A Phase I Trial of Doxorubicin, Paclitaxel, and Valspodar (PSC 833), a Modulator of Multidrug Resistance

• Published in: Clinical cancer research Vol. 7; no. 5; pp. 1221 - 1229
• Main Authors: ADVANI, Ranjana, FISHER, George A, LUM, Bert L, HAUSDORFF, John, HALSEY, Joanne, LITCHMAN, Manuel, SIKIC, Branimir I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2001
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Ataxia - chemically induced; Biological and medical sciences; Chemotherapy; Cyclosporins - administration & dosage; Cyclosporins - adverse effects; Cyclosporins - pharmacology; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Doxorubicin - pharmacokinetics; Drug Interactions; Drug Resistance, Multiple; Female; Humans; Male; Medical sciences; Middle Aged; Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - metabolism; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Paclitaxel - pharmacokinetics; Pharmacology. Drug treatments; Treatment Outcome; Antineoplastic agent; Human; Drug combination; Intravenous administration; Maximal dose; Toxicity; Treatment efficiency; P Glycoprotein; Malignant tumor; Doxorubicin; Valspodar; Chemotherapy; Treatment; Multiple resistance; Taxane derivatives; Paclitaxel; Phase I trial; Anthracyclins; Pharmacokinetics; Therapeutic protocol
• ISSN: 1078-0432; 1557-3265

Purpose: P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: ( a ) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); ( b ) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and ( c ) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel. Experimental Design: For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses. Results: Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m 2 doxorubicin and 150 mg/m 2 paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m 2 doxorubicin and 70 mg/m 2 paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m 2 doxorubicin and 90 mg/m 2 paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel. Conclusions: PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring ∼60% dose reductions for equivalent degrees of myelosuppression.