504 Phase I study with paclitaxel in combination with ifosfamide in pretreated patients with advanced ovarian carcinoma

Abstract

Introduction Patients (pts) with advanced ovarian carcinoma and an inadequate response to first line platinum based combination chemotherapy have a very poor prognosis. Salvage regimens were clearly needed. In order to determine the maximal tolerable dose (MTD) of the combination paclitaxel (P) and ifosfamide (IFO), we performed this ongoing phase I study. Treatment Pts were treated with P 3 h i. v. infusion after standard premedication on day (d) I, IFO was given as I h i. v. infusion with the standard use of Mesna i.v. on d.2-5. The next cycle was given on d.22. Number of cycles depending on response and toxicity. We chose the following dose levels (dl): [mg/m2] d11: P 135/IFO 1500; d12: P135/IFO 2000; d13: P 175/IFO 2000; d14: PI75/IFO 1500. MTD was defined: neutropenia 4° longer than 5 days or febrile neutropenia, thrombopenia ≥3°, other organ toxicity >2° according to WHO criteria. Patient Characteristics 14 pts entered this ongoing trial. 13 pts entered d11-3 and so far 1 pt d14; age 52 yrs (37–66), WHO PS 1 (0-2). Pretreatment All pts had had a platinum based combination chemotherapy for advanced stage ovarian carcinoma prior to study entry. 10/14 pts had cisplatinum refractory disease with disease progression while receiving prestudy treatment. Number of prior treatment regimens 1.5 (1–3). Toxicity and Results With regard to P treatment, after standard premedication neither mild nor severe HSR's occurred. The following toxicities could be observed in 10 pts and 51 treatment cycles at dl's 1 + 2 [grade WHO (number of cycles)]: neutropenia 2° (6), 3° (21), 4° (24); anemia 2° (24), 3° (6); thrombocytopenia 1° (7), 2° (6); nausea/vomiting 1° (33),2° (18); myalgia 1° (33); peripheral neuropathy 1° (36), 2° (12); mucositis 1° (39), 2° (8); diarrhea 1° (13), 2° (3). After we performed dose escalation of IFO up to 2000 mg/m2 during dl 2 and 3 in 2 out of 8 pts treatment interruptions have to be performed because of CNS toxicity 3° WHO and in one additional patient suffering from nephrotoxicity grade 3 WHO. The MTD of IFO used in the combination with P and given over 4 days is 1500 mg/m2. In order to enhance the efficacy of P we escalated the dose up to 175 mg/m2 and intend to treat the following pts according to d14. At all dl's responses could be observed. d11 (5 pts): PR 2, SD 3; d12 (5 pts): CR1, SD3, PO 1; d13 (3 pts): CRI, PR2; d14 (I pt): not evaluable for response and toxicity so far. Conclusions The combination of P and IFO is leasable and active in the treatment of pretreated advanced ovarain carcinoma pts. 014 will be further evaluated during this ongoing study.