Building the Nation's Cancer Research Capacity

National Clinical Trials Program in Treatment and Prevention

The Challenge

As we decipher the molecular changes that cause a cell to become cancerous, a new paradigm in cancer treatment and prevention is emerging. Increasingly, new anti-cancer agents are directed at distinct molecular targets present within cancer cells, leaving healthy cells unharmed. In light of the unique challenges arising from this paradigm shift, NCI must provide a versatile clinical trials system that will quickly and safely move proven anti-cancer interventions into healthcare settings where patients will benefit.

NCI must provide leadership, resources, and expertise at all stages of clinical development for molecularly targeted agents. In the early stages of research, when candidate drugs are identified and shown to have promising potential, NCI forms collaborations and partnerships that help researchers from public, industrial, and academic settings to develop cancer fighting agents for a broader array of tumor types and at a faster pace than would otherwise be possible. After establishing proof-of-principle in early clinical trials, researchers move on to verify the presence of relevant molecular targets in populations of patients and test for improvements in outcomes, such as tumor response, time to tumor progression, and improved survival. During this stage, NCI provides resources to test promising leads in large numbers of patients.

NCI has made substantial progress in building a clinical trials system that meets these requirements. However, a number of critical issues remain to be addressed. We must:

• Identify the most important questions in prevention and treatment that can be addressed through clinical trials.
• Create flexible mechanisms that allow for easy cooperation among basic scientists, clinicians, industry, academia, and the NCI.
• Explore how molecular targeted therapies can be used in combination with conventional treatments or other molecular targeted agents.
• Develop surrogate endpoints to improve the efficiency of small translational trials.
• Identify the most promising treatment or prevention agents for movement into large, easily accessible trials.
• Improve support to physician researchers.
• Improve access to clinical trials by physicians and their patients.
• Help ensure that treatments are made available to all patients who need them.

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Progress Toward Meeting the Challenge

Building the Capacity for Successful Clinical Trials Research

As more private sector companies are beginning to develop anti-cancer drugs, NCI is expanding its role in public-private partnerships. Because pharmaceutical companies tend to seek FDA approval or licensing of a new agent for a single or few tumor types, NCI can help ensure that new agents are evaluated against the full range of cancers (or pre-cancers) for which they may be effective, and in combination with treatments such as surgery, radiation therapy, or other drugs. In one recent success, the collaboration between Novartis Pharmaceuticals and NCI-supported researchers led to the development of imatinib (previously called Gleevec™) to treat chronic myelogenous leukemia and now gastrointestinal stromal tumors. In another public-private partnership, the arthritis drug celecoxib is being tested as a targeted drug for colorectal cancer prevention and treatment.

NCI also recognizes the increasing need for collaborating with laboratory scientists in conducting clinical trials for molecular targeted agents. The cellular pathways and interactions involved in these molecular targets are extraordinarily complex and inter-related, and they require scientists to develop new techniques and tests to identify patients whose tumors contain the relevant targets and to monitor drug effects during treatment. More than half of NCI-sponsored cancer treatment trials initiated over the last two years have included correlative studies with laboratory scientists and this trend is increasingly seen in cancer prevention trials.

NCI continues to simplify the administration of clinical trials to make it easier for physicians and their patients to participate in NCI-supported trials. In 2000, we launched the online Cancer Trials Support Unit (CTSU) site to centralize the common administrative, financial, and data collection activities of its clinical trials cooperative groups. Cooperative group investigators can download information about clinical trials, enroll patients, arrange for reimbursement of research costs, and receive alerts when new trials begin. Since May 2002, CTSU physicians outside NCI cooperative groups have also been able to enroll patients into these NCI-sponsored clinical trials. NCI's efforts are having a noticeable effect, with accrual to NCI-sponsored cancer treatment trials increased by an unprecedented 18 percent in 2001.

Making Strides in Cancer Treatment through Clinical Trials

NCI's focused investment in clinical trials is paying off with increased survival and better quality of life for patients with a variety of cancers. Researchers are finding ways to improve conventional cancer therapies and are applying new, molecular-based approaches to treatment. Just a few of the advances emerging from recent clinical trials are listed here:

• Adjuvant therapy with oxaliplatin provides a modest survival advantage to some colorectal cancer patients who undergo conventional chemotherapy. Researchers are hopeful that oxaliplatin may produce significantly greater improvements in survival of colorectal patients who have minimal residual disease at the time of treatment.
• Tamoxifen, a targeted agent that has been shown to improve survival in some women with breast cancer when given together with chemotherapy, improves disease-free survival even better if given when chemotherapy has been completed.
• Treatment with high doses of the drug methotrexate improves the event-free survival of children with T-cell acute lymphoblastic leukemia (ALL) as well as or better than any other drug reported in the medical literature. The trial is an example of the type of research that has led to a 75 percent decline in mortality rate for children with ALL over the last 27 years, through improvement of conventional cancer therapies.
• A new immunotoxin called BL-22, in early development in NCI's intramural program, has shown great promise against hairy cell leukemia (HCL). This drug will soon be evaluated in other forms of leukemia and lymphoma that have a molecular signature similar to HCL.

Making Strides in Cancer Prevention through Clinical Trials

From years of scientific research, we know that cancers are not caused by a single, catastrophic event, but result from a complex and long-evolving process. Since many cancers take decades to develop, we have the time and opportunity to intervene to stop or reverse its progress before patients become sick. NCI's clinical trials for cancer prevention seek to determine which person is at risk for cancer; define ways to prevent or reduce that risk; detect cancer at its earliest stages; and actively intervene to prevent invasive cancer. The following represents a small sampling of the progress made in these areas:

• Because some women suffer serious side effects with tamoxifen treatment, NCI is sponsoring clinical trials for other preventive agents, such as raloxifene, an osteoporosis prevention drug. NCI-supported researchers are also developing risk assessment tools to determine which patients are most likely to benefit from various prevention strategies with the fewest side effects.
• In partnership with the pharmaceutical industry, NCI researchers have found that an arthritis treatment drug, celecoxib, may help reduce the development of colon cancer in some patients. Thus far, researchers have determined that this drug can reduce the number of pre-cancerous colon polyps in patients with Familial Adenomatous Polyposis, an inherited syndrome that predisposes them to colon cancer. Correlative laboratory studies are showing striking examples of celocoxib prevention of other cancers - such as esophageal, bladder, and skin cancers - in mouse models and in cells grown in the laboratory. NCI is working with its industrial partners to discover whether celecoxib can prevent these cancers in people.
• The newest prostate cancer prevention trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), was launched in July 2001. The 12-year study will answer whether or not seven or more years of daily dietary supplementation with selenium and/or vitamin E will reduce the incidence of prostate cancer. Of note, one third of the 32,400 men needed were accrued within the first eight months of the trial. Serum and white blood cells are being collected for correlative laboratory research and preliminary results from early studies are encouraging. Studies examining cells grown in the laboratory have suggested that selenium might slow the growth of prostate cancer and kill the cancerous cells by apoptosis - a cell suicide mechanism.
• Investigators recently discovered that patients with a history of colon polyps might reduce their risk of developing colon cancer by taking low doses of aspirin in addition to having their regular colorectal cancer screenings. Higher doses were not as effective and researchers are now conducting studies to find the optimal dosage.

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The Plan - National Clinical Trials Program in Treatment and Prevention

Goal
Ensure that NCI's clinical trials program is poised to address the most important medical and scientific questions in cancer prevention and treatment quickly and effectively through state-of-the-art clinical trials. Ensure that the trials are broadly accessible to cancer patients, populations at risk for cancer, and the physicians who care for them. Incorporate relevant correlative laboratory studies into clinical trials to enable strong translational research.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

1.	Identify and develop the most promising new agents for cancer treatment and prevention.	$84.50 M
2.	Strengthen scientific planning and leadership for the large, definitive clinical trials that evaluate and define the efficacy and clinical benefit of new treatments and prevention strategies.	$26.0 M
3.	Double the rate at which Phase III trials are completed. $223.50 M	$223.5 M
4.	Reduce outcome disparities caused by lack of access to trials or follow-up care.
Management and Support		$6.1 M
Total		$340.1 M

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Objective 1: Identify and develop the most promising new agents for cancer treatment and prevention.
Expand partnerships and create flexible collaborations with industry, the FDA, and other public, private, and academic organizations to speed development of promising agents and to bring together the best laboratories, institutions, and investigators (including surgeons, pathologists, and radiologists, in addition to traditional participants) for early translational research.	$4.0 M
Expand resources for the Rapid Access to Intervention Development and Rapid Access to Preventive Intervention Development programs. (Budgeted in Molecular Targets)
Expand capacity to file Investigational New Drug Applications and New Investigational Technology Applications to facilitate early proof-of-principle clinical trials.	$0.5 M
Create broadly based working groups to identify clinically relevant surrogate endpoints. Develop resources and standardize assays, approaches, and clinical trial designs to validate these endpoints.	$2.0 M
Build translational research capacity to use correlative studies more extensively.	$8.0 M
Increase funding for Interdisciplinary Research Teams for Molecular Target Assessment to develop resources to assess the effects of promising agents on their molecular targets.	$20.0 M
Develop molecular assays required to characterize/classify tumors and make them widely available. Support a national tissue resource system to facilitate rapid evaluation of new assays and relevant clinical correlations as new targets are identified. (Budgeted in Molecular Targets)
Increase the pace of development and clinical testing of promising new therapeutic and preventive agents by (1) substantially increasing the number of promising agents entering NCI-sponsored clinical trials over the next two to three years as well as the number of pivotal early clinical trials, (2) tripling annual patient accrual to early clinical trials of promising agents, (3) providing financial incentives for timely initiation of clinical trials and adherence to developmental milestones, and (4) expanding the rapid grant review process, Quick Trials, for mechanism-based clinical trials.	$35.0 M
Support the NCI intramural clinical trials program by increasing the number of data managers, research nurses, biostatisticians, and clinicians available to support a critical mass of clinical investigators, and continuing the Tissue Array Research Program to identify key molecular alterations in cancers.	$15.0 M
TOTAL	$84.5 M

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Objective 3: Double the rate at which Phase III trials are completed.
Increase the number of patients accrued to national trials, and shorten the duration of accrual, to substantially increase the number of new treatments or interventions that can be evaluated. Increase funding for nursing, data management, and other infrastructure costs at local clinical trial sites, and for operations, data management, and statistical offices. Increase the number of (and capacity of existing) Community Clinical Oncology Programs.
Facilitate successful participation by new clinical trials investigators through a "start-up" loan program (repayable by reduced future reimbursements) for training, research nurse, and data management support.
Provide extensive information about prevention and treatment clinical trials to enable patients and physicians to make informed choices. With the NCI Office of Communications, patient advocacy groups, and others, create educational, marketing, and communications strategies to inform patients and physicians about clinical trials. Develop novel strategies, including use of alternative media, for working with minority and under-represented patient populations and their primary care physicians.
Expand the Cancer Trials Support Unit to consolidate the administrative tasks and to provide a single interface for investigators to enroll patients. Develop uniform electronic case report forms and data reporting systems. Expand NCI's audit program to ensure continued high quality accurate data from new sites and increased accrual to clinical trials.
Provide funding directly to participating patients with special needs to cover costs associated with travel, child care, and other relevant limiting expenses. Work with state and local government agencies to address barriers to access for patients dependent on state health agencies for healthcare coverage.
TOTAL	$223.5 M

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Objective 4: Reduce outcome disparities caused by lack of access to trials or follow-up care.
Increase access of underserved populations to state-of-the-art clinical trials. (Budgeted in Reducing Cancer-Related Health Disparities)
Encourage local sites to identify existing resources for helping underserved patients receive appropriate follow-up care and ensure that follow-up care is offered.

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Treatment with Imatinib Builds on Early Success

In May 2001, the U.S. Food and Drug Administration (FDA) gave fast track approval to the molecularly targeted drug imatinib (then called Gleevec™ or STI571) for the treatment of chronic myelongous leukemia (CML). Imatinib blocks the cancer causing effects of a genetically altered protein commonly found in this disease. More recently, the FDA approved imatinib for treatment of gastrointestinal stromal tumors (GIST), a cancer caused by genetic modification of another imatinib sensitive protein. GIST is a relatively uncommon but high mortality cancer, notoriously resistant to any kind of chemo- or radiation therapy. When given to GIST patients in clinical trials, imatinib either dramatically reduced tumor size or arrested tumor growth. Clinical trials are underway to test the use of imatinib in treatment of over 15 other cancers. Some patients have already responded remarkably, including a chronic myelomonocytic leukemia patient whose blood was completely cleared of cancer in only one month.

Despite these unprecedented successes, researchers are finding that, for a number of reasons, many patients with advanced stage disease eventually stop responding to imatinib therapy. Based on intensive research, investigators are identifying strategies to overcome imatinib resistance, such as:

• Administering imatinib as early as possible in the course of the cancer.
• Increasing the dosage of imatinib.
• Developing targeted treatments designed to destroy, rather than control, the genetically altered protein, without harming healthy cells.
• Developing more potent molecular targeted drugs.
• Treating patients with a combination of molecular targeted drugs early in the course of their illness.

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The Next Step in Targeted Therapy - Hitting Multiple Targets

Scientists know that cancer develops as a result of mutations in genes that in turn alter the normal structure of certain proteins (those that regulate cell growth and other critical functions). These genetically altered proteins disrupt "cellular pathways," or the ordered interactions among the diverse molecules in the cell, resulting in uncontrolled cell growth and cancer. As scientists gain a better understanding of these molecular changes, they are able to develop drugs designed to stop cancer development in its tracks by targeting the faulty proteins that wreck havoc on normal cellular pathways.

Increasingly, however, investigators are learning that targeting one protein or one pathway is not always enough. Cellular pathways are tremendously complex, involving intricate and ordered contact among thousands of molecules. As one targeted pathway is shut down within its cells, the tumor may begin to die, but then start growing again. It may be that an alternate pathway, one not affected by the drug, is able to perform the same function as, and thus compensates for, the targeted pathway. This type of "cellular redundancy" occurs naturally and, although it is healthy and beneficial in normal cells, it makes cancer cells harder to kill. To contend with this reality, researchers have begun developing drug treatments that use combinations of targeted drugs to simultaneously shut down alternative pathways so that the cell cannot escape the effects of treatment. Furthermore, since some patients are resistant to one type of drug but not another, using combinations of drugs targeting critical junctures of multiple pathways should increase the patient's chances for successful treatment.

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