CYCLOSPORINE-A AND DOXORUBICIN-IFOSFAMIDE IN RESISTANT SOLID TUMORS - A PHASE-I AND AN IMMUNOLOGICAL STUDY

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 Ih 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 greater than or equal to 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.