Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

BACKGROUND: We conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2(+)) metastatic breast cancer (MBC). PATIENTS AND METHODS: The study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m² orally on days 1 to 14, vinorelbine 25 mg/m² intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR. RESULTS: Of 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months). CONCLUSIONS: This triplet combination demonstrated promising activity in patients with HER2(+) MBC.

Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336.

PURPOSE: We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease. PATIENT AND METHODS: Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle. RESULTS: Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months. CONCLUSION: Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.

Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results.

PURPOSE: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. METHODS: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m(2)/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m(2). A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. RESULTS: There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 clearance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. CONCLUSIONS: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

Subcutaneous interleukin-4 (IL-4) for relapsed and resistant non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group, NCCTG 91-78-51.

Interleukin-4 (IL-4), a pleiotropic cytokine, has in vitro activity against non-Hodgkin lymphoma (NHL). This phase II study was conducted to learn the efficacy and toxicity of IL-4 in patients with NHL. Patients with relapsed or refractory indolent or aggressive NHL were eligible to receive 2.5 or 5.0 mcg/kg of subcutaneous IL-4 for 28 days of a 42-day cycle. Patients with response and acceptable toxicity after two cycles were eligible to continue treatment for six cycles. The target overall response rate (ORR) was 20%. Forty-one patients were enrolled and assessable for toxicity; two were ineligible after histology review. The ORR was 13% (5/39) with one complete and four partial responses. All responders were treated with 5.0 mcg/kg; the median time to progression was 84 days, the median duration of response for responders was 8.3 months. The most common toxicities of any grade in all patients were edema (66%), malaise (56%), and elevated liver function tests (56%). Grade 3 and 4 toxicities were more common at 5.0 mcg/kg, leading to a reduction in the starting dose. Although the study observed anti-tumor activity with IL-4, the ORR goal of the study was not achieved. Agents that target the IL-4 receptor can potentially benefit patients with NHL; however, alternative schedules using IL-4 in shorter duration and in combination with other agents would be required to overcome toxicities observed in this study.

Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study.

PURPOSE: Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. PATIENTS AND METHODS: Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). RESULTS: Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P <.05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P <.01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. CONCLUSION: This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

Weekly carboplatin and paclitaxel in elderly non-small-cell lung cancer patients (>or=65 years of age): a phase II North Central Cancer Treatment Group study.

The purpose of this study was to determine the tumor response rate and toxicity profile of low-dose weekly carboplatin and paclitaxel in advanced non-small-cell lung cancer (SCLC) patients 65 or more years of age. Forty-nine patients 65 years of age or more with advanced non-SCLC with a median age of 73 years (range: 65-85) and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 in 31%, 47%, and 22% of patients, respectively, were treated and evaluated. Patients received carboplatin (AUC = 2) and paclitaxel 50 mg/m2 on days 1, 8, and 15 of a 4-week cycle. The overall confirmed tumor response rate was 14% (95% CI: 4.7%, 32.5%) with no complete responses. The 1-year survival rate was 31% (95% CI: 20%, 48%). There was one treatment-related death, and there were two grade IV allergic reactions to chemotherapy. No other grade IV or V treatment-related toxicities were observed. There were only three episodes of grade III myelosuppression. Low-dose weekly carboplatin and paclitaxel, as prescribed in this trial, provides modest activity in the treatment of advanced non-SCLC patients 65 or more years of age. However, the relatively mild toxicity profile observed in this trial suggests that this regimen might remain an option for patients at increased risk for myelosuppression or with a poor performance status.

Randomized phase II study of daily versus continuous-infusion schedules of topotecan in the treatment of extensive-stage small cell lung cancers.

A randomized two-stage, phase II study was conducted to assess the antitumor activity of two different schedules of topotecan in the treatment of extensive-stage small-cell lung cancer (SCLC) in chemotherapy-naive patients. A total of 40 eligible patients were randomized to receive either the daily schedule, with topotecan being administered intravenously at 1.5 mg/m2 daily for 5 days every 3 weeks, or the continuous-infusion schedule, with topotecan administered intravenously at a dosage of 1.3 mg/m2 per day over 72 hours every 4 weeks. Randomization to the continuous-infusion schedule was discontinued due to inactivity, and an additional 20 patients were treated on the daily schedule. Patients received an average of 5 courses (range: 1-13) of the daily schedule compared to an average of 2 courses (range: 1-7) of the continuous-infusion schedule (p < 0.01). Confirmed response rates for the daily and continuous-infusion schedules are 62.5% (90% CI: 49-75%) and 15% (90% CI: 1-29%), respectively. Toxicity was predominantly hematologic with 92% (55/60) having greater than or equal to grade III neutropenia and 58% (35/60) reporting greater than or equal to grade III leukopenia for both IV schedules. Nonhematologic toxicity was very mild, with only 10% (6/60) patients experiencing grade IV toxicities. One patient died of infection on the continuous-infusion arm. Median times to progression for the daily and continuous-infusion schedules are 5 months (90% CI: 4.4-7.2) and 2 months (90% CI: 1.1-2.1), respectively. Estimated 1-year survival rates for patients receiving daily and continuous-infusion schedules are 63% (90% CI: 51-76%) and 55% (90% CI: 39-77%), respectively. Fifty percent (30/60) of patients received second-line therapy with etoposide and cisplatin. Forty-three percent (13/30) of patients who received second-line therapy achieved a confirmed response. Topotecan showed significant activity in the treatment of extensive stage SCLC when administered as a brief daily IV repeated every 3 weeks.

Comparison of nicotine patch alone versus nicotine nasal spray alone versus a combination for treating smokers: a minimal intervention, randomized multicenter trial in a nonspecialized setting.

This multicenter, randomized, open-label clinical trial was conducted to determine whether the combined use of nicotine patch therapy and a nicotine nasal spray would improve smoking abstinence rates compared to either treatment alone, without behavioral counseling. Data were collected at 15 regional cancer control oncology centers within the North Central Cancer Treatment Group. Of the 1384 smokers randomized to the study, 20% were abstinent from smoking at 6 weeks and 8% were abstinent at 6 months. At 6 weeks, the 7-day point prevalence smoking abstinence rate for the patch alone (21.1%) was superior to the spray (13.6%) but was significantly lower than the rate for combination therapy (27.1%). At 6 months, the 7-day point prevalence abstinence rates were not significantly different among the three groups. Combination nicotine nasal spray and nicotine patches were delivered safely in a nonspecialized outpatient clinical setting and enhanced short-term smoking abstinence rates, but these rates were not sustained at 6 months.