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Understanding New Cancer Treatments and Clinical Trials in Cancer Care

William Tap, MD, UCLA Assistant Professor, David Geffen School of Medicine, Director of the UCLA Sarcoma Oncology Program and Co-Director of UCLA’s Jonsson Comprehensive Cancer Center's Translational Sarcoma Team, researcher and medical oncologist

This is a summary of a lecture presented on February 5, 2008.

In order to track developments in cancer therapies it is important to understand the key past developments that set scientific directions in medical oncology. In 1970 there was a key study published by Dr. Vincent DeVita et al which showed that combination chemotherapy could cure advanced forms of Hodgkin’s disease. Prior to this study, very few patients were being cured; this trial illustrated how combining different treatments could increase cure rates into the 75% range. In 1980, Dr. Lawrence Einhorn and others demonstrated that combination chemotherapy could cure a solid tumor. The trial was done in patients with testicular cancer and, again, the cure rates rose into the 63-72% range. As a result of these two trials, an onslaught of clinical trials in cancer treatment began which looked at different combinations of chemotherapy. In 1999 one study had six different arms of treatment for advanced non-small cell lung cancer. As this and other trials show, it is possible that we are reaching a plateau as to what combination chemotherapy can offer patients with wide spread cancer.

The New Era of Cancer

By the mid 1990s a new era in cancer research was already underway. This new era is called the molecular era of cancer. The goals in this new stage were to use evolving molecular biology techniques to understand what was going wrong with cells at the DNA level that was leading to cancer.

This new era led to a better understanding of the hallmarks of cancer. Researchers found that cancer cells develop an ability to evade normal programmed cell death, called apoptosis. We also learned cancer cells become self-sufficient at giving growth signals while also developing insensitivity to signals that tell a normal cell to stop growing. As cancer cells form into a mass, known as a tumor, they need increasing amount of nutrients in order to grow. Cancer cells are capable of telling the body to create new blood vessels, a process known as angiogenesis, which carry nutrients to encourage growth. Cancer cells also have a limitless ability to replicate, to invade tissues, and to travel to other organs, thereby developing satellite communities called metastases. These hallmarks of cancer have now become the focus of targeted efforts to arrest the development of cancer cells at a molecular level. Instead of using chemotherapy, which is like a non-specific bomb that goes off hopefully killing the cancer cells while not doing too much damage to other cells, the new era led to the notion of discovering targeted therapies, or smart bombs.

There have been some early successes in this new era of cancer treatments. Here at UCLA, Dr. Dennis Slamon became intrigued with a sub-population of women with breast cancer who had a poorer prognosis. He discovered that these women expressed large amounts of a protein on the top of the breast cancer cells and that this particular protein tells the cells to grow, grow, and grow. Normal breast cancer cells might have 20,000-50,000 Her2 receptors, but the women who over-expressed this protein had up to 2,000,000 Her2 receptors. About 25 % of breast cancers have Her2 over-expression. This research identified a target for which treatments could be tailored. Through laboratory research an antibody was found that binds to and blocks the Her2 receptor. This antibody is now known as Herceptin. Herceptin blocks the Her2 receptor and inhibits growth pathways that cause the cancer cells to replicate. Clinical trials using Herceptin in women with breast cancer, found that Herceptin combined with chemotherapy created the best outcomes. What this research demonstrated, like other key studies, was that if you identify the reasons why a cancer cell grows uncontrollably, new therapies can be developed that target the ‘molecular’ abnormality. This approach can really improve on the efficacy and side effect profiles of our current chemotherapy regimens.

One of the new targeted approaches has been to investigate angiogenesis, the process by which cancer cells are able to create new blood supplies, thus allowing small tumors to grow into larger tumors and to spread to other parts of the body. Research has documented that tumors actually release growth factors into the body which tells the blood vessels to grow toward the tumor. The vasculature not only helps to feed the tumor but also creates pathways for cells to travel to other parts of the body forming metastases. When tumors create these new blood supplies, they are often abnormal compared to the vasculature of other tissues. Tumor vasculature is dilated, highly intertwined and chaotic in the way that they wrap around and through the tumor and there is no hierarchical vessel arrangement. As a result, it makes it more difficult to deliver chemotherapy to the tumor. There are many scientists who are trying to figure out how to target this aspect of tumor growth. They have identified VEGF (vascular endothelial growth factor) which is an important signaling protein in the development of blood vessels from pre-existing vasculature. VEGF promotes endothelial cell activation, proliferation, migration and capillary tube formation. VEGF is a central mediator of angiogenesis.

Research efforts to stop the growth of blood supplies by way of blocking VEGF have been creative. Researchers have been developing antibodies that bind to the growth factor essentially acting as a sponge. Other efforts have created antibodies that sit on the receptor like a hat, thus blocking their ability to connect and communicate. Other antibody research has focused on creating antibodies that look like a receptor, thus fooling the growth factor to attach to the false receptor. Antibodies have also been used to penetrate and disrupt the signals. These are all examples of the new targeted approach in the area of antiangiogenesis drugs and are adjuncts to chemotherapies and/or in some situations a replacement.

Each cancer cell is different and relies upon multiple mechanisms for growth, thus making the regulation of cancer cells a complicated process. The key is to try to shut-off multiple aspects of a cancer cell’s ability to survive. This new approach has led to the development of about 10 new targeted agents per year.

Translational Research and History of Clinical Trials

Translational research is a two way process in which information from the laboratory is brought into the clinic environment while information gained in clinics through the care of patients is brought back into the lab. Clinical trials sit in the middle of this process and are the method by which treatments are evaluated for their efficacy and safety. It is important for research endeavors to be closely tied to patient care and for researchers to be able to get their ideas out to patients. There is an important history of how clinical trials have evolved both with regard to design of experiments and the ethics which guide their practice. This history is reviewed below:

• In 1747 one of the first controlled clinical trials was conducted by James Lind in response to a large number of people developing scurvy. He assigned 10 people each to get different things, e.g., vinegar, rest, limes and lemons. He found that those who got the limes and lemons got better. This was the foundation for offering different treatment arms.

• In the 19th Century, the idea of testing drugs against a substance that has no biological effect was introduced to research. The placebo emerged as a “substance having no pharmacological effect but administered as a control in testing experimentally or clinically the efficacy of a biologically active preparation.”

• In the 20th Century many important research paradigms evolved and are described individually below:

• Randomization – Participants are randomly assigned to receive one treatment or another. One of the first was a tuberculosis treatment in which Sancrysin was compared to a placebo. This type of trial could not be done today.

• Manufacturers need to demonstrate safety (1938) – US Food, Drug and Cosmetic Act. This occurred after 107 patients died after taking sulfanilamide, an antibiotic that contained anti-freeze.

• Potency and Purity of Drugs – (1941) The FDA required potency and purity of insulin to be tested and began to set standards.

• Multi-center trials (1944) – The same drug protocols are tested in different locations to acquire more participation.

• Nuremberg Codex (1947) – Development of protection of human subjects as participants in experimental/clinical trials. People must have comprehensive information about their participation in a trial and must consent. There must be anticipated beneficial results from the new experimental trial and the risk that the person was being subject to as a result of the trial had to be proportionate to the significance of the problem being addressed by the trial.

• Proof of efficacy as well as safety (1962) – Kefauver-Harris Drug amendment required that drug companies had to demonstrate proof of efficacy as well as safety. In 1970 this was interpreted to mean that efficacy was not based on commercial success but rather on how well the patient does.

• Declaration of Helsinki (1964) – Ethical code to direct physicians and other participants in medical research involving human subjects. According to this code research with humans should be based on the results from laboratory and animal experimentation. Research protocols should be reviewed by an independent committee prior to initiation. Informed consent from research participants is necessary. Research should be conducted by medically/scientifically qualified individuals. Risks should not exceed the benefits.

This history led to what we now understand and expect from clinical trials in the medical environment.

Clinical Trials

Clinical trials are research studies conducted with patients or healthy volunteers. Each type of trial is designed to answer specific scientific questions. Clinical trials are important because they help deliver new drugs and treatments or refine others. New approaches must be proven to be safe and effective in a clinical trial setting before they can become widely available. Most of our current approaches were first shown to be effective in clinical trials. There are many different kinds of clinical trials, e.g., prevention, screening, diagnostic, supportive care and treatment. The time line for new drug development can vary, but on average it is about 10 years from the time a promising drug is identified in pre-clinical testing until it receives approval by the FDA for use in humans. Certain drugs may be moved through the approval process more rapidly; however, this is sometimes done by risking safety issues. There are four clinical trial phases with very specific goals associated with each. The main three will be discussed here.

Phase I Clinical Trials

A phase I clinical trial is the first test of a new anti-cancer drug in patients. It should answer the following questions: 1) what is the safe/effective dose of the drug? 2) What are the side effects? and, 3) How is the drug processed by the body? Patients with several different types of advanced cancer are usually able to participate in these trials and there are usually a small number of patients.

Limited patients are usually offered the drug to ensure there are no unforeseen side effects at the offered dose. For example, one to three patients receive the drug at a starting dose that is thought to be safe based on laboratory studies. If all of the patients tolerate the drug without unacceptable side effects, the dose is increased by a certain percentage and another group of patients receives the drug at the new higher dose. This process of escalating the dosage of the drug continues until one patient develops an unacceptable side effect such as an abnormality in a blood test or a symptom that cannot be controlled by usual methods. Additional patients are enrolled in the trial and treated at that dose level, usually up to six patients. If a second patient develops the unacceptable side effect, then the dose escalation is stopped.

The typical phase I trial takes about 12 to 18 months to complete and enrolls about 30 patients. At the end of the study, scientists may not know if the drug works because patients with different kinds of cancer were included in the trial. In addition, patients received different doses of the drug. The endpoints for this type of study are “dose limiting toxicity” and “maximum tolerated dose.” Dose-limiting toxicity is based on the side effect that causes the study to be stopped. The maximum tolerated dose is usually the dose below the dose that caused the ‘dose limiting toxicity.’ This is how dosages are decided for drugs. The maximum tolerated dose in the phase I study is what is used for further clinical trials. Phase I trials are an excellent way to learn what a drug does to the human body and what the human body does with a drug.

Phase II Clinical Trials

Phase II clinical trials test a new treatment in a defined patient population that should potentially benefit form the agent. A phase II clinical trial addresses the following issues: 1) gathering of further safety data, 2) preliminary evidence of the drugs efficacy and, 3) determination of the best way to study the drug. There are often concurrent phase II trials which may use more than one defined patient population. For example, a drug might be tested in a group of patients with breast cancer and a group of patients with lung cancer. A typical phase II trial takes about 12 to 18 months to complete and enrolls about 50-300 patients. Phase II trials often involve a control as a basis for comparison. It can be a placebo versus another active treatment and it can be blinded or double-blinded. (Blinded means that the patients do not know whether they are getting the test drug and double blinded means neither the patients nor the physicians/scientists know who is getting what treatment. In a double-blinded trial, someone on the research team is keeping track of who is getting what treatment and is watching the patient data so that if problems develop, the physician caring for the patient is given the information needed to respond to the patients’ needs.) If a phase II trial indicates that the treatment has efficacy with an acceptable risk, the drug will move to a phase III trial.

Phase III Clinical Trials

A phase III clinical trial is a much larger study usually involving between 1000 and 5000 people. They have very well thought-out, detailed protocols. It often takes years to complete although there may be interim analyses. These studies are often multi-institutional and can be national or international. Sometimes they are run within a cooperative group of institutions. In phase III studies people are randomly assigned to the treatment arm of the study and they have a control group (either the current standard of care or if there is no standard of care they are assigned to a placebo) for comparison. Sometimes they have more than one control group. These studies address issues such as: 1) further tests of efficacy, 2) monitoring of side effects and, 3) comparison to the standard of care. The data obtained in both phase II and phase III clinical trials are analyzed using statistical techniques to determine whether the effects are due to true treatment effects or whether they represent chance findings. In addition, they have the following endpoints or outcomes which are monitored:

• Overall Survival

• Disease Free Survival

• Time to Progression

• Quality of Life

• Tolerability – which include both laboratory and clinical side effects which are graded on a scale from 1-4 with 4 representing very severe.

Deciding to participate in a clinical trial is an individual decision and one that should be thoroughly discussed with your physician and the physician who is conducting the trial. A person who participates in a clinical trial could get access to promising new treatments that are not yet available off study, although there is no guarantee that the medication will work. Another possible benefit is the regular and careful medical attention from the research team in addition to the regular care provided by a patient’s physician. There is also the opportunity to advance science and to help future patients. Without clinical trials and people’s willingness to participate, there would be no advances in treatments for cancer. In some cases, a clinical trial may offer an approach that is even more effective than a standard approach and the participants in the trial will be the first ones to benefit.

In addition to possible benefits, there are also potential risks. The new approach may not be better than the standard approach and it may have side effects that are unpredictable or worse than the standard approach. Participants in randomized trials cannot choose the approach they will receive so participating does not guarantee that you will get the new approach. Health insurance may not cover all costs. For many patients, insurance companies will pay for the standard of care and the research study will pay for additional testing required, but some insurance companies refuse to pay for the standard care if any research is being conducted. It is important to understand what your insurance company will cover. Participants may be required to make more visits to the doctor or to have more tests than they would if they were not participating in a clinical trial. This can create more time and cost in transportation and disruption in a patient or caregiver’s daily schedule.

Anyone who participates in a clinical trial must give their informed consent. This is an FDA requirement. Informed consent includes information about the type of agent being studied, the purpose of the research, how long the participant will be in the study, what will happen in the study and what parts are experimental. Informed consent also discloses possible risks, discomfort and possible benefits as well as alternative treatments and procedures. Informed consent explains how your confidentiality will be protected and should notify you that your participation is voluntary and that you can withdraw from the study at any time without any consequences to you. These are important protections and you should feel free to ask questions about any of these areas before you decide to participate in a trial. Below is a list of questions that people should ask before participating in a trial:

• Why consider a clinical trial?

• Is a clinical trial right for you?

• Does the clinical trial make sense?

• What are the investigator’s goals with the trial?

• What other alternatives are there?

• What will the trial entail?

• Who is counseling me?

Finding clinical trials can sometimes be a challenge. One of the best web sites for you to visit is www.clinicaltrials.gov. This site is a registry of federally and privately supported clinical trials conducted in the United States and around the world. If you have further questions, talk to your doctor or seek an opinion at an academic medical institution that engages in a lot of research. NCI designated comprehensive cancer centers conduct research and are often affiliated with community practices as well. The physician/scientists at academic medical centers can often advise you about studies going on at their institution and may have relationships with other scientists doing research in a specific disease category. Just like standard treatments, patients and caregivers can and should have access to the information they need to select the best care for their individual situation. Clinical trials help to advance the field and the more quickly they are completed, the more quickly answers are found and new directions are taken.

 

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