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January 2008 Clinical Trial Reports

OBTN, January 2008, Volume 2, Issue 1

The Clinical Trials reported in this issue include:PHASE III:

%u25BA PHASE III

Atamestane Plus Toremifene Compared With Letrozole for Advanced Receptor-Positive Breast Cancer Treatment

A phase III double-blind trial was recently conducted in 60 centers in the United States, Russia, Ukraine, and Canada to compare the efficacy of the steroidal aromatase inhibitor atamestane (ATA) used with toremifene (TOR) to obtain complete estrogen blockage versus the nonsteroidal aromatase inhibitor letrozole (LET) in postmenopausal women with receptor-positive advanced breast cancer.

The primary endpoint in the study was time to progression, and the secondary objectives included overall survival, objective response, and time to treatment failure.

The researchers included postmenopausal patients with receptor-positive advanced breast cancer who had completed adjuvant hormonal therapy more than one year before enrollment. Four hundred thirty-four patients were randomly assigned to receive treatment with daily ATA 500 mg with TOR 60 mg, and 431 were assigned to receive LET 2.5 mg.

The investigators revealed that the time to progression of disease was 11.2 months in both groups. The median times to treatment failure were not statistically different (ATA TOR, 9.24 mo vs. LET, 10.44 mo). The mean hazard ratios were 1.00 for time to progression, 0.99 for time to treatment failure, and 0.98 for overall survival. The frequency of objective responses was slightly greater in the LET group (ATA TOR group, 30% vs. LET, 36%). Adverse events were similar in both groups, with serious adverse events experienced in 10% of the ATA TOR group and 11% in the LET group.

The researchers concluded that time to progression was identical in both treatment groups of postmenopausal women, and believe that this regimen represents the first endocrine therapy that is comparable with LET in advanced breast cancer. The efficacy of the aromatase inhibitor was not decreased by adding an antiestrogen, they added, unlike that seen in a previous major trial (the Anastrozole, Tamoxifen, and Combined trial). They believe that these results warrant further investigation of aromatase inhibitors with highly selective estrogen-receptor modulators.

Mean Hazard Ratios For The Two Treatment Regimens.

ATA = Atamestane, TOR = toremifene, LET = letrozole.

Criteria

ATA TOR

LET

Time to Progression

1.00

0.99

Time to Treatment Failure

1.00

0.99

Overall Survival

1.00

0.98

Goss P, Bondarenko, IN, Manikhas GN, et al: Phase III, double-blind, controlled trial of atamestane plus toremifene compared with letrozole in postmenopausal women with advanced receptor-positive breast cance

2007;25:4961-4966.

r. J Clin Oncology

%u25BA PHASE III

Tamoxifen Superior to Arzoxifene for Locally Advanced or Metastatic Breast Cancer

Arzoxifene is an investigational selective estrogen receptor modulator, which, according to animal models, is more potent than raloxifene in preventing mammary cancer. Researchers from Bangalore, India, sought to test the efficacy of arzoxifene compared with tamoxifen for treating locally advanced or metastatic breast cancer.

The study group comprised women with estrogen- or progesterone-receptor—positive breast cancer who had not received previous systemic therapy, or those who had relapsed more than 12 months after adjuvant hormonal therapy was stopped. They were randomly assigned to receive arzoxifene 20 mg or tamoxifen 20 mg daily. The primary endpoint was progression-free survival. Secondary end points included tumor response, safety, and overall survival.

P

P

A planned interim analysis of the first 200 patients in each group suggested that arzoxifene was significantly inferior to tamoxifen, and the researchers halted enrollment into the study (study enrollment was anticipated to be 240 total). For the 352 patients who had been randomly assigned when enrollment ceased, the median progression-free survival was 4.0 months for the arzoxifene group and 7.5 months for the tamoxifen group. Patients receiving tamoxifen had better progression-free survival ( = .011) and time to treatment failure ( = .029) than those receiving arzoxifene. The two groups were comparable in terms of median response duration and overall tumor response rate. Adverse events were similar for both treatment groups except for nausea (more frequent with arzoxifene) and vaginal discharge (more frequent with tamoxifen).

Significantly longer progression-free survival and time to treatment failure was found with tamoxifen compared with arzoxifene in treating locally advanced and metastatic breast cancer, the researchers noted. This study revealed that the clinical benefit rate, tumor response rate, and median response duration were similar between the two groups.

Deshmare V, Krishnamurthy S, Melemed AS, et al: Phase III double-blind trial of arzoxifene compared with tamoxifen for locally advanced or metastatic breast cancer

2007;25(31):4967-4973.

. J Clin Oncol

%u25BA PHASE III

Head and Neck Cancer Treatment With Cisplatin, Fluorouracil, and Docetaxel

The standard regimen of cisplatin and fluorouracil (PF) plus docetaxel (TPF) may improve outcomes in squamous-cell carcinoma of the head and neck, according to previous phase II studies. Belgian researchers recently compared TPF with PF as induction chemotherapy in patients with local or regionally advanced, unresectable disease in a phase III trial.

A total of 358 eligible patients (age range, 18—70 yr) with stage III or stage IV disease and no distant metastases were randomly assigned to receive either TPF (docetaxel and cisplatin, day 1; fluorouracil by continuous infusion, days 1 to 5) or PF every 3 weeks for 4 cycles. After chemotherapy was completed, radiotherapy was given to patients who did not demonstrate any disease progression within 4 to 7 weeks.

P

At randomization, 177 individuals were assigned to the TPF group and 181 to the PF group. The median progression- free survival was 11.0 months in the TPF group and 8.2 months in the PF group at the median follow-up of 32.5 months (hazard ratio for disease progression or death in the TPF group, 0.72; = .007). The risk of death was reduced 27%

P

( = .02) by TPF treatment; median overall survival was 18.8 months in the TPF group compared with 14.5 months in the PF group. Grade 3 and 4 neutropenia and leukopenia were experienced more commonly in the TPF group, whereas the PF group experienced more common grade 3 and 4 nausea, vomiting, thrombocytopenia, hearing loss, and stomatitis. Deaths resulting from toxic drug effects were 2.3% in the TPF group and 5.5% in the PF group.

Progression-free and overall survival were improved significantly by induction chemotherapy and docetaxel, noted the researchers, as compared with the standard cisplatin and fluorouracil treatment in patients with unresectable squamous-cell carcinoma of the head and neck.

Median Progression-Free Survival.

TPF Group

11.0 months

PF Group

8.2 months*

TPF = Cisplatin and fluorouracil

plus docetaxel, PF = Cisplatin and

fluorouracil, *P = .007.

Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer

2007;357:1695-1704.

. N Engl J Med

%u25BA PHASE II

Temsirolimus Treatment Does Not Increase Survival in Patients With Small-Cell Lung Cancer

Inoperable, extensive small-cell lung cancer has a poor prognosis, and researchers are seeking ways to increase patients’ progression- free survival (PFS). In yet another trial emanating from the Eastern Cooperative Oncology Group registry, researchers from seven cancer centers from around the nation evaluated the PFS as well as toxicity associated with 25- and 250-mg doses of temsirolimus for disseminated small-cell lung cancer.

The study group comprised patients with either stable or responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan. Four to 8 weeks after induction therapy was completed, the enrollees were randomized to receive either 25 or 250 mg of temsirolimus intravenously every week until the disease progressed.

Of the 85 patients (42 men, 43 women, median age, 59 yr) out of 87 who were eligible for inclusion in the study, 44 received temsirolimus 25 mg (group A) and 41 received 250 mg (group B). Brain metastases were present in 12.9% of subjects. For all eligible patients, the overall median follow-up period was 34.6 months.

P

The overall median and 1-year PFS was 2.2 months for group A and 4.7%, respectively. Median PFS was 1.9 months for group A and 2.5 months for group B ( = .24). Patients’ median overall survival was approximately 8 months from the study randomization. Reported toxicities in 86 patients included 36 grade 3 toxicities (42%), with the most common being thrombocytopenia, fatigue, and hypophosphatemia. Grade 4 toxicities were seen in 12 patients (14%), with neutropenia being the most common.

The PFS in this patient population was not increased, the researchers concluded, using temsirolimus given in either weekly dosage.

Pandya KJ, Dahlberg S, Hidalgo M, et al: A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive- stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: A trial of the Eastern Cooperative Oncology Group (E1500)

2007;2(11):1036-1041.

. J Thorac Oncol

%u25BA PHASE II

AntiVEGF Active for Recurrent Ovarian Cancer

Tumor progression for epithelial ovarian cancer and primary peritoneal cancer may be increased by vascular endothelial growth factor (VEGF). A nonrandomized, noncontrolled trial was recently conducted by California researchers to evaluate the efficacy and tolerability of monotherapy with bevacizumab, an anti-VEGF monoclonal antibody.

Eligible study participants had measurable disease, persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer and had tried up to two cytotoxic regimens. Their Gynecologic Oncology Group performance score was at least 2. The investigators administered bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Clinical response and progression-free survival at 6 months were primary endpoints.

A total of 62 eligible and evaluable subjects (median age, 57 yr) were enrolled in the trial. Among these individuals, 41 (66.1%) had received two earlier regimens, and 26 (41.9%) were considered platinum resistant. Clinical responses (2 complete, 11 partial; median response duration, 10 mo) were reported in 13 patients (21.0%). Progression-free survival of at least 6 months was experienced by 25 patients (40.3%). Median progression-free survival was 4.7 months, and median overall survival was 17 months. No significant association was seen between age, platinum sensitivity, performance status, or number of attempted chemotherapeutic regimens and the hazard of progression or death.

Adverse events possibly related to bevacizumab were Grade 3 hematologic, hepatic, thromboembolism, coagulation, constitutional, and dyspnea (each experienced by 1 patient); allergy (2 patients); gastrointestinal symptoms and pain (3 patients each); and hypertension (6 patients). Grade 4 adverse events included vomiting and constipation, proteinuria, and pulmonary embolus (1 patient each).

Bevacizumab was active in the second- and third-line treatment of patients with EOC/PPC, concluded the clinicians, and seemed to be well tolerated.

Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study

2007;25(33):5165-5171.

. J Clin Oncol

%u25BA PHASE II

Stereotactic Body Radiation Therapy for Liver Tumors

A high local control rate for primary and metastatic liver tumors can be achieved using stereotactic body radiation therapy (SBRT). Does it improve quality of life as well as tumor status? Researchers from Rotterdam, The Netherlands, claim to have completed the first study on patient quality of life—related use of SBRT in liver cancer.

From October 2002 to March 2007, 28 individuals were enrolled in this trial. Criteria for study inclusion consisted of unsuitability for other local treatments and a Karnofsky performance status of at least 80%.

The quality-of-life measurement tools used in this investigation included the EuroQol-5D (EQ- 5D) and EuroQoL-Visual Analogue Scale (EQ-5D VAS), both generic instruments, and the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ C-30), a disease-specific questionnaire. Patients were assessed before receiving therapy and at 1, 3, and 6 months post-therapy.

The researchers revealed that mean quality of life for the patient group was not significantly influenced by treatment with SBRT using the EQ-5D index, EQ-5D VAS, and QLQ C-30 global health status. The clinicians noted, however, a tendency toward improvement. This is actually a positive finding, in that many other therapies are thought to result in reductions in quality of life.

Stereotactic body radiation therapy unites a high local control rate by bringing a high dose per fraction and no significant change in quality of life, stated the researchers.

Romero AM, Wunderink W, van Os RM, et al: Quality of life after stereotactic body radiation therapy for primary and metastatic liver tumors

2007; Nov 7 (E-pub ahead of print).

. Int J Radiat Oncol Biol Phys

%u25BA PHASE I

Safety of Gefitinib and Radiation in Advanced Head and Neck Cancer

Combination chemotherapy and radiation therapy is often tried in patients with locally advanced squamous cell of the head and neck. Researchers from multiple U.S. centers conducted a small, phase I study to investigate the safety and toxicity of daily gefitinib used in combination with radiation or with concurrent chemoradiotherapy for treating individuals with locally advanced squamous-cell head and neck cancer (LAHNC).

Treatment for the study participants with intermediate-stage LAHNC consisted of concomitant boost radiation alone with daily gefitinib in escalating doses (250 or 500 mg; cohort 1). After a safety profile was established with radiation therapy alone, subjects with high-risk disease then began therapy with daily gefitinib 250 or 500 mg, once-daily radiotherapy, and weekly cisplatin 30 mg/m² (cohort 2). After the initial regimen, patients were given gefitinib 250 mg/day for up to 24 months.

The results from 23 study enrollees were evaluable for toxicity associated with treatment. Patients in cohort 1 did not exhibit dose-limiting toxicities at either the 250 or 500 mg daily dose of gefitinib with concomitant boost radiation therapy to 72 Gy. Among the patients in cohort 2 who received gefitinib and chemoradiotherapy, toxicities that limited dosing included one case of grade 4 neutropenic fever and one patient with grade 4 diarrhea. Eight of 15 patients (53%) who started maintenance gefitinib therapy had grade 1 to 2 diarrhea and acne-like skin rash, the researchers noted, without grade 3 or 4 toxicity reported.

Gefitinib given either 250 or 500 mg daily with concomitant boost radiation therapy or concurrent chemoradiotherapy was well tolerated, they concluded, as well as protracted administration of gefitinib (250 mg daily) for up to two years.

Chen C, Kane M, Song J, et al: Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer.

2007;2531:4880-4886.

J Clin Oncol