Clinical Trial Reports: November 2007

%u25BA PHASE III

Trastuzumab and Anastrozole Extend Breast Cancer Survival in Patients Who Received Anastrozole Alone Earlier

post hoc

Treatment with trastuzumab plus anastrozole significantly improved progression-free survival in postmenopausal women with HER2/ hormone receptor—positive metastatic breast cancer who had earlier received the hormonal therapy alone, according to results from the TAnDEM study, which include 77 centers from 22 countries around the world.

One hundred four patients were randomized to receive the aromidase inhibitor alone (oral anastrozole 1 mg/day), and 103 received combination therapy (oral anastrozole 1 mg/day plus intravenous trastuzumab 4 mg/kg on day 1, followed by 2 mg/kg every wk) until progression of disease. Patients in the monotherapy arm could cross over to the combined arm if so desired after progression. Seventy-three of the patients in the monotherapy arm did cross over to the combined chemotherapy arm.

P

The investigators noted slightly longer overall survival in the combined therapy group compared with the anastrozole monotherapy group (28.5 vs. 23.9 mo; = .325) in the original study.

post hoc

P

In the analysis, the researchers reported that cross over to combined therapy had a significant effect on overall survival. Patients who later received this combined treatment experienced median overall survival extended by 7.9 months to 25.1 months for subjects who received combined therapy after progressive disease, each compared with 17.2 months for patients who received only anastrozole ( = .04).

The researchers concluded that adding trastuzumab to previous aromidase inhibitor therapy in women with HER2/hormone receptor—positive metastatic breast cancer may prolong overall survival, the researchers indicated, compared with anastrozole alone.

Clemens M: Trastuzumab plus anastrozole may prolong overall survival in women with HER2- positive, hormone-dependent metastatic breast cancer: Results of a post-hoc analysis from the TAnDEM study. Presented at the annual ASCO Breast Cancer symposium. San Francisco, September 7—8, 2007.

%u25BA PHASE II

Motexafin for Non—Small Cell Lung Cancer

According to the American Cancer Society, more than 213,000 new cases of lung cancer in the United States will have occurred in 2007, and the most common form, non— small cell lung cancer (NSCLC), is incurable in its advanced stages. Motexafin gadolinium disrupts redox-dependent pathways by targeting oxidative stress-related proteins, such as thioredoxin reductase. Recent results involving the use of motexafin gadolinium injection indicate that this agent may play a promising role in patients with advanced disease.

American and Canadian researchers presented data from an open-label, multicenter phase II clinical trial evaluating motexafin as a single agent and in combination with chemotherapy as a second-line treatment at a recent lung cancer conference. Patients with non-small cell lung cancer (NSCLC) who had not responded to one platinum-based chemotherapy regimen were enrolled in the investigation.

The trial evaluated safety, tumor response, and survival in patients with recurrent NSCLC. Patients were randomized to receive either a 10-mg/kg dose of motexafin every week or a 15-mg/kg dose every three weeks. A confirmed response rate of 5%, or three partial responses, was reported in 60 of the patients who were evaluated. Stable disease was noted in 17 (30%) of the subjects. The one-year survival was 34%, with a median survival of 9.2 months. Side effects (grade 3 or higher) included hypophosphatemia (23%), fatigue (12%), dyspnea (8.3%), and pneumonia (6.7%).

The investigators concluded that motexafin appears active as second-line monotherapy for patients with advanced or metastatic NSCLC who have failed prior platinum-based chemotherapy, with a response rate similar to other approved agents and a favorable side-effect profile.

Natale RB: Motexafin gadolinium (MGd) is active as a single agent in advanced non—small–cell lung cancer (NSCLC) patients who failed platinum- based chemotherapy: Preliminary results of a phase II trial. Presented at the 2007 World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, Seoul, Korea, September 5–8, 2007.

Oral Satraplatin Monotherapy for the Treatment of Metastatic Breast Cancer Shows Little Response

Intravenous cisplatin and carboplatin are both active agents for treating metastatic breast cancer. Satraplatin, a well-tolerated platinum analog, may be a convenient oral alternative to intravenous chemotherapy. A recent study sought to determine the overall response rate in patients with metastatic breast cancer who had received at most one prior chemotherapy regimen for metastatic breast cancer.

Thirty-eight individuals (median age, 65 yr) with measurable disease or evaluable disease and with an elevated serum CA27.29 level were enrolled in the study over nine months. Treatment consisted of oral satraplatin 80 mg/m² on days 1 through 5 every 21 days in cycles 1 and 2. Subsequently, satraplatin doses were increased to 100 mg/m² if tolerated. After every 2 cycles, clinicians reassessed tumor staging to evaluate response.

Forty-eight percent of the patients had prior adjuvant chemotherapy, and 50% had previous chemotherapy for metastatic breast cancer. Thirty-five percent had not received any prior chemotherapy. Sixty percent were positive for both estrogen and progesterone receptors. All patients received a median of two treatment cycles. In 31 patients with measurable disease, the best outcomes were experienced by two patients (6%) who had a partial response (response duration, 4.3 and 9.5 mo, respectively). Sixteen patients (52%) had stable disease and nine patients (29%) experienced progressive-disease. Median survival was 13.3 months with a median progression free survival of 2.8 months. The most common grade 3-4 toxicities included neutropenia (28%), thrombocyptopenia (25%), and anemia (8%).

As a single agent for the treatment of metastatic breast cancer, satraplatin administered orally has limited activity, with an objective response rate of only 6%, acknowledged the researchers. However, trials are ongoing for the utility of satraplatin in combination chemotherapy.

Smith JW: A Phase II trial of oral satraplatin in patients with metastatic breast cancer. Presented at the annual ASCO Breast Cancer symposium. San Francisco, September 7—8, 2007.

First-Line Treatment for Metastatic Breast Cancer

An active combination for the treatment of metastatic breast cancer is platinum compounds and taxane medications, even though optimal scheduling of these agents is unknown. Weekly paclitaxel may be superior to treatment every 3 weeks, according to previous research, but there are conflicting data regarding the benefits of weekly carboplatin therapy compared with administration every 4 weeks.

Researchers from Memphis, Tennessee, presented the results of a study enrolling individuals who had no prior chemotherapy for metastatic breast cancer and no prior exposure to platinum agents. The patients were stratified by HER2 status and randomize to received either carboplatin, with a dose fixed to an area under the curve (AUC) value equaling 2, on days 1, 8, and 15 (weekly) plus paclitaxel 80 mg/m² administered on days 1, 8, and 15 or carboplatin, with its dose fixed to an AUC value of 6 given on day 1 (q4wk) and paclitaxel 80 mg/m² given on days 1, 8, and 15 in a 28-day cycle. Patients testing positive for HER2 received trastuzumab weekly at 2 mg/kg after a loading dose of 4 mg/ kg. After every 2 cycles of treatment the overall response rate was evaluated.

Of 41 patients enrolled (median age, 53 yr), 23 were HER2 positive. Thirty eight were evaluable for response and 36 for toxicity. Twenty participants had prior adjuvant therapy. No difference was seen between the two carboplatin groups in the number of cycles completed. Eighty-three patients completed 3 cycles in each group, and 41% completed 6 cycles. In the carboplatin study arm, the overall response rate was 47.4% (9 partial responses, no complete responses). The overall response rate for those who were HER2 positive was 60% compared with 33% for patients who were HER2 negative.

Significantly more grade 3 and 4 toxicities were noted in patients receiving the higherdose, longer duration therapy compared with patients receiving the once-weekly carboplatin regimen (P < .004; see Figure). Five patients in the once-weekly carboplatin group and 7 patients in the every-four-weeks group required dose reductions.

The investigators concluded that carboplatin given either weekly or q4wk with paclitaxel (with or without trastuzumab) is an active regimen for metastatic breast cancer, but the risk of severe toxicity is significantly less with weekly carboplatin dosing.

Schwartzberg LS, Tauer K, Schnell FM, et al: Randomized phase II trial of two different schedules of carboplatin (C and paclitaxel (P) /- trastuzumab (T) as first-line treatment for metastatic breast cancer (MBC). Presented at the annual ASCO Breast Cancer symposium. San Francisco, September 7—8, 2007.

Breast Cancer Treatment With Sorafenib

Sorafenib is an interesting oncological agent that targets not only multiple tyrosine kinase inhibitors but also Raf kinase. It is theorized to exert an effect on not only the tumor cells themselves but also on tumor vasculature.

A multicenter study from Italy was conducted to determine the efficacy and safety of sorafenib in patients with metastatic breast cancer. Women with advanced metastatic breast cancer (life expectancy of at least 12 wk) and who had failed at least one prior chemotherapy were considered for the trial. Treatment consisted of oral sorafenib 400 mg bid continuously until evidence of tumor progression, unacceptable toxicity, or consent being withdrawn. Biomarker analyses were carried out for blood and tumor samples.

Fifty-four subjects (median age, 56 yr; median Eastern Cooperative Oncology Group performance status, 0) received at least one dose of sorafenib. Most individuals had estrogen and progesterone receptor—positive tumors, 69% had been given up to four prior chemotherapy regimens, and 48% had at least 3 tumor sites.

Stable disease was observed in 20 (37%) of patients, and 1 (2%) had a partial response. Prolonged stabilization was seen in 22% and 11% of patients at 4 and 6 months, respectively. Only one grade 4 drug related—adverse event was experienced—the patient’s gamma glutamyl transpeptidase level was increased signifi- cantly. Grade 3 drug related–adverse events were noted in 18.5% of patients. Bleeding and hypertension were rare, and usually mild.

Monotherapy with sorafenib appeared to be safe and well tolerated, with a manageable toxicity profile in heavily pretreated patients with advanced metastatic breast cancer.

Bianchi GV, Loibl S, Zamagni C, et al: Phase II multicenter trial of sorafenib in the treatment of patients with metastatic breast cancer. Presented at the annual ASCO Breast Cancer symposium. San Francisco, September 7—8, 2007.

Colorectal Cancer Treatment With Cetuximab plus FOLFOX-4

Adding cetuximab to standard first-line treatment for patients with metastatic colorectal cancer can improve response rates, according to researchers from multiple European centers.

The OPUS investigators recruited 337 patients (181 male, 156 female; median age, 61 yr) into the study between July 2005 and March 2006. All of the patients had epidermal growth factor—expressing tumors. Over 70 European cancer treatment centers participated. Patients were randomized to receive cetuximab 400 mg/m² as an initial dose, then 250 mg/m2/wk plus FOLFOX-4 every 2 weeks [oxaliplatin 85 mg/m²day 1; leucovorin 200 mg/m² day 1 and 2; 5-fluorouracil 400 mg/m² bolus 600 mg/ m² infusion over 22 hours, day 1 and day 2]) or to receive FOLFOX-4 only.

The overall response rate was 45.6% in the cetuximab plus FOLFOX-4 group and 35.7% in the FOLFOX-4 only group. Response rates for patients with an Eastern Cooperative Oncology Group performance status of no greater than 1 were 49.0% in the cetuximab group and 36.8% in FOLFOX-4 only group (odds ratio 1.648, 95% CI [1.043-2.604]). Overall survival data were not reported. The most common grade 3 or 4 adverse event in both groups was neutropenia, which occurred in 31.5% of patients in the FOLFOX-4 group and in 27.6% of patients receiving the combination.

Response rates were higher with the addition of cetuximab to FOLFOX-4 in the first-line treatment of metastatic colorectal cancer, the authors noted, than in those who were treated with FOLFOX-4 alone.

Bokemeyer C: Cetuximab plus 5FU/FA/oxaliplatin (FOLFOX4) in the first-line treatment of metastatic colorectal cancer (mCRC): A large-scale phase II study, OPUS. Presented at the 14th annual European Cancer Conference, Barcelona, Spain, September 23—27, 2007.

Tyrosine Kinase Inhibitor Improves the Treatment of Advanced Gastric Cancer

An open-label, multicenter study found promising outcomes with the use of monotherapy with sunitinib, a tyrosine kinase inhibitor, for the treatment of patients with previously treated gastric cancer.

Individuals with measurable stage IV disease, who had received one prior chemotherapy regimen, and had an Eastern Cooperative Oncology Group performance status score of less than 1 were eligible for enrollment. They received sunitinib 50 mg/day for 4 weeks followed by 2 weeks offtreatment, administered in 6-week cycles.

Forty-two patients (median age, 56 yr; ≥ 2 metastatic sites) were evaluable as of April 2007. Partial response was confirmed in 2 subjects. Fifteen patients had stable disease—12 had stable disease for greater than 3 months and three for more than 6 months). Overall survival and median progression-free survival were 50.7 weeks and 12.3 weeks, respectively.

The most common adverse events were usually grade 1 or 2 in severity and included stomatitis, diarrhea, fatigue, skin discoloration, nausea and vomiting. At the meeting, Yung-Jue Bang, MD, Professor of Internal Medicine of the Seoul National University College of Medicine, said, “Though preliminary, these results are promising and support additional study of sunitinib in advanced gastric cancer, which typically has a poor prognosis; its 5-year survival is around 25%.”

Treatment with sunitinib for advanced gastric cancer

Survival Type

Weeks

Overall Survival (median)

50.7

Progression-free survival (median)

12.3

A second cohort of patients has recently been enrolled for further study. Sixteen patients are still being treated.

Bang Y: Preliminary results from a phase II study of sunitinib as second-line treatment for advanced gastric cancer. Presented at the 14th annual European Cancer Conference, Barcelona, Spain, September 23—27, 2007.