By Jan Buckner, MD, Edith Perez, MD, Fran Palmieri, RN, MSN, OCN, and Lynn Flickinger, MA
North Central Cancer Treatment Group
Jan Buckner, MD, is Chair of the North Central Cancer Treatment Group (NCCTG). In the article that follows, he—along with Edith Perez, MD, Chair of the NCCTG Breast Committee, and colleagues Lynn Flickinger and Fran Palmieri—discusses an actively recruiting phase III NCCTG-sponsored clinical trial (N063D) that seeks to determine the rate of disease-free survival following novel anti- HER2 strategies as adjuvant therapy for HER2-positive breast cancer, using trastuzumab, lapatinib, or both agents.
Investigators at the NCCTG and the other cooperative groups developed and participated in the trials that established trastuzumab-based regimens as critically important to improving the disease-free and overall survival of patients with HER2-positive breast cancer. These trials also demonstrated that not all patients are cured by the introduction of trastuzumab to other therapies. These findings led us to coordinate the development of a study, in collaboration with the Breast International Group, that will build on the understanding of the importance of the HER2 pathway in the setting of breast cancer.
Lapatinib was the logical agent to evaluate as part of an adjuvant therapy trial, which is how N063D, also known as BIG 2-06 and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) Study, was developed. This investigation is based on lessons learned from the original trastuzumab trials, as well as the biology of HER2 and the activity of lapatinib in preclinical and clinical models of advanced breast cancer.
The primary endpoint is disease-free survival, which has been established as an appropriate endpoint in the setting of adjuvant therapy in breast cancer. Secondary endpoints include overall survival, time to disease recurrence, and the safety and tolerability of the agents. The trial also features some very interesting secondary endpoints to evaluate quality of life, such as incidence of brain metastases in the different treatment arms. There are very comprehensive plans for translational studies to look at markers that may be predictive of response to therapy.
Inclusion criteria are based, essentially, on two basic principles: characteristics of the tumor and characteristics of the patient. Tumors must be HER2-positive, identified either by protein analysis or gene analysis. Patients are identified as having HER2-positive disease by local laboratories. Before official enrollment, we will verify the expression at central laboratories. Patients need to be in good health aside from their breast cancer diagnosis, and they cannot have abnormal cardiac function. Participants must also be able to understand the consent form and comply with protocol requirements.
The ALTTO study opened in Europe in May 2007 and in the United States in February 2008. North American patients are already being screened, which we are very happy about, and worldwide accrual is actually going more quickly than anticipated—thanks, likely, to the background of science that exists for the development of this study. Fifty countries have already activated the ALTTO study. As of May 2008, 1,100 are patients enrolled in the study, out of 8,000 required. We anticipate a three- to four-year accrual.
This is a definitive, novel trial in that it is the first global study to incorporate a second line of HER2 therapy, lapatinib, in the setting of early breast cancer. There are similar studies that have recently been initiated, but they are much smaller in scale. This trial is a collaborative development that has integrated the different sciences (including clinical and laboratory scientists), the National Cancer Institute, breast cancer advocates, and industry. It has been a true collaboration from the beginning.
Based on the available science, we believe that lapatinib, alone or in combination with trastuzumab, may increase the cure rate for women with localized HER2 breast cancer. There are multiple correlative science studies planned that will help us understand the reasons that patients either do or do not benefit from treatment. There are important quality of life endpoints incorporated to help us understand the consequences of the treatment.
Enrolling Patients in BIG 2-06/N063D
Title: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Study—A randomised, multi-centre, open label, phase III study of adjuvant lapatinib, trastuzumab, their sequence, and their combination in patients with HER2/ErbB2-positive primary breast cancer.
Endpoints: The primary endpoint is disease-free survival, analyzed after 1,386 events using a two-sided stratified log-rank test. Secondary endpoints include overall survival, distant disease-free survival, rate of brain metastases as first site of metastatic disease, safety/tolerability of the agents, quality of life, and translational studies.
Inclusion Criteria: Eligibility criteria include—but are not limited to—patients with resectable or resected HER2-positive breast cancer, as determined by protein or gene analysis, who have received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen. Patients must also be 18 years or older and exhibit normal cardiac function.
Contact Information: Edith Perez, MD, Principal Investigator; Lynn Flickinger, Study Manager
Phone: 904-953-0707; 507-538-7034
E-mail: altto@mayo.edu
Patients can obtain information through their physicians or by calling the ALTTO Patient Hotline: 1-888-313-5689.
Full protocol information is available on the National Institutes of Health clinical trials website.
ASCO Partners with National Cancer Institute to Collect Standardized Forms
The National Cancer Institute (NCI), as part of its caBIG health informatics initiative, plans to create a core library of harmonized and standardized phase II and III case report forms (CRFs) and data collection modules for oncology clinical trials. The U.S. Food and Drug Administration (FDA) has also initiated a process to develop standardized CRFs as a part of its Critical Path Initiative. NCI is using the CRF elements generated by the FDA as a starting point for its standardized CRF.
To assist these agencies and streamline the information reported during clinical trials, ASCO will launch a number of activities related to standardized CRFs, to be organized by a Subcommittee composed of CRF designer and end-user representatives from cooperative groups, private research networks, industry, FDA, and members of the international cancer research community. This group will review NCI’s proposed standardized CRFs and make recommendations based on the practical needs of oncology clinical researchers.
ASCO will also undertake the following CRF activities, using Cancer Policy Today—the Society’s biweekly electronic communication about legislative and regulatory issues in health care—as a vehicle:
- Solicit CRF forms, which will be used to establish commonly used fields for standardization
- Solicit volunteers for NCI working groups related to CRF standardization
- Request reviews of publicly released standardization domains of CRF, which will ensure that ASCO Members have the opportunity to comment on the proposed forms
Cancer Policy Today is sent via e-mail to domestic ASCO members and is available to everyone on ASCO.org
