Expanding Therapy Options for Advanced Cancer

From OncoLog, February 2008, Vol. 53, No. 2

Expanding Therapy Options for Advanced Cancer

by Dianne C. Witter

Twenty-nine-year-old Jamie McMahan was not ready to die. But after her Ewing sarcoma metastasized to her lungs and neither surgery nor chemotherapy stopped its progression, further treatment options were limited, and her prognosis was not good.

That’s when she looked to M. D. Anderson’s Department of Investigational Cancer Therapeutics for alternatives, in the form of early clinical trials of new agents that showed promise in the laboratory. Since its inception in 2004 as the Phase I Program, the department has significantly increased the number of experimental agents available to patients who are essentially out of standard treatment options.

Phase I trials are a gamble; most patients don’t experience a dramatic turnaround in their disease, but a few do. A few more may experience a partial remission or a reduction in tumor size. Traditionally, the primary purpose of phase I trials has been to gather dosing and toxicity data, but these trials also evaluate response to therapy.

“The old way of thinking was that phase I trials should look only at toxicity, that we weren’t looking for response until phase II trials,” said Razelle Kurzrock, M.D., chair of the Department of Investigational Cancer Therapeutics. “Our philosophy is completely different. One of the most important objectives of our trials is to look for response signals and identify which tumor type or types a drug is showing some promise in, then expedite the transition to a phase II study of that drug in that type of cancer.”

Ms. McMahan wasn’t in the lucky minority who benefited from the drug being studied in her first phase I trial; her disease continued to progress despite the new therapy. Nor did she respond to the drugs in her second or third phase I trials.

“Whenever I was told that a treatment wasn’t working, I just asked, ‘What are we going to do next?’” said Ms. McMahan. “Never give up. You never know if the next drug will be the one to work.” Her physician, Robert Benjamin, M.D., worked closely with Dr. Kurzrock, trying to determine which trials would have the best chance of working for her, based on what was known about the biology of her disease.

In December 2006, Ms. McMahan started her fourth trial, that of a monoclonal antibody that targets the insulinlike growth factor-1 receptor. This time, she hit the jackpot. Her tumors shrank remarkably, and she has had a sustained response since that time. She is still receiving therapy and says she is feeling great, has better stamina, and is working full time.

While success stories like this are the exception rather than the rule in phase I studies, they have helped fuel the fast growth of Investigational Cancer Therapeutics. From an initial two active trials, the research has expanded to 71 trials—and the program recently became a formal department.

The goal of the department is to quickly expand the pipeline of newly developed drugs. These drugs are for the most part developed by the pharmaceutical industry. Some are sponsored by the National Cancer Institute, and a small—but increasing—number of new drugs are developed at M. D. Anderson. The department also has several phase I trials looking at new combinations of drugs that are already approved, on the premise that hitting several targets at once may more effectively shrink the tumors.

“We now know a lot more about which molecular changes drive the growth of tumors,” said Dr. Kurzrock. “We try to pick drugs that are likely to have the greatest impact on the signaling pathways that are abnormal in cancer, and then we try to match specific drugs with specific tumor types.” The goal is to make new drugs available to patients for whom standard therapy has been ineffective and to more efficiently move drugs that elicit response in early trials into phase II trials.

People with a variety of cancers are included in any given study, allowing researchers to quickly evaluate the potential effectiveness of a drug or combination therapy across tumor types. This approach can identify efficacies that weren’t apparent in mouse models and that otherwise may never have been identified.

For example, explained Dr. Kurzrock, since the program started, nine drugs that showed unexpected benefits in cancers other than the ones they were developed for have been transitioned into phase II studies for those cancers. For example, the insulin-like growth factor-1 receptor inhibitor Ms. McMahan responded to was not originally developed for Ewing sarcoma, but seeing some dramatic responses in these patients made the investigators rethink how this drug should be developed. It is now entering phase II studies by a global collaboration of sarcoma investigators. The study will look at Ewing sarcoma patients as well as patients with other specific sarcomas that are thought to have the same biological pathways. Similarly, several new drugs elicited response in thyroid cancer, which is rarely studied in preclinical models, and this has led to further trials in this disease.

The most likely candidates for the Department of Investigational Cancer Therapeutics program are patients who have no standard treatment options available, who are in good health other than their cancer, who want experimental treatment, and who can stay in Houston for treatment for 1 to 2 months, Dr. Kurzrock said.

The program also has specialized trials for patients who often have difficulty finding clinical trials appropriate for them, such as people with brain metastasis, those with liver or kidney failure, people older than 60 years, and children.

“We’re entering a whole new era of drug development,” Dr. Kurzrock said. “We want to make sure our early clinical trials are efficiently linking the many patients looking for experimental therapy with the new drugs becoming available.”

For more information or to refer a patient for a phase I study in the Department of Investigational Cancer Therapeutics, contact Christie Carver-Fryer, R.N., B.S.N., at 713-563-9819 or visit www.mdanderson.org/departments/phase1.

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