Clinical Studies in the Pipeline: The Therapies of Tomorrow in Trials Today
October 23, 2007
SAN FRANCISCO - Studies presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics demonstrate the flexibility of targeted therapy techniques, where new drugs can be developed and tested in human trials more quickly and safely than ever before.
Among the studies presented include a pair of reports on two separate novel insulin-like growth factor receptor enzyme inhibitors, both currently involved in solid tumor clinical trials. In addition, researchers will be offering details on two Phase II trials involving already-approved drugs in new applications: sunitinib in a form of liver cancer and sorafenib, combined with the cell-signaling molecule IL-21, in metastatic renal cancer.
Efficacy, safety, and changes in angiogenic markers following sunitinib monotherapy in patients with advanced hepatocellular carcinoma: Experience from a phase II study: Abstract PR 7.
Use of sunitinib, designed to reduce tumor angiogenesis, appears to offer early evidence of antitumor activity for patients with a difficult to treat liver cancer known as advanced hepatocellular carcinoma (HCC), say researchers at Dana Farber Harvard Cancer Center.
Results from a 30-patient Phase II study in HCC of the agent, which is approved for use in kidney and rare stomach cancers, show that cancer stabilized in 10 patients for at least three months while one patient had a partial response. Overall, the agent offered a progression-free survival of four months, says the study's lead investigator, Andrew X. Zhu, M.D., Ph.D., an attending oncologist at Massachusetts General Hospital Cancer Center and an assistant professor of medicine at Harvard Medical School.
"We have seen preliminary evidence of anti-tumor activity, and although it is modest, it is also encouraging because all of these patients have cancer that cannot be removed by surgery or which has metastasized," Dr. Zhu said. "This is a small, single arm study so there is need for more research to confirm this potential benefit, and to examine safety more closely." The treatment was generally well tolerated in most patients, Dr. Zhu says, but adds that grade three and four toxicities were observed in approximately three to 20 percent of patients, depending on the specific side effect.
HCC is most commonly found in patients with chronic viral hepatitis (B or C) or with cirrhosis, and surgery to remove tumors is only possible in a small percentage of patients. Generally, patients have a poor prognosis because these tumors produce a lot of proteins, such as VEGF and VEGFR2, that make them highly vascular and able to build a solid and nurturing blood supply with increased ability to invade surrounding major vessels and to metastasize, Dr. Zhu says. Sunitinib is a receptor tyrosine kinase inhibitor designed to target and block VEGFR2 activity, among other pro-growth molecules.
To find out if sunitinib could target HCC, the research team employed a number of research tools to measure changes in the patients' blood and tumor perfusion. "Instead of just trying to determine if the drug is attacking the tumor, we want to get a sense of what kind of changes the agent might be inducing," Dr. Zhu said. "We want to know what the mechanisms are that might confer benefit as well as toxicity."
The team used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess changes in the permeability of tumor blood vessels and found that it decreased by an average of 38 percent after two weeks of sunitinib therapy. Using protein arrays to test for angiogenic biomarkers in the blood, the investigators found that the levels of VEGF and PIGF increased, while that of soluble VEGFR2 declined in most patients. Also, flow cytometry analyses of blood cells suggested that circulating endothelial cells increased in some patients while circulating progenitor cells were significantly decreased, indicating that sunitinib may indeed target key angiogenesis pathways in relevant cell populations.
"These are very interesting changes in blood markers induced by sunitinib. Ongoing studies of these and of other markers might help us to understand how the drug works in HCC and what changes might be relevant in predicting the potential clinical benefits in these patients," Dr. Zhu said.
The Harvard Medical School research team involved in this study includes Dushyant Sahani, M.D., and Rakesh K. Jain, Ph.D. The study was funded by Pfizer, Inc., manufacturers of sunitinib (marketed as Sutent).
Recombinant IL-21 in combination with sorafenib: Preliminary results from a phase I/II study in patients with metastatic renal cell cancer: Abstract A 60.
Two drugs appear to work better than one in treatment of patients with metastatic kidney cancer, according to early results from the first and only clinical trial testing a combination of sorafenib and recombinant interleukin-21.
Among 11 patients with renal cell carcinoma who have gone on to have two or more rounds of combination treatment, 10 have experienced tumor shrinkage, and four patients have had 30 percent or greater reduction in tumor size as measured by the investigators. A total of 13 patients have been enrolled so far in this Phase I study, which is testing three different dose levels.
"These preliminary data are encouraging, as treatment with sorafenib alone was associated with a confirmed overall response rate of only two percent in the Phase III trial that led to regulatory approval," said the study's lead investigator, John A. Thompson, M.D., a professor of medicine at the University of Washington and a member of the Fred Hutchinson Cancer Research Center. The study was funded by Zymogenetics, which developed recombinant interleukin-21 (IL-21).
"However, at this point the number of patients treated in our study is still small and it is too early to draw a definite conclusion concerning the efficacy of interleukin-21 in combination with sorafenib compared to use of sorafenib alone," he said. To date, most adverse events seen have been mild and moderate, Dr. Thompson adds.
Because the two drugs work in very different ways and both have low toxicity profiles, the researchers predicted they would have additive or even synergistic effects when used in combination. Pre-clinical studies in mice showed that, indeed, the two together work better than either alone, Dr. Thompson says.
Sorafenib, a tyrosine kinase inhibitor approved for use in December 2005 under the trademark Nexavar, blocks enzymes in cancer cells that promote tumor growth and also blocks blood vessel growth in tumors, thereby depriving the tumor of nutrients and oxygen. "Although sorafenib does not typically cause a large shrinkage of the tumor, it can prevent the tumor from growing further, and has been shown to delay the progression, or growth, of kidney cancer," Dr. Thompson said.
Recombinant IL-21 activates the immune system to kill cancer cells. "Immune therapies have been shown to work in kidney cancer in the past, but those previously available were very toxic and poorly tolerated by most patients. Recombinant IL-21 is well tolerated by most patients," Dr. Thompson said. "In our clinical trial of recombinant IL-21 by itself, we saw encouraging responses in patients with kidney cancer."
Therefore, treatment with sorafenib may make the cancer more susceptible to a killing response by an activated immune system, he says. "We are looking forward to the Phase II portion of the study to better evaluate the overall safety profile and anti-tumor activity," Dr. Thompson said.
Preclinical characterization of OSI-906: A novel IGF-1R kinase inhibitor in clinical trials: Abstract: C192
Preclinical studies suggest that a small molecule inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) may be an effective anticancer drug in patients, and may have even more benefit when combined with the drug erlotinib (Tarceva), say researchers from OSI Pharmaceuticals, Inc.
OSI-906 is the first small molecule that selectively targets the IGF-1R receptor to enter Phase I trials - two multi-center dose escalation studies of patients with advanced solid tumors. The researchers offer their first presentation of the agent's structure and preclinical pharmacology at the 2007 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting.
The insulin-like growth factor receptor (IGF-1R) is an enzyme expressed on the surface of many human cancer cells, and is known to be a driver of tumor growth. OSI-906 blocks IGF-1R activation of the key cancer cell signaling pathways AKT and MAP kinase, researchers say. In laboratory studies of 28 human tumor cell lines, OSI-906 reduced growth of 15 cell lines representative of colorectal, lung, breast, pancreatic, and pediatric tumors and in mouse models. OSI-906 was particularly effective against tumors that are highly IGF-dependent such as colorectal cancers. According to the researchers, OSI-906 not only slowed tumor growth in mice, but decreased the size of some pre-existing tumors.
"Blocking IGF-1R may not always be enough because cancer cells can use other receptors to grow, especially the epidermal growth factor receptor (EGFR) which is known to be activated in many human cancers," said Jonathan Pachter, Ph.D., senior director of Cancer Biology at OSI Pharmaceuticals, Inc. "Therefore, we hypothesized that the combination of OSI-906 to block IGF-1R together with the anticancer drug Tarceva, which blocks EGFR, would lead to even more effective reduction of cancer growth in cellular and animal models."
In mice with human colorectal cancer tumors, oral administration of OSI-906 or erlotinib alone significantly reduced further growth of the tumors. But when the two drugs were combined, tumor growth was fully halted, and the tumors decreased in size by 22 percent, the researchers say.
OSI Pharmaceuticals, which also developed Tarceva, discovered OSI-906 in its research laboratory in Long Island, N.Y.
A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist given weekly in patients with advanced solid tumors: Abstract A 78.
Targeting the receptor for insulin-like growth factor 1 has been a recent trend in cancer drug development. IGF-1 is one of most potent natural activators of the AKT and MAPK signaling pathways which promote cell growth and cell survival. Now, one of the first anti-IGF-1R agents to be tested in a Phase I clinical trial shows the drug to be safe, with few serious side effects and with early evidence of promising benefit in patients with sarcomas.
In a Phase I clinical trial of R1507, a human monoclonal antibody, administered weekly by intravenous infusion, nine of 34 adult patients with advanced solid tumors experienced a period of stable disease, and the seven heavily pretreated patients who remain on study all have sarcomas and show shrinkage or continued lack of growth of their tumors. Four of these patients have Ewing's sarcoma, a rare cancer usually found in children or young adults. These results have led to follow-up studies testing the agent in both pediatric patients and in adults with sarcoma. This study is sponsored by Roche.
"For these patients to have control of their disease implies significant activity, but because the number of patients studied is so small, it is impossible to draw significant statistical conclusions," says one of the study's lead investigators, Stephen Leong, M.D., assistant professor of medical oncology at the University of Colorado Cancer Center.
"This drug and others like it that attack the IGF pathway may provide a new class of drugs to treat a variety of cancers, including breast, prostate, colon, melanoma, myeloma and a variety of sarcomas, which could greatly add to the way that we currently treat these patients," said Dr. Leong.
The researchers found that once a week administration of R1507 was well tolerated with very few side effects and none of those typically associated with cancer therapy, such as low blood counts, risk for infection, hair loss, severe nausea and vomiting. Although the vast majority of side effects were mild - lower than what the researchers classified as grade 3 intensity - there were two serious adverse events (stroke and high bilirubin, a breakdown in red blood cells) in patients while they were on treatment. But it is not certain that the adverse events were caused by the drug, Dr. Leong says. "With a very small number of patients treated, the true and related side effects are still being evaluated," he said.
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