Cancer Clinical Trials: The Basics Whether you are a cancer survivor, someone who is touched by cancer, or someone who works with people with cancer, this presentation will help answer some of the most important questions you may have about clinical trials.   The presentation will include a discussion about: Why cancer clinical trials are important How clinical trials work How clinical trials advance cancer care How participants are protected Some of the barriers to participating in clinical trials And finally, I’ll talk about ways you can find clinical trials in your community.

What Are Cancer Clinical Trials? Research studies involving people Try to answer scientific questions and find better ways to prevent, diagnose, or treat cancer Clinical trials are research studies involving people. Clinical trials are the final step in a long research process that includes preliminary laboratory research and animal testing.   Clinical trials try to answer specific scientific questions to find better ways to prevent, detect, or treat diseases, or to improve care for people with diseases. In cancer research, a clinical trial is designed to show how a certain anticancer approach—for instance, a promising drug, a new surgical procedure, a new diagnostic test, or a possible way to prevent cancer—affects the people who receive it.

Why Are Cancer Clinical Trials Important? Cancer affects all of us Each year in the U.S.A: More than half a million people are expected to die of cancer — more than 1,500 people a day 1 of 4 deaths is from cancer More than 1 million new cancer cases are expected to be diagnosed It is important to understand that cancer affects us all, whether we have it, care about someone who does, or worry about getting it in the future. Each year in the United States:* About half a million people are expected to die of cancer—more than 1,500 people a day. It is the second leading cause of death, exceeded only by heart disease More than 1 million people are diagnosed with cancer How many people find this surprising? * American Cancer Society. (2001). Cancer facts and figures. Atlanta, GA.

Why Are Cancer Clinical Trials Important? Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer It is important to understand what clinical trials do to fight cancer: ·         Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer. ·         Clinical trials contribute to knowledge and progress against cancer. Many of today’s most effective cancer treatments are based on previous study results. Because of progress made through clinical trials, many people treated for cancer are now living longer. ·         The more people that participate in clinical trials, the faster we can answer the critical research questions that will lead us to better treatment and prevention options for all cancers.       The more people that take part, the faster we can: Answer critical research questions Find better treatments and ways to prevent cancer

Do Many People Participate in Cancer Clinical Trials? Only 3 percent of U.S. adults with cancer participate in clinical trials Fewer than 5 percent of U.S. adults with cancer participate in clinical trials—far fewer than the number needed to answer the most pressing cancer questions quickly. We’ll talk more later about why so few participate.

Types of Cancer Clinical Trials Treatment trials Prevention trials Early-detection trials/screening trials Diagnostic trials Quality-of-life studies/supportive care studies There are at least 5 types of cancer clinical trials: 1. Treatment trials seek to find out: ·         What new treatment approaches can help people who have cancer ·         What is the most effective treatment for people who have cancer   2. Prevention trials seek to find out what approaches can prevent a specific type of cancer from developing in people who have not previously had cancer 3. Early-detection/screening trials seek to discover new ways of finding cancer in people before they have any cancer symptoms 4. Diagnostic trials seek to find out how new tests or procedures can better identify cancer in people when we think it is there 5. Quality-of-life/supportive care trials seek to find out what kinds of new approaches can improve the comfort and quality of life of people who have cancer

Clinical Trial Phases Phase 1 trials How does the agent affect the human body? What dosage is safe? Clinical trials take place in phases. Once laboratory studies (in test tubes and animals) show that a new approach has promise, a phase 1 trial can begin. A phase 1 trial is the first step in testing a new cancer agent in humans.   In these studies, researchers look for the best way to give people the new agent (for example, by pill or by injection), how often it should be given, and what the safest dose is. These studies also include special laboratory tests such as blood tests and biopsies to evaluate how the new agent is working in the body. In phase 1 cancer trials, small groups of people with cancer are treated with a certain dose of a new agent that has already been extensively studied in the laboratory. The dose is usually increased group by group in order to find the highest dose that does not cause harmful side effects. This process determines a safe and appropriate dose to use in a phase 2 trial. While the primary purpose of phase 1 trials is to find the safest dose of a new agent, researchers also evaluate whether the new agent benefits patients. People with cancer who are eligible for phase 1 studies have no known effective treatment options, or they have already tried other treatment options. Many participate in these trials because they want to help others and contribute to cancer research. Phase 1 cancer trials usually have 15 to 30 participants.

Clinical Trial Phases Phase 2 trials Does the agent or intervention have an effect on the cancer? Phase 2 trials continue to test the safety of the new agent, and begin to evaluate how well it works against a specific type of cancer.   In phase 2 trials, the new agent is given to groups of people with one type of cancer or related cancers, using the dosage found to be safe in phase 1 trials. If a new agent has demonstrated that it works against cancer and is safe for people in phase 2 trials, it enters a phase 3 trial. In general, people with cancer who take part in phase 2 trials have been treated with chemotherapy, surgery, or radiation, but the treatment has not been effective. Participation in these trials is often restricted based on the previous treatment received. Phase 2 cancer trials usually have less than 100 participants.

Clinical Trial Phases Phase 3 trials Is the new agent or intervention (or new use of a treatment) better than the standard? Participants have an equal chance to be assigned to one of two or more groups Phase 3 trials focus on learning how a new treatment compares to “standard treatment” (the most widely accepted treatment, based on results of past research). Researchers want to learn whether the new treatment is better than, the same as, or worse than the standard treatment.   In most cases, trials move into phase 3 testing only after a treatment shows positive results in phase 2 trials.    In phase 3 trials, participants have an equal chance of being assigned to one of two or more groups (also called “arms”). The process of assigning participants to groups is called randomization. Many people with cancer choose to get their first treatment in a phase 3 cancer trial. The type of participant varies, depending on the kind of question being asked about a particular cancer. Phase 3 trials usually have hundreds to thousands of participants, in order to find out if true differences exist in the effectiveness of the treatments being tested.

Randomized Trials Participants have an equal chance to be assigned to one of two or more groups: One gets the most widely accepted treatment (standard treatment) The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than standard treatment Phase 3 trials are randomized clinical trials, and some phase 2 trials may also be randomized. Randomization is a method used to prevent bias in research. Treatment assignments are generated by a computer, and each participant hae an equal chance of being assigned to one of two or more groups, the control group and the treatment group: The control group is made up of the people who get the most widely accepted treatment (standard treatment) for their cancer The investigational group is made up of the people who get the new treatment being tested. The next slide illustrates how randomization works.  

Randomization Explain slide

Why Is Randomization Important? So all groups are as alike as possible Provides the best way to prove the effectiveness of a new agent or intervention If participants or doctors choose a particular group based on what they think is best, then one of the groups would likely be very different than the other, making comparison between the groups difficult. Randomization eliminates this bias because participants have an equal chance of being assigned to either group and the subgroups are as similar as possible. Comparing similar groups of people taking different treatments for the same type of cancer is a way to ensure that the study results are caused by the treatments rather than by chance or other factors.

Cancer Treatment Trials What new treatments can help people who have cancer? What is the most effective treatment for people who have cancer? Most cancer clinical trials are treatment trials. These clinical trials involve people who have cancer. These studies try to answer specific questions about the effectiveness of a new treatment or a new way of using an existing treatment.

Cancer Treatment Trials Placebos are almost never used: Placebos are used only when no standard treatment exists Patients are told of this possibility before deciding to take part Placebos (treatments, often drugs, designed to look like the medicine being tested but that don’t contain any active ingredient) are almost never used in cancer treatment trials. Placebos are used in treatment trials only when we don’t yet have a known approach (standard agent) for a particular type of cancer. Patients are told if this is a possibility before they decide whether to take part.

Cancer Prevention Trials Evaluate the effectiveness of ways to reduce the risk of cancer Enroll healthy people at high risk for developing cancer Unlike treatment trials, cancer prevention clinical trials are studies involving healthy people who are at high risk for developing cancer. These studies try to answer specific questions about and evaluate the effectiveness of ways to reduce the risk of cancer.

Cancer Prevention Trials Action studies (“doing something”) Agent studies (“taking something”)—also called “chemoprevention studies” There are two kinds of prevention trials: ·         Action studies (“doing something”) focus on finding out whether actions people take, such as exercising more or quitting smoking, can prevent cancer. ·         Agent studies (“taking something”) focus on finding out whether taking certain medicines, vitamins, minerals, or food supplements (or a combination of them) may lower the risk of a certain type of cancer. Agent studies are also called “chemoprevention studies.”

Chemoprevention Trials Phase 3 chemoprevention trials compare a promising new agent with either a: Standard agent Placebo Chemoprevention trials also go through phases, as outlined earlier for treatment trials.   However, phase 3 chemoprevention trials compare a promising new agent with either a standard agent or a placebo with two or more groups of people. 1. One group takes the promising new agent (called the study agent). 2. The other group takes either: ·         A standard agent, already being used for cancer prevention ·         A placebo Placebos are used in prevention trials when we don’t yet have a known approach (standard agent) for cancer prevention.

Clinical Trial Protocol A recipe or blueprint Strict scientific guidelines: Purpose of study How many people will participate Who is eligible to participate How the study will be carried out What information will be gathered about participants Endpoints Clinical trials follow strict scientific guidelines. These guidelines clearly state the study’s design and who will be able to participate in the study. Every trial has a head person in charge, usually a doctor, who is called the principal investigator. The principal investigator prepares a plan for the study, called a protocol, which acts like a “recipe” for conducting a clinical trial.   The protocol explains what the trial will do, how the study will be carried out, and why each part of the study is necessary. Every doctor or research center that takes part in the trial uses the same protocol. This ensures that participants are treated identically no matter where they are receiving treatment, and that information from all the participating sites can be combined and compared.

Benefits of Participation Possible benefits: Patients will receive, at a minimum, the best standard treatment If the new treatment or intervention is proven to work, patients may be among the first to benefit Patients have a chance to help others and improve cancer care Making a decision about taking part in a clinical trial is a very personal one. This is a question that only the person with cancer (or at high risk for cancer) can answer for him or herself. Some of the possible benefits of participating in a clinical trial are listed here.

Risks of Participation Possible risks: New treatments or interventions under study are not always better than, or even as good as, standard care Even if a new treatment has benefits, it may not work for every patient Health insurance and managed care providers do not always cover clinical trials While a clinical trial is a good choice for some people, there are possible risks. People need to consider these as they think about joining a trial. Some of the possible risks of participating in a clinical trial are listed here.

Patient Protection There have, unfortunately, been past abuses in patient protection Federal regulations ensure that people are told about the benefits, risks, and purpose of research before they agree to participate Although we now have strong safeguards for protecting those who participate in research, these protections have resulted from notorious abuses of human rights in the past. The first formal statement of protection for individuals in research emerged from the Nuremberg trial in Germany where Nazi scientists and physicians who conducted experiments on World War II concentration camp victims were convicted. The Nuremberg Code outlined broad concepts for the protection of human subjects and forms the basis of today’s international code of ethics for the conduct of research.   In the United States, several controversial research studies alerted us to the critical need for protection for those participating in clinical trials. None of these studies sought to inform the participants about the research or gain their consent for participating. ·         From 1932 to 1972, the infamous Tuskegee Syphilis Study followed poor African American men with syphilis but did not treat them. During the study, the men were offered free medical care and were told that they would be treated for “bad blood.” ·         In the 1960s, two other research studies received major public attention. The first was a series of experiments with mentally retarded children; another involved debilitated elderly participants. In response to these tragedies, regulations and policies were developed to ensure that people are told about the benefits, risks, and purpose of research for which they volunteer.

How Are Patients’ Rights Protected? Informed consent Scientific review Institutional review boards (IRBs) Data safety and monitoring boards Participant rights and safety are protected in four main ways.

How Are Patients’ Rights Protected? Informed consent: Purpose Procedures Risks and potential benefits Individual rights Participant rights and safety are protected through informed consent. Informed consent is a process where potential participants learn the purpose and the potential risks and benefits of a study before deciding whether they wish to participate. This process continues throughout the study. The research team, which is made up of doctors and nurses, first explains the trial to potential participants in understandable language. The team explains the trial’s: ·         Purpose ·         Procedures ·         Risks and potential benefits ·         Participant rights, including the rights to: Make an independent decision about participating Leave the study at any time without jeopardizing future treatment   This discussion is the beginning of the informed consent process. After discussing all aspects of the study with a potential participant, the team gives him/her an informed consent form, which includes written details about the information that was discussed. The form also describes the confidentiality of the participant’s records. If a person agrees to take part in the study, he or she signs the form. The informed consent process does not end once the form is signed. If new benefits, risks, or side effects are discovered during a study, the researchers must inform study participants. In addition, participants are encouraged to ask questions at any time about what is happening during the study.

How Are Patients’ Rights Protected? Scientific review Institutional review boards (IRBs) are required by Federal law for trials that are: Federally funded Subject to FDA regulation Participant rights and safety are protected through two review panels, which must approve each study protocol before it begins. Scientific Review Clinical trials that are sponsored by the NCI —whether funded by a grant, run by a cooperative group, or run through a cancer center—are reviewed through different types of panels that include experts who review the scientific and technical merit of the proposed research. Many other clinical trial sponsors, such as pharmaceutical companies, also seek expert advice on the scientific and technical merit of their trial protocols.   Institutional Review Boards IRBs are made up of people who are qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. They include medical specialists as well as lay members of the community. The IRB determines whether the risks involved in a study are reasonable with respect to the potential benefits. IRBs also monitor the ongoing progress of the trial—from when it begins to when it ends.

How Are Patients’ Rights Protected? Data and safety monitoring boards: Ensure that risks are minimized Ensure data integrity Stop a trial if safety concerns arise or objectives have been met Participant rights and safety are also protected through data and safety monitoring boards (DSMBs). For phase 3 trials that take place in many locations, a DSMB may be appointed to help ensure participants’ safety.   DSMBs: Ensure that any risks associated with participation are minimized to the extent practical and possible Avoid exposing participants to excessive risk Ensure the integrity of data Stop a trial if safety concerns arise or as soon as its objectives have been met DSMBs are made up of physicians, statisticians, other scientists, and laypeople, the majority of whom must have no affiliation with the institution leading the study.

Why Do So Few Cancer Patients Participate in Clinical Trials? Sometimes patients: Don’t know about clinical trials Don’t have access to trials May be afraid or suspicious of research Can’t afford to participate May not want to go against physician’s wishes Many people with cancer do not participate in clinical trials. Common barriers include: Lack of awareness Lack of access Fear, distrust, or suspicion of research Financial and personal concerns  

Why Do So Few Cancer Patients Participate in Clinical Trials? Doctors might: Lack awareness of appropriate clinical trials Be unwilling to “lose control” of a person’s care Believe that standard therapy is best Be concerned that clinical trials add administrative burdens Doctors might: Lack awareness of appropriate clinical trials. Physicians are not always aware of available clinical trials. Some may not be aware of the local resources, or some may assume that none would be appropriate for their patients. Be unwilling to “lose control” of a person’s care. Most doctors feel that the relationship they have with their patients is very important. They want what is best for the patient, and if the person must be referred elsewhere to participate in a trial, doctors fear they may lose control of the person’s care. Believe that standard therapy is best. Many health care providers may not adequately understand how clinical trials are conducted or their importance. Some believe that the treatment in clinical trials is not as good as the standard treatment. They also might be uncomfortable admitting that there is uncertainty about which treatment is best in a phase 3 clinical trial. Be concerned that clinical trials add administrative burdens. The length and details of most research protocols may deter providers from participating in clinical trials. The possibility of incurring additional costs and expenses that might be inadequately reimbursed is a deterrent for many.

NCI Information Resources NCI Web site www.cancer.gov Cancer Information Service 1-800-4-CANCER TTY- 1-800-332-8615 www.cancer.gov/cis NCI’s Web site, www.cancer.gov, provides access to NCI’s clinical trial registry, which contains more than 1,800 ongoing clinical trials, with information about studies around the world. All clinical trials undergo review prior to inclusion. Although no single resource lists every cancer clinical trial being conducted in the United States and abroad, NCI’s registry is the most comprehensive, and contains information about trials sponsored by NCI, the pharmaceutical industry, and some international groups. You can narrow your search by looking at stage of disease, phase of trial, treatment modality, and geographic location—so it is possible for us to locate trials going on here in our community. (You may want to mention local information sources for clinical trials in your community.) Another resource is the CIS toll-free telephone service (1–800–4–CANCER). Through this service, callers speak with knowledgeable, caring staff who are experienced at explaining medical information in terms the public can easily understand. CIS information specialists answer calls in English and Spanish. They also answer calls from the deaf and hard of hearing through the toll-free TTY number (1–800–332–8615) . CIS staff have access to comprehensive, accurate information from the NCI on a range of cancer topics, including the most recent advances in cancer treatment. They take as much time as each caller needs, provide thorough and personalized attention, and keep all calls confidential. Calls are answered 9:00 a.m. to 4:30 p.m. local time, Monday through Friday. The CIS also provides live, online assistance to users of NCI Web sites through LiveHelp, an instant messaging service that is available from 9:00 a.m. to 5:00 p.m. Eastern time, Monday through Friday. Through LiveHelp, information specialists provide answers to questions about cancer and help in navigating NCI Web sites. The CIS also provides recorded information 24 hours a day, 7 days a week, through 1–800–4–CANCER. Callers can select option 4 to hear recorded information at any time.

IOWA ONCOLOGY RESEARCH ASSOCIATION

Iowa Oncology Research Association Established in 1977 as CGOP Became a member of NCCTG in 1978 Designated a CCOP in 1983 CGOP: Cooperative Group Outreach Program… CCOP: Community Clinical Oncology Program Differs from the CGOP program in its funding source, accrual requirements & affiliate policies. CGOP receives financial reimbursement from cooperative group for each pt enrolled in study. CCOP receives funding directly from NCI in form of a grant. Receive accrual credits and accrual goals established by NCI. By 1973, most clinical trials were conducted @ NCI-approved comprehensive cancer centers that received core grants from NCI to fund operations. But only about 20% of all pts with cancer were txed at these facilities. Community oncologists tx 80% of cancer pts but had no access to NCI trials. As a result, NCI developed outreach programs in an attempt to make clinical trials available to larger # of pts with cancer. These programs provided funding for community doctors to participate in NCI sponsored trials.

Affiliate Sites Mason City Ottumwa Ames Mercy Medical Centeer – North Iowa; Mercy Cancer Center Ottumwa Regional Health Center Ames William R Bliss Cancer Center / McFArland Clinic / Mary Greeley 62 investigators (approximately 50 in Des Miones area)

Clinical Trials Chemotherapy Radiation Therapy Immunotherapy Surgery Correlative Studies Cancer Control Cancer Prevention Correlative studies: lab studies, pharmacogenetic studies At any given time, 85-100 studies available

Cooperative Group Memberships North Central Cancer Treatment Group Eastern Cooperative Oncology Group National Surgical Adjuvant Breast & Bowel Project Southwestern Oncology Group NCCTG: primary ECOG: secondary NSABP: secondary SWOG: PCPT; SELECT

Protocol Development Protocol concept developed by cooperative group committees Often distributed to participating investigators, CRAs, nurses for peer review Submitted to NCI for review Often takes 1-2 years for these steps

Implementation Of Study Distributed to affiliate sites via weekly emails Optional participation Factors affecting local participation Eligibility criteria Competing studies Test requirements Local IRB review Optional participation by offices such as ours. Almost always pick up NCCTG studies and NSABP studies. WE pick and chhose ECOG studies. Eligibility criteria: Take a look at local pt population In order to be eligible for oncology clinical trials, pts must be in fairly good physical condition with PS 0-1 or 0-2. Adqequate bone marrow, kidney and liver function. Absolutely NO waivers on eligibility criteria

Patient Recruitment Treatment and control studies – Oncology patients referred by local physicians to IORA Cancer prevention studies – Various recruitment efforts utilized

Drug Procurement Drugs ordered from sponsoring cooperative group or Drugs ordered from Pharmaceutical Management Branch (PMB) of NCI

Randomization / Registration Fax Online All randoms / registrations require at minimum a completion of eligibility criteria checklist

Quality Assurance Pathology review Radiation therapy review Surgery review

Quality Assurance Continued Data & Safety Monitoring Policies Data & Safety Monitoring Board (DSMB) Site Audits

Adverse Event Reporting Common Toxicity Criteria (CTC) Adverse Event Expedited Reporting System (AdEERS)

BRAIN TUMORS

RECURRENT BRAIN TUMORS NCCTG N0272 Phase II Trial of STI=571 in Treatment of Recurrent Oligodendroglioma & Mixed Oligoastrocytoma NCCTG N0572 Phase I/II Trial of Sorafenib & CCI-779 in Recurrent Glioblastoma NCCTG N0779 Phase II Study of Vorinostat (SAHA) in Combination with Bortezomib (PS-341) in Patients with Recurrent Glioblastoma Multiforme

METASTATIC BRAIN TUMORS NCCTG N0574 Phase III Randomized Trial of the Role of Whole Brain Radiation Therapy in Addition to Radiosurgery in Patients with 1-3 Cerebral Metastases

BREAST CANCER

ADJUVANT TREATMENT CALGB C40101 Phase III, Randomized, 2 x 2 Factorial Study of Cyclophosphamide & Doxorubicin (CA x 4 Cycles) vs Paclitaxel (4 Cycles) as Adjuvant Therapy for Breast Cancer in Women with 0-3 Positive Axillary Nodes ECOG E5103 A Double-Blind, Phase III Trial of Doxorubicin & Cyclophosphamide Followed by Paclitaxel with Bevacizumab or Placebo in Patients with Lymph Node Positive & High-Risk Lymph Node Negative Breast Cancer

ADJUVANT TREATMENT ECOG PACCT-1 Program for the Assessment of Clinical Cancer Tests: Trial Assigning Individualized Options for Treatment SWOG S0221 Phase III Trial of Continuous Schedule of AC + G vs Every 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Treatment in High Risk Node Negative or Node Positive Breast Cancer

ER / PR POSITIVE NSABP B-42 A Clinical Trial to Determine the Efficacy of 5 Years of Letrozole Compared to Placebo in Patients Completing 5 Years of Hormonal Therapy Consisting of an AI or Tamoxifen Followed by an AI in Prolonging Disease-Free Survival in Postmenopausal Women with Hormone Receptor Positive Cancer CALGB C40503 Endocrine Therapy in Combination with Anti-VEGF Therapy: Randomized, Double-Blind, Placebo-Controlled Endocrine Therapy Plus Bevacizumab for Women with Hormone Receptor Positive Advanced Breast Cancer

WHOLE VS PARTIAL BREAST IRRADIATION NSABP B-39 Randomized Phase III Study of Conventional WBI vs PBI for Women with Stage 0, I or II Breast Cancer

HER2 Positive NCCTG N063D ALTTO: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Study: Randomized, Open-Label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence & Their Combination in Patients with HER2 Positive Primary Breast Cancer

METASTATIC / RECURRENT ECOG E1104 Phase I/II Study of SAHA in Combination with Herceptin in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER2 Amplified Breast Cancer ECOG E1105 Randomized Phase III Double-Blind, Placebo-Controlled Trial of First-Line Chemo & Trastuzumab With or Without Bevacizumab for Patients with HER2 Overexpressing Metastatic Breast Cancer

METASTATIC / RECURRENT NCCTG N0539 Phase II Trial of Fulvestrant & Bevacizumab in Patients with Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor SWOG S0500 Randomized Phase III Trial to Test the Strategy of Changing Therapy vs Maintaining Therapy for Metastatic Breast Cancer Patients Who Have Elevated Circulating Tumor Cell Levels at First Follow-up Assessment

OVARIAN FUNCTION SUPPRESSION IBCSG 2402 Ovarian Function Suppression: Exemestane as Adjuvant Treatment for Premenopausal Women with Endocrine Responsive Breast Cancer CALGB C40302 Endocrine Therapy With or Without Inhibition of EGF & HER2 Growth Factor Receptors: Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib for Post-Menopausal Women With Hormone-Receptor Positive Advanced Breast Cancer