As a new feature of OncoFacts, we will be highlighting some of the most interesting and potentially practice-changing clinical trials for different malignancies. Because of my particular interest in breast cancer, I have chosen to highlight these clinical trials first. I will begin by highlighting some trials for early breast cancer, and then will review a trial for advanced breast cancer.

Adjuvant Therapy for Early Breast Cancer

SOFT: Suppression of ovarian function plus either tamoxifen or exemestane compared with tamoxifen alone in treating premenopausal women with hormone-responsive breast cancer

This is a randomized phase III trial that is enrolling 3000 premenopausal women with histologically proven and resected breast cancer with ER-positive and/or PR-positive tumors who have received either no chemotherapy or remain premenopausal following completion of adjuvant and/or neoadjuvant chemotherapy.

Why is the trial being done? Chemotherapy, tamoxifen, and ovarian ablation are each effective adjuvant treatment in women under 50 years of age with ER-positive breast cancer. For those women who receive both adjuvant chemotherapy and 5 years of tamoxifen, it is unclear whether any additional benefit is derived from suppression of ovarian function. In a US Intergroup randomized trial (0100) of premenopausal women with hormone receptor-positive, node-positive breast cancer, the combination of tamoxifen plus goserelin for 5 years after chemotherapy significantly reduced recurrences compared with chemotherapy alone or chemotherapy plus goserelin. However, it remains unclear whether tamoxifen without goserelin after chemotherapy would have provided similar benefit, and this treatment arm was not tested. In addition, it is postulated that promising results with aromatase inhibitors in postmenopausal women can also be obtained in premenopausal women who undergo ovarian function suppression. Either the combination of a gonadotropin-releasing hormone (GnRH) agonist (or oophrectomy or ovarian irradiation) with tamoxifen or the combination of a GnRH agonist with an aromatase inhibitor (exemestane) has the potential to improve survival in premenopausal women over that seen with tamoxifen alone.

This trial will compare the 2 tamoxifen containing arms to assess the role of ovarian function suppression; it will compare the 2 ovarian function suppression arms to assess the role of exemestane compared with tamoxifen; and it will compare the exemestane regimen to tamoxifen alone in premenopausal women with estrogen receptor-positive or progesterone receptor-positive invasive breast cancer who either do not receive chemotherapy or who remain premenopausal at the end of their chemotherapy. The duration of hormonal treatment will be 5 years.

Who is eligible? Patients eligible for this trial are premenopausal women (estradiol [E2] levels in the premenopausal range) with histologically proven, resected breast cancer with ER-positive and/or PR-positive tumors, who have received either no chemotherapy or remain premenopausal following completion of adjuvant and/or neoadjuvant chemotherapy.

Study Schema: Patients are randomized to 1 of 3 arms. Arm A – tamoxifen for 5 years. Arm B – ovarian function suppression plus tamoxifen for 5 years. Arm C – ovarian function suppression plus exemestane for 5 years. Ovarian function suppression can be accomplished by the use of the GnRh agonist triptorelin for 5 years, surgical oophrectomy, or ovarian irradiation.

Statistical Outcomes: The primary outcome is disease-free survival (DFS) at 5 years. The secondary outcome measures include overall survival (OS) at 5 years, systemic DFS at 5 years, and quality of life. The study started in August 2003 and is anticipated to complete final data collection for the primary outcome in July 2010.

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT00066690?term=breast+cancer&recr=Open&rank=80. Accessed September 4, 2009.

E5103: A double-blind, phase III trial of doxorubicin and cyclophosphamide followed by paclitaxel with bevacizumab or placebo in patients with lymph node-positive and high-risk lymph node-negative breast cancer.

Why is this trial being done? Bevacizumab has been shown to significantly improve the progression-free survival (PFS) in women with advanced breast cancer when combined with paclitaxel or docetaxel in the front-line setting. Doxorubicin and cyclophosphamide, followed by paclitaxel has become a standard of care in the adjuvant treatment of women with high-risk, early-stage breast cancer. This randomized phase III trial is studying doxorubicin, cyclophosphamide, and paclitaxel to see how well they work with or without bevacizumab in treating patients with lymph node-positive or high-risk, lymph node-negative breast cancer.

Who is eligible? Women with lymph node-positive or high-risk lymph node-negative early breast cancer who have undergone definitive breast surgery are eligible for this trial. The eligibility for the lymph node-negative patients included 1 of the following 3 circumstances:.

1. Lymph node-negative with ER-negative tumor >1 cm
2. Lymph node-negative with ER-positive tumor >5 cm regardless of an Oncotype Dx recurrence score (RS) result
3. Lymph node-negative with ER-positive tumor >1 cm but <5 cm with a recurrence score >11.

Patients with inflammatory breast cancer or those with HER2-positive breast cancer are excluded.

Study schema: This is a randomized, partially double-blind, placebo-controlled, partially open-label, multicenter study. Patients are stratified according to planned dose schedule of doxorubicin hydrochloride and cyclophosphamide ([AC] every 3 weeks versus every 2 weeks), and the physician decides whether to give AC every 3 weeks or in a dose-dense fashion. Patients are further stratified according to estrogen receptor status (positive versus negative), lymph node involvement (node-negative versus 1-3 positive node[s] versus ≥4 positive nodes), and according to received/planned treatment to the breast (lumpectomy and whole breast radiation therapy versus lumpectomy and accelerated partial-breast radiation therapy [before or after chemotherapy] versus mastectomy without radiation therapy versus mastectomy [with local or regional radiation therapy]). Patients are randomized to 1 of 3 treatment arms. In this trial, 20% of patients are randomized to arm I, whereas 40% are randomized to arm II, and 40% to arm III.

Arm I: Patients receive doxorubicin hydrochloride intravenously (IV), cyclophosphamide IV over 20 to 30 minutes, and placebo IV over 30 to 90 minutes on day 1. Treatment repeats every 2 or 3 weeks depending on whether AC is given every 3 weeks or in a dose-dense fashion, and it is given for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15, and that treatment repeats every 3 weeks for 4 courses. Placebo IV is also given with the paclitaxel over 30 to 90 minutes on day 1 of each of those cycles.

Arm II: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I, and bevacizumab IV over 30 to 90 minutes on day 1. That treatment repeats every 2 or 3 weeks depending on how the AC is given, for a total of 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I, and blinded bevacizumab IV over 30 to 90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.

Arm III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I, and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I, and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive open-label bevacizumab IV over 30 to 90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.

Statistical Outcomes: A total of 4950 women will be accrued to the study. The study was initiated in November 2007 and is anticipated to complete final data collection for the primary outcome in November 2013.

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT00433511?term=E5103&rank=1. Accessed September 4, 2009.

Program for the Assessment of Clinical Cancer Tests (PACCT-1): Trial Assigning Individualized Options for Treatment (TAILORx Trial).

Why is this trial being done? Historically, many histologic features of ER-positive breast cancer have been used to decide upon the need for chemotherapy in addition to hormone therapy. These have included tumor size, tumor grade, and number of lymph nodes involved. Molecular signatures, such as that provided by the reverse transcription-polymerase chain reaction (RT-PCR)–based molecular technique performed as the Oncotype DX breast cancer assay have been shown to be both prognostic and predictive of the benefit from chemotherapy.

Who is eligible? Patients with operable, histologically confirmed adenocarcinoma of the female breast who have completed primary surgical treatment and meet the following criteria: ER-positive and/or PR-positive, negative axillary lymph nodes (although pN0 i+ and mol+ are allowed). In addition tumor size must be 1.1 – 5.0 cm in size or 0.5 – 1.0 cm if there is an unfavorable histology. The tumor must be HER2-negative.

Study schema: Patients with ER-positive and/or PR-positive, axillary lymph node-negative breast cancer who meet standard clinical criteria for adjuvant chemotherapy, who are medically suitable candidates for chemotherapy, will be eligible to participate in this trial. Patients will be assigned to treatment according to the schema indicated below.

• “Secondary Study Group-1” (RS <10): Patients will be assigned to receive hormonal therapy alone. An RS of <10 was selected as the threshold for low-risk because it is associated with a 10-year distant recurrence rate on average of <5% if treated with tamoxifen alone, and because no benefit from chemotherapy has been demonstrated in this group.

• “Primary Study Group” (RS 11-25): Patients will be randomly assigned to receive chemohormonal therapy versus hormonal therapy alone. The risk of distant recurrence if treated with tamoxifen alone is sufficiently high to recommend chemotherapy (approximately 10% for the entire group), but chemotherapy has not been established to be clearly beneficial in this specific group.

• “Secondary Study Group-2” (RS >26): Patients will be assigned to receive chemotherapy plus hormonal therapy. An RS of >26 was selected as the threshold for high-risk because it is associated with a 10 year distant recurrence rate of on average of 20% or more, and because chemotherapy has been shown to be beneficial in this group.

Statistical Outcomes: 11,248 patients will be accrued. The trial opened in April 2006, and it is expected that the final data collection date for the primary outcome measure is in April 2014. The primary outcome measures are DFS, distant recurrence-free survival, recurrence-free interval, and OS.

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT00310180?term=PACCT1&rank=1. Accessed September 4, 2009.

OncoFacts™ Editor:

Christy Russell, MD

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