title: Cyclosporin A and doxorubicin-ifosfamide in resistant solid tumours: a phase I and an immunological study.
abstract: In order to test whether circumvention of clinical resistance can be obtained in common solid tumours by targeting different drug resistance mechanisms, a phase I clinical and immunological study was designed. The purpose of the study was to determine the dose of cyclosporin A (CsA), in combination with doxorubicin (DOX) and ifosfamide (IFX), needed to achieve steady-state whole-blood levels of 2000 ng ml-1 and the associated toxicity of this combination. Treatment consisted of CsA 5 mg kg-1 as a 2 h loading infusion, followed by a CsA 3 day continuous infusion (c.i.) (days 1-3) at doses that were escalated from 10 to 18 mg kg-1 day-1. Chemotherapy consisted of DOX 55 mg m-2 by i.v. 24 h c.i. (day 2) and IFX 2 g m-2 i.v. over 1 h on days 1 and 3. Treatments were repeated every 4 weeks. Eighteen patients with previously treated resistant solid tumours received 39 cycles. Mean steady-state CsA levels > or = 2000 ng ml-1 were reached at 5 mg kg-1 loading dose followed by a 3 day c.i. of 16 mg kg-1 day-1 or greater. Haematological toxicity was greater than expected for the same chemotherapy alone. One patient died of intracranial haemorrhage due to severe thrombopenia. Other observed toxicities were: asymptomatic hyperbilirubinaemia (46% cycles), mild nephrotoxicity (20% cycles), hypomagnesaemia (72% cycles), mild increase in body weight (100% cycles), hypertension (15% cycles) and headache (15% cycles). Overall the toxicity was acceptable and manageable. No alterations in absolute lymphocyte number, the lymphocyte subsets studied (CD3, CD4, CD8, CD19) or CD4/CD8 ratio were observed in patients receiving more than one treatment cycle, although there were significant and non-uniform variations in the values of the different lymphocyte subsets studied when pre- and post-treatment values were compared. There was also a significant increase in the CD4/CD8 ratio. Tumour regressions were observed in two patients (epidermoid carcinoma of the cervix and Ewing's sarcoma). The CsA dose recommended for phase II trials is a 5 mg kg-1 loading dose followed by a 3-day c.i. of 16 mg kg-1 day-1 simultaneously with DOX and IFX at the doses administered in this study.
authors.affiliation: Department of Oncology, Clinica Universitaria of Navarra, Pamplona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González-Manzano
authors.forename: J
authors.initials: J
authors.lastname: Cid
authors.forename: A
authors.initials: A
authors.lastname: Brugarolas
authors.forename: C C
authors.initials: CC
authors.lastname: Piasecki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001667:Binding, Competitive; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007111:Immunity, Cellular / Q000187:drug effects*; D018655:Lymphocyte Count / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012074:Remission Induction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D004317:Doxorubicin; D016572:Cyclosporine; D007069:Ifosfamide