In Brief

From OncoLog, September 2007, Vol. 52, No. 9

In Brief

Second-line CML Drug Shows Promise as First-line Therapy

Researchers at M. D. Anderson Cancer Center recently reported that nearly all patients taking dasatinib as a first-line therapy for chronic myelogenous leukemia (CML) had a complete cytogenetic response within a year of beginning treatment.

Dasatinib is traditionally used as a second-line therapy for CML, but researchers found that it has high rates of rapid response when used as a first-line therapy in patients newly diagnosed with the disease. The findings were reported at the American Society of Clinical Oncology annual meeting in June.

“We are starting to see very good responses very early with this treatment,” said Jorge Cortes, M.D., professor in the Department of Leukemia and senior investigator on the study. “These results appear to be better than what we see after the same amount of time with the standard first-line drug, imatinib.”

The phase II trial evaluated 31 patients between November 2005 and December 2006. Patients were randomly assigned to receive dasatinib at either 100 mg once daily or 50 mg twice daily. Dr. Cortes and his colleagues noted a complete cytogenetic response, or complete disappearance of the chromosomal abnormality that causes CML, in 77% of evaluable patients at 3 months, 92% at 6 months, and 95% at 1 year. Results for the two dosing regimens were similar.

These responses compare favorably with earlier data on imatinib: at 6 months, complete response rates are 54% at 400 mg daily and 85% at 800 mg daily, and at 12 months, complete response rates are 72% at 400 mg and 92% at 800 mg. Furthermore, the side effects of dasatinib were low grade and manageable in all patients, and there was less toxicity in these patients than in CML patients taking imatinib, according to Dr. Cortes.

When used as a second-line therapy in previous studies, dasatinib had a high level of activity in patients who developed resistance to imatinib, achieving a 40% response in these patients. On the basis of these findings, the researchers hypothesized that dasatinib would produce an earlier response if used first and initiated the current study to test the drug’s efficacy as a first-line therapy for CML.

“In CML, earlier response correlates with a better chance of being alive and well long-term and less of a chance of developing treatment resistance,” said Dr. Cortes.

CML is caused by a genetic abnormality known as the Philadelphia chromosome, which causes production of a protein that sets off a chain reaction resulting in rapid cell growth. Dasatinib (BMS-354825), a multitarget kinase inhibitor, blocks expression of the protein.

So far, 35 CML patients are enrolled in the dasatinib trial. The goal is to enroll 100 patients, follow them for a longer period, and look for other measures of molecular response. “Eventually, there will be a more direct approach, a randomized trial, to test whether dasatinib does indeed work better than standard therapy,” said Dr. Cortes.

To be eligible for the current trial, patients must be age 16 years or older, have a diagnosis of CML with no or minimal prior therapy, have a good performance status, and have normal organ function. For more information, contact Dr. Cortes at 713-794-5783 or askMDAnderson at 1-877-632-6789 (or visit www.mdanderson.org).

Unknown Cancer Origin May Be Determined Using Gene Assay

A soon-to-be commercially available gene assay can help pinpoint the tissue of origin for cancer of unknown primary site (CUP), researchers at M. D. Anderson recently demonstrated. The finding is significant because the advent of targeted therapies and management strategies focused on specific cancers makes it increasingly important to determine the molecular profiles of cancers that constitute the CUP syndrome, said Gauri Varadhachary, M.D., lead author of the study.

CUP, or metastatic disease that presents without a known primary tumor, represents 3–5% of all cancers. Exactly what makes the primary tumor disappear or stay undetectable is not well understood, and advances in imaging have not significantly increased the chances of finding the site of origin, Dr. Varadhachary said.

Using a 10-gene assay developed by Veridex, the researchers prospectively studied metastatic carcinoma tissue samples taken from CUP patients. In the ongoing study, the team found that the test predicted one of six target cancer types in 60% of the 36 patient samples. Preliminary results were presented at the 2007 meeting of the American Society of Clinical Oncology in June.

This is believed to be the first assay of its kind evaluated prospectively in only CUP patients, said Dr. Varadhachary, associate professor in the Department of Gastrointestinal Medical Oncology. It is challenging to conduct such studies to determine tissue of origin in CUP because by definition there is no primary cancer, and researchers must rely on clues from a patient’s pathology, imaging data, and clinical course to indirectly validate the test results.

“Distinguishing the colon cancer profile, for example, from other disseminated CUP is of increasing significance,” Dr. Varadhachary said. “The last 10 years have brought tremendous progress in the treatment of colon cancer. These regimens may have a greater impact in the colon cancer profile subset of CUP.” Future studies will address whether this assay and other profiling studies affect treatment decisions and survival in CUP patients, she said.

Nanoparticles Deliver Tumor-Suppressor Gene

A tumor-suppressor gene has been successfully delivered into the tumors of patients with stage IV non–small cell lung cancer (NSCLC) via intravenously administered lipid nanoparticles in a phase I clinical trial at M. D. Anderson. The technique to incorporate the FUS1 tumor-suppressor gene into DOTAP:cholesterol nanoparticles was developed at M. D. Anderson.

“We’ve treated 13 patients in this first-in-human study, and we’ve seen an exciting proof of concept with no significant drug-related toxicity,” said principal investigator Charles Lu, M.D., associate professor in the Department of Thoracic/Head and Neck Medical Oncology. “The number of patients is too small to draw any definite conclusions about clinical activity, however.”

A blinded analysis of pretreatment and post-treatment biopsies of three patients’ tumors showed that expression of FUS1 was absent from pretreatment samples but present at high levels after treatment. FUS1 can induce apoptosis—programmed cell death—in cells, but the gene’s expression is frequently lost when normal cells become cancerous. It is hoped that restoration of FUS1 will shrink tumors or halt further growth.

Fever has been the only clinically significant side effect, but premedication with dexamethasone and diphenhydramine can prevent it.

The results were presented at the American Association for Cancer Research annual meeting in April.

Previous gene therapy clinical trials involved direct injection of genes into tumors. “This is the first time anyone has shown that a gene can be injected intravenously and then be taken up and expressed in cancer cells at distant sites,” said Jack Roth, M.D., professor in the Department of Thoracic and Cardiovascular Surgery and a pioneer in the field of gene therapy.

Treatment of more patients is planned. For more information, call Jenny Beach, R.N., at 713-563-9156 or Jan Jenkins, R.N., at 713-563-9152.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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