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Background: Chemotherapy in combination with small-molecule epidermal growth factor receptor inhibitors has yielded inconsistent results. Based on preclinical models, we conducted a phase I trial of two schedules of lapatinib and vinorelbine., Patient and Methods: Patients had advanced solid tumors and up to two prior chemotherapeutic regimens. Patients were enrolled on two dose-escalating schedules of lapatinib, continuous (arm A) or intermittent (arm B), with vinorelbine on days 1, 8, and 15 of a 28-day cycle. Tumors from a subset of patients were evaluated for gene mutations and expression of targets of interest., Results: Fifty-one patients were treated. The most common grade 3/4 toxic effects included leukopenia, neutropenia, and fatigue. Dose-limiting toxic effects were grade 3 infection, febrile neutropenia, and diarrhea (arm A) and bone pain and fatigue (arm B). The maximum tolerated dose was vinorelbine 20 mg/m(2) weekly and lapatinib 1500 mg daily (arm A) and vinorelbine 25 mg/m(2) weekly and lapatinib 1500 mg intermittently (arm B). One patient on each arm had a complete response; both had human epidermal growth factor receptor 2-positive breast cancer. In a subset of patients, lack of tumor PTEN expression correlated with a shorter time to progression., Conclusion: In an unselected population, two schedules of lapatinib and vinorelbine were feasible and well tolerated.

Objectives: Gemcitabine plus capecitabine has moderate efficacy in patients with advanced renal cell cancer (RCC) but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with metastatic RCC., Methods: Chemotherapy-naive patients were treated with gemcitabine at 900 mg/m2 on days 1, 8, and 15 and with capecitabine at 625 mg/m2 twice daily on days 1 through 21, and every 28 days thereafter. The primary end point was response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory analysis, we also evaluated potential markers of prognosis and treatment response, including thymidylate synthase, PTEN, pAKT, pmTOR, XRCC1, and ERCC1., Results: Of 43 patients, 1 was ineligible and 2 were not analyzable. There was 1 complete response and 3 partial responses, for an overall RR of 10% (95% CI = 3, 24). Nineteen patients (48%) had stable disease. The 6-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI = 8, 32) and 75% (95% CI = 62, 88), respectively. Median survival time was 23 months (95% CI = 10, 37). One patient each experienced grade 4 neutropenia, fatigue, thrombocytopenia, and hemolysis with renal failure. The most common grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have decreased expression of PTEN and increased expression of pmTOR., Conclusions: Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile.

A phase II trial was designed to evaluate the efficacy and toxicity of gemcitabine in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-containing regimens and prospectively categorized for platinum response status. Treatment consisted of gemcitabine 1000 mg/m2 given intravenously on days 1 and 8 of a 21-day cycle. The status of p53 in pretreatment tumor tissue was assessed by immunohistochemistry (IHC). Sixty-one patients who progressed or recurred following platinum-based therapy were enrolled, 26 platinum-sensitive and 35 platinum-refractory. A median of 4 treatment courses (range, 2-7 courses) was delivered. Of the 55 patients assessable for response, there was 1 confirmed complete response and 3 with a confirmed partial response for an overall response proportion of 7%. Twenty-one patients had stable disease while 28 progressed and 2 patients had an unconfirmed partial response. Three of the responders (2 confirmed, 1 unconfirmed) were platinum-refractory. Median progression-free survival (PFS) and overall survival for all patients were 4.1 months and 8.6 months, respectively. Median PFS and overall survival for the platinum-sensitive and platinum-refractory cohorts were 5.4 months versus 3.1 months, and 11.9 months versus 7.1 months, respectively. Toxicity was principally hematologic with grade 3/4 neutropenia in 21% and grade 4 platelets in 8%. There were no treatment-related deaths. Twenty-four of 33 patients (73%) had p53-positive tumors. Although no significant association between platinum sensitivity and p53 status was seen, patients with platinum-sensitive disease and negative p53 by IHC had a trend toward longer survival compared to those with platinum-refractory disease and/or p53 positivity (P = 0.06). We concluded that salvage gemcitabine in this dose and schedule is safe and tolerable in previously platinum-treated patients with NSCLC.

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.

Purpose: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status., Materials and Methods: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled., Results: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type., Conclusion: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.

Objectives: To evaluate the feasibility and activity of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma (TCC) of the urothelium and to relate the activity of this combination to the mutational status of p53., Methods: In the Phase I portion, paclitaxel 200 mg/m(2) (3-hour infusion), carboplatin dosed to an area under the curve (AUC) of 6 mg/mL. min, and methotrexate 10 mg/m(2), increasing in 10-mg/m(2) increments, were administered on day 1 and every 21 days thereafter with granulocyte colony-stimulating factor (G-CSF) and leucovorin support. Subsequently, a Phase II study was initiated in which the carboplatin dose was lowered to an AUC of 5 to allow treatment without G-CSF. p53 expression was evaluated using immunohistochemistry., Results: Thirty-three patients were accrued. Median age was 66 years. No dose-limiting toxicities were seen in the Phase I portion despite escalation of the methotrexate to 60 mg/m(2). Principal toxicities were myelosuppression and neuropathy. The overall response rate (Phase I and II) was 56% (95% confidence interval 38% to 74%). Median survival was 15.5 months; 88% of patients overexpressed p53 at the primary site., Conclusions: Paclitaxel, carboplatin, and methotrexate were well tolerated and active in advanced TCC. The high response rate to this regimen despite frequent p53 mutation is consistent with the p53-independent mechanism of paclitaxel. Whether this regimen is superior to methotrexate/vinblastine/doxorubicin/cisplatin, other paclitaxel-based regimens, or to paclitaxel alone will require comparative trials.