Barbara Pizzo

Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non–Small-Cell Lung Cancer

PURPOSE Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, induces radiographic regressions and symptomatic improvement in patients with non-small-cell lung cancer (NSCLC). Phase II trials suggested female sex and adenocarcinoma were associated with response. We undertook this analysis to identify additional clinical and pathologic features associated with sensitivity to gefitinib. PATIENTS AND METHODS We reviewed medical records, pathologic material, and imaging studies of all 139 NSCLC patients treated on one of three consecutive studies of gefitinib monotherapy performed at our institution. We identified patients experiencing a major objective response and compared their clinical and pathologic features with the others. Univariate and multivariable analyses were performed on potential predictive features associated with sensitivity to gefitinib. RESULTS Of 139 patients, 21 (15%; 95% CI, 9% to 21%), experienced a partial radiographic response. Variables identified as significant in univariate analysis included adenocarcinoma versus other NSCLC (19% v 0%; P=.004), adenocarcinoma with bronchioloalveolar features versus other adenocarcinomas (38% v 14%; P<.001), never smoker status versus former/current (36% v 8%; P<.001), and Karnofsky performance status > or =80% versus < or =70% (22% v 8%; P=.03). Multivariable analysis revealed the presence of adenocarcinoma with any bronchioloalveolar features (P=.004) and being a never smoker (P=.006) were independent predictors of response. CONCLUSION Our data suggest that individuals in whom gefitinib is efficacious are more likely to have adenocarcinomas of the bronchioloalveolar subtype and to be never smokers. These observations may provide clues to mechanisms determining sensitivity to this agent and suggest that NSCLC has a different biology in patients who never smoked and those with bronchioloalveolar carcinoma.

Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin.

Purpose: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicity of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant. Experimental Design: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production. Results: Five of six patients at the 30-μg dose and three of five patients at the 10-μg dose mounted IgM responses of 1:80 or greater. These antibodies were confirmed by flow cytometry in seven of eight cases. None of the patients at the 3-μg dose had titers above 1:80. One patient at the 30-μg dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complement-mediated cytotoxicity of tumor cells. Conclusions: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing fucosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic fucosyl GM1 vaccine at a dose of 30 μg with vaccines against three other antigens—GM2, Globo H, and polysialic acid—to test in patients with SCLC after initial chemotherapy.

Phase II Trial of Docetaxel and Vinorelbine in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.

Phase II study of dolastatin-10 in patients with advanced non-small-cell lung cancer

Dolastatin-10 is an agent isolated from the organism Dolabella auricularia, a shell-less mollusk known as a sea hare. Its structure is comprised of four amino acids, three of which are unique to this organism, bound to a complex primary amine, also unique [1]. Dolastatin-10 has demonstrated anti-tumor effects in several preclinical models including hematologic and solid tumor malignancies [2, 3]. The antiproliferative effect of dolastatin-10 is derived from its inhibition of microtubule assembly. The peptide portion of the molecule binds to tubulin, inhibiting polymerization and tubulin-dependent GTP hydrolysis similar to the effects seen with vinca alkaloids [4]. Dolastatin-10 also induces apoptosis, in part, through phosphorylation and subsequent inactivation of the BCL-2 protein [3]. Two phase I trials of dolastatin-10 have been reported [5, 6]. In both trials, dolastatin-10 was administered intravenously every three weeks. The dose limiting toxicity was granulocytopenia. The recommended dose for patients with minimal prior treatment was 400 ug/m [5]. We used this dose in a phase II trial to study the efficacy of dolastatin-10 in patients with advanced non-smallcell lung cancer (NSCLC).

A Phase 1 Study of Pralatrexate in Combination with Paclitaxel or Docetaxel in Patients with Advanced Solid Tumors

Purpose: Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer. Experimental Design: Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B12 and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation. Results: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m2 plus docetaxel 35 mg/m2 administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non–small-cell lung cancer. Conclusions: Pralatrexate (120 mg/m2) plus docetaxel (35 mg/m2) plus vitamin supplementation is well tolerated with signs of efficacy against non–small-cell lung cancer that merit phase 2 testing.

Oral cisapride for the control of delayed vomiting following high-dose cisplatin

Abstract Although combination antiemetics prevent vomiting during the initial 24 h after high-dose (≥100 mg/m2) cisplatin, many patients experience delayed emesis 24–120 h afterwards despite receiving prophylactic dexamethasone and metoclopramide during this time. Cisapride is a prokinetic agent, which stimulates propulsive motility throughout the gastrointestinal tract without causing extrapyramidal effects. In this phase II trial, we tested the ability of cisapride to prevent delayed emesis following cisplatin. Twenty patients receiving initial cisplatin ≥100 mg/m2 were entered. All patients received intravenous dexamethasone with either metoclopramide or ondansetron to prevent acute emesis 0–24 h after receiving cisplatin. Patients who had experienced two or fewer acute vomiting episodes then received cisapride 20 mg orally four times daily for 4 days (24–120 h after cisplatin). Cisapride prevented delayed emesis in 2 patients (10%) during the entire 4-day period (95% confidence interval, 1–32%). Abdominal cramping and pain occurred in 35%. At the dose and schedule tested, oral cisapride prevented delayed emesis in only 10% of patients receiving cisplatin ≥100 mg/m2 and caused abdominal cramping in 35%. Since in prior trials among similar patients, placebo prevented delayed emesis in 11%, further study of cisapride and dose escalation for this indication are not recommended.

C-kit protein expression in tumor specimens as a predictor of sensitivity to imatinib mesylate in patients with small cell lung cancer (SCLC): A phase II clinical trial

7218 Background: Imatinib (Gleevec) inhibits the tyrosine kinase c-kit which accounts for its activity in GI stromal tumors. The high rate of c-kit protein expression in SCLC provided a rationale for studying imatinib in this disease. We conducted this phase II single-institution study of imatinib in patients with relapsed SCLC that expressed c-kit protein. METHODS Patients with progressive SCLC after one or two prior chemotherapy regimens consented to have their pathology screened by immunohistochemistry (CD117, DAKO) for c-kit protein expression. If present, patients were then eligible for treatment. Imatinib was dosed at 400 mg po twice daily (total 800 mg/day). Patients had a CT scan after 4 weeks of treatment and then every 8 weeks. Sample size was based on a Simon two-stage design with 12 patients in the first stage (p0=0.05, p1=0.20). RESULTS Pathology: 25/32 (78%) samples were c-kit positive, 3 samples were not evaluable. To date, 10 patients have received treatment. 6 patients had one prior regimen, 4 patients had 2 prior regimens. 6 patients had refractory disease (progression < 90 days after first-line therapy). The response rate was 0%. No patient stayed on treatment more than 4 weeks. 7 patients experienced edema, grade 1-2 patients, grade 2-3, grade 3-2. Other toxicities included electrolyte abnormalities and lymphopenia. One patient had grade 3 transaminitis which did not resolve with discontinuation of drug and was likely due to progression of liver metastases. CONCLUSIONS 91% of tumor samples were adequate for c-kit testing. Even with the presence of c-kit protein (which was not prospectively assessed in the prior phase II trial reported by Johnson et al, ASCO 2002), no patient with SCLC responded to imatinib. The absence of c-kit mutations in SCLC may explain the lack of response. This study was supported by Novartis. [Table: see text].