Matthew A. Arquette

HER2 Expression in Salivary Gland Carcinomas: Dependence on Histological Subtype

Purpose: Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression. Experimental Design: Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression. Results: The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%). Conclusions: Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.

A Phase 1 Escalating Single-Dose and Weekly Fixed-Dose Study of Cetuximab: Pharmacokinetic and Pharmacodynamic Rationale for Dosing

Purpose: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies. Experimental Design: Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity. Results: Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses ≥100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P = 0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect. Conclusion: This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.

Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors. Experimental Design: In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m2. Zosuquidar was escalated from 100 to 300 mg/m2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained. Results: Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization. Conclusions: Docetaxel at 75 or 100 mg/m2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m−2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m−2 and escalated in an accelerated titration design to 25 mg m−2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m−2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m−2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies

Pegylated liposomal doxorubicin (PEG‐LD) and gemcitabine have single‐agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies.

Phase I dose and sequencing study of pegylated liposomal doxorubicin and docetaxel in patients with advanced malignancies

Pegylated liposomal doxorubicin (PEG‐LD) and docetaxel have single‐agent activity in several malignancies. The authors conducted a Phase I trial to evaluate the maximum tolerated dose (MTD), toxicities, and effect of dose sequencing of this combination in patients with advanced malignancies.