Tom R. Fitch

Phase II Study of Erlotinib (OSI-774) in Patients With Advanced Hepatocellular Cancer

PURPOSE Epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and ligand expression is frequently seen in hepatocellular cancers (HCCs). Erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY) is a receptor tyrosine kinase inhibitor with specificity for the EGFR/HER1. METHODS The primary objective of this study was to determine the proportion of patients with advanced HCC who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was given continuously at a dose of 150 mg per day orally. RESULTS Thirty-eight patients with HCC were enrolled. Median age of the patients was 69 years (range, 27 to 83 years). A majority of patients (63%) had an Eastern Cooperative Oncology Group performance status of 1. Forty-seven percent of patients had received prior chemotherapy for advanced HCC. EGFR/HER1 expression was detected in 88% of the patients. Median number of cycles per patient was two (range, 1 to 26). Twelve (32%; CI 95%, 18 to 49) of the 38 patients with HCC were progression-free at 6 months. Three patients had partial radiologic responses of duration of 2, 10, and 11 months, respectively. Disease control was seen in 59% of the patients. Median overall survival time was 13 months. Ten patients (26%) had toxicity-related dose reductions of erlotinib. Grade 3/4 skin toxicity or diarrhea was encountered in five and three patients, respectively. CONCLUSION Results of this trial suggest a benefit for EGFR/HER1 blockade with erlotinib in patients with HCC manifested by disease control. Additional studies with erlotinib as a single agent or in combination with other agents are warranted.

Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study

PURPOSE To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. PATIENTS AND METHODS Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight. RESULTS Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P =.0001) for appetite and 11% versus 3% (P =.02) for > or = 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate-treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. CONCLUSION In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.

Phase II Study of Erlotinib in Patients With Advanced Biliary Cancer

PURPOSE Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months. METHODS Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. RESULTS Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. CONCLUSION Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

Phase III Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Black Cohosh in the Management of Hot Flashes: NCCTG Trial N01CC1

PURPOSE Hot flashes can cause significant morbidity in postmenopausal women undergoing or finished with breast cancer treatment. Black cohosh has been used to treat hot flashes, but definitive clinical data about efficacy have been equivocal. METHODS A double-blind, randomized, cross-over clinical trial with two 4-week periods, was used to study the efficacy of black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) for the treatment of hot flashes in women. Participants kept a daily hot flash diary during a baseline week and then during two 4-week crossover treatment periods. Hot flash scores were measured by assigning points (1 to 4 for mild to very severe) to each hot flash based on severity and then adding the points for a given time period. RESULTS Between October 31, 2003, to March 4, 2004, 132 patients were randomly assigned. Toxicity was minimal and not different by treatment group. Patients receiving black cohosh reported a mean decrease in hot flash score of 20% (comparing the fourth treatment week to the baseline week) compared with a 27% decrease for patients on placebo (P = .53). Mean hot flash frequency was reduced 17% on black cohosh and 26% on placebo (P = .36). Patient treatment preferences were measured after completion of both treatment periods by ascertaining which treatment period, if any, the patient preferred. Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment. CONCLUSION This trial failed to provide any evidence that black cohosh reduced hot flashes more than the placebo.

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.

Low-Molecular-Weight Heparin in Patients With Advanced Cancer: A Phase 3 Clinical Trial

OBJECTIVE To prospectively assess whether low-molecular-weight heparin (LMWH) provides a survival benefit in patients with advanced cancer. PATIENTS AND METHODS Between December 1998 and June 2001, we performed a randomized controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival. RESULTS Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank P =.46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms. CONCLUSION This trial was unable to demonstrate any survival benefit for LMWH in patients with advanced cancer.

Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group study, N047A

BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2‐stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28‐day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty‐three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression‐free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade ≥3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted. Cancer 2009.

Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7

PURPOSE Vasomotor hot flashes are a common problem in menopausal women. Given concerns regarding estrogen and/or combined hormonal therapy, other treatment options are desired. Prior trials have confirmed that progestational agents and newer antidepressants effectively reduce hot flashes. This current trial compared a single intramuscular dose of medroxyprogesterone acetate (MPA), depot preparation, versus daily oral venlafaxine as treatment for hot flashes. METHODS Women with bothersome hot flashes were entered onto this trial, were randomly assigned to treatment, and then had a baseline week where hot flash scores were recorded without treatment. They were then treated and observed for 6 weeks; daily diaries were used to measure hot flash frequencies and severities. There were 109 patients per each arm randomly assigned to receive MPA 400 mg intramuscularly for a single dose versus venlafaxine 37.5 mg per day for a week, then 75 mg per day. RESULTS During the sixth week after random assignment, hot flash scores were reduced by 55% in the venlafaxine arm versus 79% in the MPA arm (P < .0001). In an intention-to-treat analysis, 46% of venlafaxine patients (50 of 109) compared with 74% of the MPA patients (81 of 109) had a decrease in hot flashes by more than 50% from baseline (P < .0001). Less toxicity was reported in the MPA arm. CONCLUSION A single MPA dose seems to be well tolerated and more effectively reduces hot flashes than does venlafaxine.

5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial.

BACKGROUND Despite widespread use of short-acting antagonists for the 5-hydroxytryptamine (5-HT) receptor, about 50% of patients given moderately emetogenic chemotherapy have delayed nausea. We aimed to assess whether a 5-HT-receptor antagonist was more effective than was prochlorperazine for control of delayed nausea and delayed vomiting caused by doxorubicin. METHODS 691 patients who previously had not had chemotherapy and who were scheduled to receive doxorubicin were given a short-acting 5-HT-receptor antagonist and dexamethasone before doxorubicin (day 1), and were randomly assigned to one of three regimens for days 2 and 3: 10 mg prochlorperazine taken orally every 8 h; any first-generation 5-HT-receptor antagonist (except palonosetron) taken as standard dose intravenously or orally; or 10 mg prochlorperazine taken as needed. Nausea and vomiting were assessed by use of a home record. The primary endpoint was mean severity of delayed nausea. The secondary endpoint was quality of life. Analyses were done by intention to treat. FINDINGS 519 (77%) of the 671 evaluable patients had delayed nausea, with a mean severity of 3.33 (95% CI 3.22-3.44). 161 (71%) of 226 patients assigned prochlorperazine every 8 h reported delayed nausea (mean severity 3.37 [3.16-3.58]), as did 179 (79%) of 226 patients assigned 5-HT-receptor antagonists (3.29 [3.09-3.48]) and 179 (82%) of 219 patients assigned prochlorperazine as needed (3.33 [3.15-3.50]); groups did not differ in mean severity (p=0.853, one-way ANOVA). Patients allocated prochlorperazine every 8 h had less delayed nausea than did those allocated 5-HT-receptor antagonists (p=0.05, t test) and those allocated prochlorperazine as needed (p=0.009, t test). INTERPRETATION Short-acting 5-HT-receptor antagonists are no better than is prochlorperazine in control of delayed nausea caused by doxorubicin. Although fewer patients taking prochlorperazine report delayed nausea, the proportion was unacceptably high.

Gemcitabine and ISIS-2503 for Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma: A North Central Cancer Treatment Group Phase II Trial

PURPOSE Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.