380 Phase I study with weekly Paclitaxel (1 h) infusion in heavily pretreated advanced breast cancer and ovarian cancer patients

Abstract

Introduction With the introduction of Paclitaxel (P) severe acute hypersensitivity reactions (HSR) attributed to the drug during phase I clinical trials led to subsequent changes. First, premedication was initiated prior to treatment and second, the duration of paclitaxel infusion was lengthened mostly up to 24 h. Recently in randomised trials the 3 h schedule and as well the 1 h schedule have proven to be safe there was no significant difference in acute HSR's, but a significant reduction of myelosuppression with the shorter infusion schedules. The optimal dose and schedule of P remained undefined especially with regard to combination chemotherapy. Therefore we performed a phase I study with a weekly 1 h infusion of P in heavily pretreated breast and ovarian cancer patients. Treatment Patients (pts) were treated with P (1 h infusion) once weekly. Each treatment cycle comprised of six weeks followed by two weeks rest. All pts were treated under outpatient conditions. Predmedication: dexamethason 8 mg p.o. 12 h and 6 h prior to each paclitaxel infusion and 30 min before treatment 400 mg cimetidine and 2 mg clemastine i.v. During Phase I we chose the following dose levels (di): dll 70 mg/m 2 , dl2 80 mg/m 2 , dl3 90 mg/m 2 , dl4 100 mg/m 2 . Maximal tolerable dose was defined: neutropenia 4°, thrombopenia ≥ 3°, other organ toxicity >2° according to WHO criteria. Patient characteristics 19 pts entered this trial (15 pts with advanced breast cancer, 4 pts with ovarian cancer): dll 7 pts [86 single weekly doses (SWD) of P], dl2 5 pts (51 SWD), dl3 3 pts (37 SWD), dl4 4 pts (12 SWD). The characteristics were: age 54 yrs (32–73). WHO performance status 1 (0–2), metastatic disease sites 2 (1–4). Pts had a median number of 3 pretreatment regimens (1–4). All pts had anthracycline refractory disease in case of breast cancer and cisplatinum refractory disease in case of ovarian cancer. Toxicity and results No dose limiting toxicities occurred during dll–3. With regard to the reduced premedication program in order to avoid corticosteroid side effects using the weekly schedule, it must be emphasized, that neither mild nor severe HSR's occurred. The following toxicities could be observed in 15 pts (dll–3), 29 treatmeant cycles and 174 weekly doses of paclitaxel [grade WHO (number of cycles)]: neutropenia 3° (1), 2° (5), nausea/vomiting 1° (3); myalgia 1° (3); peripheral neuropathy 1° (6); mucositis 1° (7). After the second weekly application of paclitaxel at dl4 in 3 out of 4 pts the next infusion had to be postponed for 1 week because of neutropenia grade 4 WHO. So far no hospitalisations must be performed. Pts received a median of 2 treatment cycles. At ail dl's responses could be observed, dll: PR 1.SD5, PD 1;dl2: PR 1, SD1, PD 3; dl3: PR 1, SD 1, PD 1; dl4: PR 1 not evaluable 3. MTD was reached using dl4, D1 3 is recommended for phase II. Conclusions As with other antineoplastic agents, P is likely to make an impact when used in combination therapy. Our phase I study underlines that P, given in a weekly 1 h infusion, is safe and active in heavily pretreated breast cancer and ovarian cancer patients. Its moderate toxicity, especially with regard to myelosuppression, should lead to further studies using dl3 in order to better denne the value of this schedule for the use in combination protocols.