Drugs in the Pipeline: New Therapies that Could Change Treatment Strategies
SAN DIEGO, Calif., April 15, 2008– New drug
compounds, and old ones put to new use, offer doctors and patients
new hope for treating and preventing cancer. Studies presented at
the 2008 Annual Meeting of the American Association for Cancer
Research, April 12-16, show promise and progress against brain,
colorectal, rectal and ovarian cancers and lymphoma.
A Multidisciplinary Phase II Study of AZD2171 (cediranib), an Oral
Pan-VEGF Receptor Tyrosine Kinase Inhibitor, in Patients with
Recurrent Glioblastoma: Abstract LB-247
The investigational drug AZD2171 (cediranib) may help shrink tumors
and prolong survival of patients with a relatively common,
aggressive type of brain cancer, according to results from a
clinical trial conducted by Boston researchers.
In a phase II study of 31 patients with recurrent glioblastoma,
researchers observed that daily treatment with cediranib decreased
tumor volume by more than half in 56 percent of patients.
Nearly 26 percent of patients were alive and their cancer had not
progressed six months into treatment. On average, patients
experienced a progression-free survival of 117 days and overall
survival of 221 days. In addition, cediranib was found to alleviate
brain swelling – a major cause of morbidity among these
patients.
Cediranib is a selective signaling inhibitor for vascular
endothelial growth factor (VEGF), which promotes formation of new
blood vessels that tumors need for nourishment and growth. The drug
targets all three receptors for VEGF, one of which is expressed on
the endothelial cells in glioblastoma.
“These are promising, early results but are from a single
study of 31 patients, so ongoing larger studies will be critical to
determine if the findings are corroborated,” said lead author
Tracy Batchelor, M.D., M.P.H., executive director of the Stephen E.
and Catherine Pappas Center for Neuro-Oncology at the Massachusetts
General Hospital Cancer Center. “One important question is
whether a combination of cediranib and chemotherapy will be more
effective than cediranib alone. We have designed a randomized trial
in patients with recurrent glioblastoma that will open at multiple
sites in Europe, the U.S., Canada and Australia this summer that
will address this and other questions.”
Two of the 31 patients were removed from the current study because
of toxicity (fatigue). However, dose reductions or short breaks
from the drug were required for most patients, usually due to
hypertension, diarrhea and fatigue.
By analyzing blood samples from patients, the researchers found
that the biomarkers FGF (fibroblast growth factor) and Tie-2 were
associated with tumor progression and could be used to predict
treatment failure in this study population, Batchelor says. FGF is
a protein tied to new blood vessel growth; Tie-2 is a receptor that
binds to and is activated by the angiopoietins – protein
growth factors required for the formation of blood vessels.
Evaluation of the effects of anti-VEGF therapy in a
multidisciplinary phase I/II study of neoadjuvant bevacizumab with
chemoradiation therapy in rectal cancer: LB304
Adding bevacizumab to standard chemotherapy and radiation in
patients with rectal cancer fully prevented tumor spread and
“normalized” tumor blood vessels enough to enable
effective therapy, researchers report.
“I know of no other therapy in this patient population
where we can even get close to 100 percent tumor control. Although
this needs to be confirmed in a randomized trial against a placebo
group, these are very impressive numbers,” said Rakesh Jain,
Ph.D., Andrew Werk Professor of Tumor Biology at Harvard Medical
School.
Bevacizumab is currently approved for colorectal cancer, and works
by destroying the blood vessels that tumors need to grow.
“This mechanism of action was a conundrum for scientists
because in order for radiation and chemotherapy to work, you need
blood vessels,” Jain said. “However, the current study
adds evidence to a concept called normalization whereby restoring
order to blood vessels inside a tumor opens up a window of
opportunity for treatment.”
Blood vessel normalization allows the vessels that remain to
perform more efficiently. “With a drug like bevacizumab, some
of the tumor vasculature is pruned away immediately, but the
vessels that remain become less abnormal,” Jain said.
“These normalized vessels make the surviving cancer cells
more vulnerable to the treatments that can now be delivered more
efficiently. Cancer therapies in this environment should be
maximally effective.”
In the current study, researchers enrolled 24 patients with
late-stage rectal cancer. All patients completed four cycles of
therapy including bevacizumab, additional standard chemotherapy,
radiation and surgery.
At four years, local control, or the absence of cancer spread
beyond the original tumor site, was observed in 100 percent of
patients and disease-free survival in 88 percent.
Of the 24 patients treated, five had no residual cancer. Of the 19
patients with residual disease, 12 displayed severe disease.
Downstaging of the tumor was observed in 12 out of 22 observable
tumors.
“We had shown in previous mouse studies that normalizing
blood vessels would decrease tumor activity, but the question with
mouse studies is whether it will work in humans,” Jain said.
“This is the first study to confirm the idea of the effect of
normalization in patients.”
Preliminary results of a Phase I study of AME-133v, an
Fc-engineered humanized monoclonal antibody, in low-affinity
Fc?RIIIa patients with previously-treated follicular lymphoma:
LB-70
A second generation, highly targeted monoclonal antibody appears to
provide benefit for some patients with follicular lymphoma for whom
other treatments have failed, according to results of a phase I
clinical trial.
In the 16 patients evaluated so far, four have achieved either a
partial or complete response with use of the novel agent AME-133v,
said the study’s lead investigator, Andres Forero, M.D.,
associate scientist at the University of Alabama, Birmingham,
Comprehensive Cancer Center.
“These first results suggest that AME-133v provides a
mechanism of action that may be more potent and ultimately more
effective than the treatments we have on hand for a subset of
patients with this cancer,” Forero said. “Given these
encouraging results, patients are currently being enrolled in a
phase II study.”
The majority of patients in this study either did not initially
respond or relapsed after use of rituximab, the first monoclonal
antibody therapy approved for use in lymphoma treatment. AME-133v
is a second-generation therapy that is believed to be a more
specific treatment for follicular lymphoma in general, compared to
rituximab, but is also thought to offer particular benefits for
those patients who have a variant in the immune cells needed to
attack the cancer, Forero says.
“Monoclonal antibodies were the first successful targeted
therapy for cancer, and we have now moved on to a whole new class
of second generation antibodies for the treatment of many different
lymphomas,” Forero said. “This is an exciting
time.”
Follicular lymphoma is a particularly difficult to treat subtype of
non-Hodgkin lymphoma, which is a cancer that arises from white
blood immune cells known as lymphocytes. Rituximab binds to CD20, a
cell surface antigen expressed on almost all B-cell lymphomas as
well as on normal B cells, and works to kill the cancer cell via a
mechanism that is not yet understood.
Although treatment with rituximab as a single agent has resulted in
significant responses in patients with almost every subtype of
B-cell lymphoma, including follicular lymphoma, recent evidence has
shown that some patients with effector immune cells that carry a
mutation in the receptor protein Fc?RIIIa 158-F do not have the
same response, Forero says. This is an issue that is related to the
patient’s own biological makeup, not to the cancer cells
themselves, he adds.
There are three different classes of Fc? receptors to which the
monoclonal antibody binds on leukocyte effector cells – T
helper cells -- that direct other immune cells to the antigen.
Response to rituximab depends on variants in the receptors these
helper cells use.
AME-133v is an anti-CD20 antibody engineered to bind more strongly
to these variant receptors. In preclinical studies, it demonstrated
a 10-fold improved killing power of human B cells, compared with
rituximab, researchers report.
Of the 22 patients treated with AME-133v in this study, 20 had been
treated with rituximab and 18 also had chemotherapy. All were
Fc?RIIIa 158-F carriers. This was a dose escalation study, and
researchers report that the agent was well tolerated at all doses
– 90 percent of patients experienced only grade I adverse
events.
“AME-133v appears to be capable of binding with high
specificity to cell-surface antigens, resulting in targeted killing
of malignant cells, relative sparing of normal tissues, and low
toxicity,” Forero said.
Promising clinical activity of an NAB paclitaxel plus gemcitabine
combination in a disease-specific phase I trial in patients with
advanced pancreatic cancer: Abstract 4179
A novel combination of nanoparticle albumin-bound (nab) paclitaxel
and gemcitabine showed a significant clinical benefit in more than
70 percent of pancreatic cancer patients, according to
researchers.
“Unfortunately most patients with pancreatic cancer have a
very poor survival” said Daniel Von Hoff, M.D., Physician in
Chief of the Translational Genomic Research Institute (TGen) and
Chief Medical Officer for the Scottsdale Clinical Research
Institute at Scottsdale Healthcare in Arizona.
SPARC (Secreted Protein Acidic and Rich in Cysteine) was noted to
be commonly found in pancreatic cancer specimens in an ongoing
Target Now Research Program being performed by Caris-MPI. This
finding, also described by other investigators, was the basis for
this phase I clinical trial that Von Hoff presented here.
“Chemotherapy often means combining more than one drug, and
we do not want to just take the next thing off the shelf. We want
to know as much about a tumor as possible going in,” Von Hoff
said.
In this trial, patients received escalating doses of nab-
paclitaxel (which binds to a potential target SPARC in pancreatic
cancer specimens) from 100 mg/m2 to 150 mg/m2 combined with 1000
mg/m2 of gemcitabine. Researchers from TGen/SHC, Johns Hopkins,
University of Alabama, and South Texas Hematology/ Oncology
reported on the first 20 patients who received nab-paclitaxel 100
mg/m2 of what will eventually be a 42-patient trial. Investigators
assessed tumor response by measuring levels of the cancer marker CA
19-9 and by PET and/or CAT scan. A drop in CA 19-9 levels had been
previously linked in other research with improved survival.
Of the original 20 patients enrolled at the nab-paclitaxel 100
mg/m2 dose, 17 had levels of CA 19-9 that could be evaluated. CA
19-9 levels dropped more than 20 percent in 82 percent of patients,
researchers report. Reductions in CA 19-9 of more than 70 percent
were observed in 64 percent of patients. Utilizing CAT scan
criteria, 9 of the 16 patients (56 percent) who had serial scans
had responses. Twelve of the 16 (75 percent) had responses or
stable disease for more than four months.
“This was a phase I trial, and phase I trials are usually
designed to test safety and hoping for efficacy. The fact that we
saw this kind of activity in a phase I trial is impressive,”
Von Hoff said.
Side effects were considered tolerable. The most common side effect
was low blood counts, followed by fatigue and occasional peripheral
neuropathy (numbness and/or tingling of hands and feet).
Mifepristone abrogates repopulation of ovarian cancer cells in
between courses of cisplatin treatment: Abstract 1210
Researchers from the Sanford School of Medicine at The University
of South Dakota have demonstrated that mifepristone prevents
regrowth of ovarian cancer cells that survive standard
chemotherapy.
“Utilizing a cell culture system, our work provides evidence
that giving mifepristone between courses of cisplatin has the
potential to improve treatment success,” said Carlos M.
Telleria, Ph.D., the study’s senior author and assistant
professor of biomedical sciences at the university.
The regrowth of cancer cells between chemotherapy cycles is a
major treatment challenge, Telleria says. One strategy to prevent
regrowth is the use of drugs like mifepristone, which has been
shown in separate studies to prevent cancer cells from
multiplying.
Telleria and colleagues observed whether mifepristone would prevent
ovarian cancer regrowth if administered with cisplatin. Ovarian
cancer cells in culture were treated with cisplatin at 20 µM
for one hour every 12 days for 36 days. Researchers assessed the
number and viability of cancer cells, and how likely they were to
reproduce, every four days.
Cisplatin killed the majority of cancer cells, but those that
remained were able to reproduce. However, when mifepristone was
added at a dose of 5, 10 or 20 µM the cells, and their
ability to reproduce, decreased.
The larger the dose of mifepristone the stronger the effect; at the
20 µM dose, the cultures contained no cancerous cells to test
by day 12 of the study.
The mission of the American Association for Cancer Research is to
prevent and cure cancer. Founded in 1907, AACR is the world's
oldest and largest professional organization dedicated to advancing
cancer research. The membership includes nearly 27,000 basic,
translational, and clinical researchers; health care professionals;
and cancer survivors and advocates in the United States and more
than 70 other countries. AACR marshals the full spectrum of
expertise from the cancer community to accelerate progress in the
prevention, diagnosis and treatment of cancer through high-quality
scientific and educational programs. It funds innovative,
meritorious research grants. The AACR Annual Meeting attracts more
than 17,000 participants who share the latest discoveries and
developments in the field. Special Conferences throughout the year
present novel data across a wide variety of topics in cancer
research, treatment, and patient care. AACR publishes five major
peer-reviewed journals: Cancer Research; Clinical Cancer Research;
Molecular Cancer Therapeutics; Molecular Cancer Research; and
Cancer Epidemiology, Biomarkers & Prevention. Its most recent
publication and its sixth major journal, Cancer Prevention
Research, is the only journal worldwide dedicated exclusively to
cancer prevention, from preclinical research to clinical trials.
The AACR also publishes CR, a magazine for cancer survivors,
patient advocates, their families, physicians, and scientists. CR
provides a forum for sharing essential, evidence-based information
and perspectives on progress in cancer research, survivorship, and
advocacy.
Media Contact:
Staci Vernick Goldberg
267-646-0616
Staci.goldberg@aacr.org
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Posted: April 2008
