Rubin, MD, director of clinical pharmacology there, explains that the search for
treatments begins in the laboratory, where scientists test new ideas. When a drug
is actually developed, it is tested on laboratory animals to determine its effects-good
and bad-on a living being. If the treatment is relatively safe and effective,
it goes into clinical trials, which are carried out in three stages, Phase I (one),
II (two) and III (three). Not only are new drugs tested in this manner, but new
ways to use old drugs must go through similar steps.
I establishes the best method of administering the drug - by mouth, injection
or intravenously - the best dosage, and what side effects, if any, may occur.
"Some of the newer drugs have few, if any, side effects, so determining the dosage
can be very complex," Rubin says. "We have to monitor patients extremely closely."
The physician is also an associate professor of medicine and pharmacology at UMDNJ-Robert
Wood Johnson Medical School.
a limited number of patients who would not be helped by other known treatments
are enrolled. Usually there are between a dozen and 30 participants. Ray Greger
is a veteran of Phase I clinical trials. The 59-year-old Sandy Hook resident is
currently participating in his sixth. Two have worked, four have not. But Greger
continues to enroll.
story began in 1995 when physicians determined he had bladder cancer. The bladder
was removed, and an artificial one, fashioned from his large intestine, was inserted.
An avid angler since his youth, Greger did his share of fresh- and salt-water
fishing during the subsequent three years that he was cancer free.
in 1998, he began experiencing a great deal of back pain. Physicians discovered
it was being caused by a tumor on his sacrum - the bone between the hip bones
of the pelvis - that was pressing on his continued spine. Since the cancer had
metastasized and the tumor was difficult to surgically remove, Rubin recommended
Greger enter a Phase I clinical trial. Besides possibly helping develop a new
drug to benefit others, Greger says he was hoping it would quell his own disease.
bladder cancer spreads to the other vital organs, particularly the liver," he
says. "I was very concerned that the drug wouldn't work, and I was also worried
about the possible side effects. But I did well." He suffered very little, he
says, having only mild flu-like symptoms and slight nausea. What made him even
happier, however, was that after four cycles, or 16 weeks, the combination of
taxol, the number one cancer drug used, carboplatin, also a commonly used chemotherapy
drug, and a new drug Gemzar, shrank the tumor, thus relieving the pain. His disease
stayed under control for five months.
the medication began to lose effectiveness and the pain returned. Greger enrolled
in a second trial, but it, along with the following three trials, was not helpful.
Rubin explains that the efficacy of drugs in animals is not always the same in
people. "We don't know why they sometimes don't work," he says.
the four trials, Greger's tumor either stayed the same size or grew a little,
and he suffered severe side effects, including nausea, vomiting, diarrhea and
tremors. He lost his appetite and 20 pounds. There were complications, too - an
infection and a blood clot - that required hospital stays. But losing all his
hair, he says, was the worst.
a personal part of your makeup and you want to keep it, even if it's not the greatest,"
he says. "That was really the only downer. I wore a hat and tried not to dwell
on it. Except for that, I never really got depressed."
was concerned about what the drugs might do to his mental capabilities. A former
bank executive, Greger hated having to give up his job in 1998 because of his
illness. But even worse, he thought, would be if he finished a trial and wasn't
"still mentally sharp." That didn't happen.
says he never once felt like a guinea pig. "The risk is minimal because you are
watched so carefully. The first concern is always the patient," he explains. "A
physician or a nurse practitioner is always on call to answer questions or help
you. And if things aren't going just right, they find out why or stop the treatment
in his sixth Phase I trial, Greger is taking a combination of the drugs taxol,
retinoic acid and interferon. This cocktail was designed at CINJ, based on work
done there. "We found evidence to suggest cancer can become resistant to taxol,"
says Rubin. "We believe this combination may reverse that process."
If Greger's response is any indication, it may work. He
is slowly getting off his pain medication, has a full head of hair, has regained
much of his energy and is slowly putting on some weight. In early April, he started
getting his boat ready to launch for another season of fishing. Like many with
serious diseases, he takes one day at a time and rarely makes long-range plans.
He does, however, plan to continue participating in clinical trials.
know I'm terminal, but I'm not even close to death," he says. "And except for
cancer, there's nothing wrong with me: I don't have diabetes or heart problems
or the like. If these trial medications can keep the cancer in check, I could
live a long time. And I may even help come up with a cure in the meantime."
Phase I trials are of great value, Rubin explains, because
of their potential. "We aren't certain how patients will react, but there can
be some very dramatic responses," he says. "We're always hopeful that a new drug
or new combinations of drugs will help curb or even cure the disease."
The second phase of trials continues to test the drug's
safety and begins to evaluate how well it works. Does it shrink tumors? Are test
results improved? This phase also uses a small number of patients who all have
the same type of cancer.
third and final phase generally enrolls large numbers of people at sites across
the country and sometimes even abroad. They are randomly placed into one of two
groups by a computer, to eliminate any possibility of bias. One group, known as
the intervention group, is given the new treatment, while the other, the control
group, receives the standard treatment. At the conclusion of the trial, the responses
of the two groups are compared.
a Phase III study will be what's known as "single blind." This means the patient
is not told whether he is getting the standard treatment or the new drug. Only
the doctor knows. A "double blind" study - commonly used in Phase III trials -
is one in which neither the physician nor the patients knows who is getting the
experimental drug or the new drug. These studies are designed to eliminate the
placebo effect, or the belief by patients that they are feeling better even though
they are not taking the new drug.
But that is the only fact that may be kept confidential.
Participants are given a consent form that presents all the facts, in minute detail,
on what will be done during the study and why, and all possible risks and benefits.
The form is reviewed with the physician and patients take it home. They have up
to a week to discuss it with loved ones and make a decision. And patients don't
have to remain in a study if they become uncomfortable. They may drop out at any
the start of the trial, participants receive a detailed action plan, or protocol.
It explains what the trial will do, what agent will be taken, the number and type
of patients enrolled, when and what tests will be done, and what information will
be gathered. It also contains a day-by-day treatment schedule.
Aisner, MD, associate director for clinical sciences at CINJ, says clinical trials
are reviewed at their onset for safety, and there are a number of controls in
place to make sure they continue to be conducted that way. At CINJ, trials begin
with tumor study groups. There is a group for each type of cancer - breast, prostate,
etc. - consisting of specialists from all disciplines of cancer care. The scientist
who is directly managing the study, known as the principal investigator, is never
a member of the tumor group reviewing his or her trial. A physician who starts
a new trial, say for a breast cancer drug, presents his or her study concept to
the breast tumor study group. The members help develop the protocol and set priorities
for its use. They meet weekly to discuss patients they've seen, and decide which
ones are best suited for particular trials. The study groups also meet at least
once a month to discuss the trials themselves.
Once the tumor study group has formulated the trial, a
proposal is submitted to the Scientific Review Board (SRB) at CINJ. The board
is comprised of physicians, surgeons, radiation oncologists, biostatisticians,
bioethicists, and lay people. These people have the task of deciding if the study
concept is significant enough to proceed, if the methods are valid and appropriate,
and if the research is statistically feasible. "The SRB also examines how the
trial will impact our resources," Aisner says. Once the SRB accepts the trial
proposal, the protocol is forwarded to the CINJ Institutional Review Board (IRB),
which again reviews it for human safety.
Phase I study groups add another dimension of safety.
Their members help determine the correct dosages by examining the pharmacokinetics
of the drug. That is the study of what happens to the drug once it's in the body.
How the drug is distributed, how long it stays there and how it is eliminated
are all appraised. "This helps us understand how to use the drug," Aisner says.
"For example, if a pain medication lasts only 90 minutes, taking it every four
hours won't do the job." This group also looks at the drug's pharmacodynamics,
or the drug's effect on the body. When a drug produces a toxic effect, for instance,
the dose may continued be too high. The Phase I study group also meets weekly
and passes its findings onto the SRB as well.
research activities are monitored by outside agencies, including the National
Cooperative Groups, the FDA and NIH's National Cancer Institute.
to the development of new drugs is the research pharmacy. Susan Goodin, Pharm
D, director of the pharmacy at CINJ, says her department is responsible for the
tracking, preparation and dispensing of all investigational treatments. "Since
many of our protocols involve drugs that are in limited supply, it's important
before starting a therapy to verify that we have enough in stock to complete the
course," Goodin says.
pharmacy sometimes improves ways of administering treatments. Since the drugs
are in the early stages of development, many have been given only on a limited
basis. Methods of preparation and administration haven't been established. "In
those situations," she says, "we work closely with the company developing the
product to establish preparation and administration guidelines."
of dosages is a critical part of the job. First the pharmacist checks that the
dosage of the drug on the patient's order matches the one outlined in the protocol.
Next he or she makes sure the dosage is the correct one for the patient, based
on height, weight and organ function. Finally, the pharmacist makes certain that
there will be no adverse interactions with other drugs being taken by the patient,
including any alternative medications.
Goodin works closely with the SRB and IRB to assure dosages
on protocols are written clearly. "We want to avoid any type of nonspecific language,"
she explains, "particularly for multiple-day therapies." She and her department
consult with physicians on pain management and other supportive patient-care issues.
And Goodin is currently involved with her own clinical trial. She is testing green
tea as a preventative for mouth sores in patients receiving chemotherapy and radiation.
investigators at CINJ are very optimistic about finding a cure in the near future.
Rubin says that's because there's been a revolution in the way cancer research
is now being approached. "Years ago we didn't know what caused cancer, so scientists
took a variety of plants, ground them up, purified the active ingredients and
we had cancer drugs," he explains. "We now have an understanding of cancer at
its molecular level, so we can target a specific mechanism within the cell and
design drugs to halt or interfere with it."
main target is the communication of the cells with one another, which is called
signal transduction. Cells send signals back and forth using "messenger" proteins.
The genes provide the information on the protein. When communication lines work
properly, cells perform their normal functions. But if the lines break down or
send the wrong signal, problems, like cancerous tumors, develop. The goal is to
disrupt or change the communications process when it's being used by the disease.
- genes that can transform a cell into a tumor cell - are sometimes responsible
for cell communication problems. Antioncogenes are drugs that suppress specific
oncogenes. An example is herciptin, which inhibits the oncogene Her2/neu. Scientists
believe it may be responsible for some breast cancer. It proved to be successful
in clinical trials on women who had previously been treated for that disease.
"We hope that eventually we can give it to women in the very early stages of breast
cancer," Rubin says.
Another, bcr-abl, has been shown to be a good target for
chronic myelogenous leukemia. The drug STI 571 has been effective in trials against
it, even in patients who did not do well on other treatments. "This is a very
exciting time in cancer research," he says. "We've moved from asking if we should
study the proteins in the cells, to which specific protein should we target."
inhibitors are another promising new area of research. This is a group of compounds
that block the development of new blood vessels, a process known as angiogenesis.
A solid cancer tumor can't grow more than about the size of a pinhead without
new blood vessels to supply it with oxygen. If blood vessels can't grow, researchers
believe, the tumor will die.
that target microtubules, which are part of the architecture that lets a cell
divide, are also being studied. Blocking them means cancer cells will be unable
to furiously reproduce into tumors.
Some of these types of drugs are found in nature. One,
known as epothilone, is found in fungus, and another, the very common taxol, comes
from Pacific yew trees.
too, are under investigation as possible ways to slow down or even stunt the growth
of cancer. One currently in clinical trials that looks promising attacks prostate
the best medicine of all, Rubin says, has also taken giant leaps forward. CT and
PET scans and MRIs are all greatly improved. "Until recently we had to wait months
sometimes, to find out if a lump was scar tissue or a tumor," he says. "Now we
can find out almost immediately. And we now can see if a tumor has formed new
blood vessels and if it's growing."
Even information on the Internet, he says, has been responsible
for people getting to doctors sooner, when they suspect problems. "I'm happy when
people come in with printouts from the Net," the physician says. "It's so much
better than comparing their disease to Aunt Nellie's."
A cure may be right around
the corner, but for now developing new therapies is still the foremost hope.
To do that, however, clinical trials must go on, and it's often difficult
to recruit patients.
cancer is more curable than adult cancer, Rubin says, yet the percentage of kids
who enroll in trials is far higher, at 85 percent, than that of adults at only
as high as 10 percent.
that New Jersey has passed legislation to pay for experimental drug therapy, we're
hoping that will change," he says, "because future treatments are our best hope
for making cancer a disease of the past."