
authors.lastname: Schuetz
authors.forename: A
authors.initials: A
authors.lastname: Scharf
authors.forename: M
authors.initials: M
authors.lastname: Eichbaum
authors.forename: H-P
authors.initials: HP
authors.lastname: Sinn
authors.forename: M
authors.initials: M
authors.lastname: Kaufmann
authors.forename: C
authors.initials: C
authors.lastname: Sohn
authors.forename: A
authors.initials: A
authors.lastname: Schneeweiss
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D018270:Carcinoma, Ductal, Breast / Q000097:blood / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D013873:Thionucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D004317:Doxorubicin; C408162:oblimersen; D003520:Cyclophosphamide