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Immunotherapy Clinical Tests Spur Hope, and Plenty of Headaches

Xconomy National — 

Thanks to remarkable results in a small group of patients, including former U.S. President Jimmy Carter, cancer immunotherapy has spurred talk of once impossible-to-imagine cures and has gained its share, perhaps more than its share, of hype.

But immunotherapy is also creating new challenges and exacerbating old ones for doctors, patients, and researchers. These new treatments, which recruit patients’ own immune systems to the fight against tumor cells, are forcing re-assessments of the standards used to gauge a patient’s condition, and complicating clinical trial designs.

Doctors and researchers around the country are worried that patients who want access to a treatment that’s in the headlines will sign up for a clinical trial but drop out if they are assigned to the control group—which usually receives a form of chemotherapy that, until something better is proven out, remains the standard of care.

Trials for cancer drugs are more often “open label” than trials for other kinds of drugs, meaning that volunteers know whether they’re receiving the experimental drug or the control treatment. Blinding many studies is futile, say clinicians. Savvy patients who have done their homework know the telltale side effects of various drugs, and experimental immunotherapies are administered differently than standard chemotherapies.

“A number of patients are sick and tired of chemo, so they’ll roll the dice, knowing they won’t stay on the study” if they are assigned to take chemo, says Andrew Ko, a gastrointestinal cancer specialist at the University of California, San Francisco. “They’re coming from far distances to do something experimental. Patients enter trials with preconceived biases, and I can understand it.”

Ko has seen the problem firsthand. He had patients take part in a pancreatic cancer trial, dubbed ECLIPSE, which compared two kinds of experimental immunotherapy from the Berkeley, CA-based Aduro Biotech (NASDAQ: ADRO) against chemotherapy. Aduro reported in May that more dropouts than expected scuttled the trial. Aduro CEO Steve Isaacs says the design—assigning about a third of the patients to one of several chemotherapy options—was an FDA requirement. “We didn’t have much choice,” he says.

Some doctors aren’t just sympathetic to patients. They actively encourage patients to leave a trial if they don’t get the cutting-edge cancer drug. “I only put patients on trials that may help them, and sometimes the only access to a specific drug is through a trial,” says oncologist Steve Perkins, who sees patients with a wide variety of cancers in Dallas, TX. “I tell them the control arm won’t help you, so if you get randomized to a control arm, drop out and try something else.”

It doesn’t happen often—about once a year, says Perkins—but his practice, staffed by seven oncologists and not affiliated with a large research center, only places about 20 patients in trials per year.

Because so many of the immunotherapy trials currently underway are testing drugs, called “checkpoint inhibitors,” that work in a similiar fashion—a concern that the FDA’s top cancer regulator Richard Pazdur voiced earlier this year—patients in some locations can shop around.

Mary Tagliaferri, vice president of clinical development at Nektar Therapeutics (NASDAQ: NKTR) in San Francisco, agrees with Pazdur. She says companies have an obligation to develop a wider variety of immunotherapy agents—as Nektar is doing—“just as patients and doctors are beholden to ethically complete clinical trials and adhere to what they’ve consented to.”

Perkins has a different view. “My only obligation is to the patient, not to the trial,” he says.

(As part of the Obama administration’s “cancer moonshot” initiative, a panel of experts is weighing in today with recommendations for changes in cancer research and treatment. One recommendation is for a clinical trial network dedicated to immunotherapy.)

Dropouts are not a new problem for clinical trials. But the problem could be starker with some immunotherapies because the gap between their performance and that of the old standard of care is extraordinary for some patients, and others don’t want to be denied the chance at a similar result. “People are coming to get those new drugs, which could be lifesaving even in a Phase 1 setting,” says Scott Lippman, director of the Moores Cancer Center at UC San Diego.

Just how often are patients dropping out of immunotherapy trials after being assigned to the control group? No hard data have emerged yet, but a top cancer statistician says to watch for data from ongoing or recently completed studies of approved drugs like nivolumab (Opdivo) or pembrolizumab (Keytruda) in new types of cancer, or in new combinations. (Pembrolizumab is the drug that knocked out President Carter’s melanoma; the FDA has also approved it for certain lung and head-and-neck cancers.)

“Now that these agents are approved, it might be harder to get people to stay” in trials if they don’t get the immunotherapy, says Brad Hirsch, who at Duke University studied … Next Page »

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