Treatment > Carboplatin · Tamoxifen · Topotecan

Meeting Abstract

Phase I trial of tamoxifen (Tam), carboplatin (C), and topotecan (T) in recurrent or metastatic brain tumors

Robert Morgan Jr., Timothy Synold, Adam Mamelak, Kim Margolin, Al-Kadhimi Zaid, Przemyslaw Twardowski, Lucille Leong, Dean Lim, Sandeep Reddy, Isan Chen, Warren Chow, Stephen Shibata, George Somlo, Yun Yen, Paul Frankel, James H Doroshow

City of Hope Medcl Ctr, Duarte, CA; M.D. Anderson Cancer Center, Houston, TX

To determine the maximally-tolerated dose and dose-limiting toxicities (DLT) of the combination of Tam 100 mg po bid, T 0.25, 0.5, 0.75, or 1.0 mg/m²/d as a 72 h continuous infusion (CI) on days 1-3, followed by C AUC=3 by iv bolus, we performed a phase I study.
17 patients (pts) with recurrent brain tumors received 39 cycles of treatment: median 2, (range 1-5).
There were five recurrent glioblastomas, three anaplastic astrocytomas, five metastatic lung cancers, and one medulloblastoma, ependymoma, metastatic breast and colon carcinoma.
Median Karnofsky performance status was 70% (range 60-90) and age 54 years (range 24-75).
Eleven were female and six male.
Treatment-related DLT was defined as any grade 3 or 4 non-hematologic toxicity, grade 4 thrombocytopenia, or grade 4 neutropenia lasting >5 days or with fever.
At 1.0 mg/m²/d two pts developed hematologic DLTs.
One pt at 0.75 mg/m²/d had treatment-related and one had tumor-related deep venous thrombosis.
Plasma and cerebrospinal fluid (CSF) T levels, total and lactone, were measured during steady state.
At 1.0 mg/m²/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%).
The mean total plasma T in two pts with DLT was 5.2 ng/ml (range 4.63-5.87) and 3.4 ng/ml (range 3.02-3.83) in three others without DLT.
Plasma lactone levels were ~33% of the total; CSF penetration was ~20% of the total plasma levels.
4/8 pts with high-grade gliomas had stable disease for a median of 3 cycles (range 2-5).
Two minor responses in previously treated gliomas and two partial responses in heavily pre-treated lung cancer pts were seen.
We conclude that T, Tam, and C on this schedule is tolerable with manageable toxicity.
Recommended phase II doses are: Tam 100 mg po bid, T 0.75 mg/m²/d as a 72 h CI, and C AUC=3.
The responses in pts with high-grade gliomas and metastatic carcinomas suggest that this combination merits further testing in phase II trials.
(Supported by CA 33572 and SmithKlineBeecham Oncology)

© Copyright 2002 American Society of Clinical Oncology