Drugs in the pipeline: new therapies that could change treatment strategies

Apr 16 2008

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

Late-breaking data will be presented at the meeting.

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.

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