Choosing a Path

Paths of Progress Spring/Summer 2014

What Patients Should Know About Clinical Trials

by Elizabeth Dougherty

Late last winter, Justin Perry set out from his home in Wells, Maine, for an afternoon appointment at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), expecting to begin chemotherapy to treat recently diagnosed stage IV lung cancer. Before lunch, his plans had changed. Results from genetic tests done on his tumor revealed a mutation in the ALK gene that qualified Perry, an active 23-year-old, for a clinical trial of an experimental targeted drug.
Instead of an infusion of chemo, Perry went home with a bottle of pills and, though he didn't know it yet, a new lease on life.

Perry is among the 15 to 20 percent of patients at DF/BWCC who opt to participate in clinical trials. "Without patients who participate, the field would not advance at all. Period. It just wouldn't happen," says Robert Soiffer, MD, chief of Hematologic Malignancies at DF/BWCC.

Clinical trials not only provide new treatment options for current patients, they also make it possible for tomorrow's patients to receive treatments that are better than those available today. For patients to participate, however, they must know which trials are available, how they work, and how science is transforming the drug development process into a faster and more effective mechanism for bringing new treatments to patients everywhere.

Entry Criteria

At the most basic level, the role of clinical trials is to answer critical questions: Does a drug work? Is it safe? How much should be given, how often, and for how long?

To successfully vault from trial to standard use, an experimental agent must pass through several phases of clinical trials, as defined by the Food and Drug Administration.

Trials exist for patients of all stages, from those with stage I cancer, the earliest detectable cancer, to those with stage IV cancer, the most advanced disease. Clinical researchers carefully select which trials to offer, aiming to give a broad range of patients the most promising options available. "You want to open up trials that can move the field forward," says Ursula Matulonis, MD, medical director of Gynecologic Oncology in the Susan F. Smith Center for Women's Cancers at Dana-Farber. "If you have 10 trials looking at the same patient population, you haven't been able to prioritize what's important."

Recurrent cancer, disease that has returned after initial treatment, tends to be harder to treat. In lung cancer, for example, only three drugs have been approved for second-line treatment, fewer than the number approved for first-line treatment. Not only are there fewer options, those approved options have only about a 10 percent response rate, with a duration of just two months. The strong need for second- and later-line treatment options means there are often more trials available for patients who have been previously treated, provided they are healthy enough to participate, says Bruce Johnson, MD, chief clinical research officer and thoracic oncologist at DF/BWCC.

The new Blood Cancer Research Partnership formed by Dana-Farber, the Lymphoma and Leukemia Society (LLS), and the LLS Therapy Acceleration Program is taking aim at another constraint: proximity. For the most part, trials draw participants from the narrow set of individuals who live near — or have the means to visit — a major cancer center, such as DF/BWCC.

"A large number of patients do not have access to sophisticated, cutting-edge clinical trials because of their geographic location," says Soiffer. The Blood Cancer Research Partnership is helping to improve access to trials for those who live far away from major medical centers.

Make Me a Match

Increasingly, trials are based on the genetic features of patients' tumors in an attempt to precisely match treatment to the genetic mutations that are driving the particular cancer. As more of these targeted drugs enter clinical testing, more phase 1 trials are recruiting patients based on the tumor's genetic profile, regardless of the type of cancer. "The goal is to try to use genetic tumor profiling information to make a more intelligent choice about which trial might be helpful to the patient," says Geoffrey Shapiro, MD, PhD, director of the Early Drug Development Center at DF/BWCC.

Such matchmaking is changing the way trials unfold, as illustrated by the story of crizotinib, a drug that inhibits several proteins thought important for cancer growth, including a protein called anaplastic lymphoma kinase (ALK). In 2006, a standard phase 1 trial began testing the drug in patients with all tumor types. "Not much was happening," says Shapiro. In 2007, however, it was recognized that ALK activation occurs in about 5 percent of lung cancers as a result of gene rearrangement. Shortly after, several lung cancer patients with ALK rearrangements in their tumors enrolled. "Lo and behold, they responded."

The trial rapidly morphed to enroll 80 patients who fit the profile. The response rate soared to 61 percent. Approval of the drug occurred soon after, in 2011. "This is the paradigm we should be following in every type of cancer," says William Hahn, MD, PhD, deputy chief scientific officer at Dana-Farber.

Now, next-generation ALK inhibitors are in trials at DF/BWCC, including AF802 and the drug Justin Perry is taking, LDK378, which was awarded Breakthrough Therapy status by the FDA in March 2013 based on positive phase 1 results. When Perry learned that his lung cancer was ALK-positive, he could have taken the already approved therapy, crizotinib. Instead he elected to join a trial of LDK378.

"My cancer was really bad," says Perry. "I figured I could help them learn about this cancer. I could help them out and possibly help myself out, too."

Within four months, 98 percent of Perry's cancer had cleared. He's now been taking LDK378 for 10 months and remains virtually cancer-free.

According to Shapiro, evidence is building that patients enrolled in trials that are considered a good match for their tumor profiles tend to live longer. "Generally patients do better, so the approach has merit," he says. "But there are still many instances where this strategy doesn't work for the patient. It's still experimental."

It is also not clear how long Perry's strong response will last. "If this drug does stop working, they have other trials down the line," says Perry, such as trials testing combinations of therapies to stave off recurrence. "They're constantly working to build newer treatments."

Improved Tools for Research

To begin systematically building the evidence-based matchmaking that has helped rapidly advance targeted cancer treatment, Dana-Farber and Brigham and Women's Hospital teamed in 2011 to launch Profile, a research program that analyzes the DNA in tumor samples of all consenting cancer patients. The program now also includes patients at Boston Children's Hospital. Researchers plan to mine the data collected by Profile to find patterns that suggest, for instance, which treatments work best for a given tumor profile or why some cancers progress while others don't.

More than 20,000 patients have consented to participate and 6,000 tumors have been profiled. Each tumor profile includes information on the genetic coding of more than 300 genes, a panel that includes the key players implicated in cancer.

Profile information is making it easier for trials to follow the crizotinib paradigm by helping researchers home in on the patient population for which a drug is working. The Profile database also allows researchers to readily identify patients who are good matches for a trial without having to take the time to profile each candidate one-by-one during recruitment. With these tools, says Johnson, "we're moving toward faster answers and more effective treatments."

At the same time, traditional cancer delineations are beginning to blur. Some phase 2 and 3 trials are following the lead of phase 1 trials and accepting patients with the same tumor profile but varying types of cancer. "We have a scientifically-based idea about who might respond and we want to test all of those patients," says Hahn, who is seeing enthusiasm build for these so-called umbrella trials. "We're really at the beginning of a new era in clinical trials; one in which there is less empiricism and more science."

More science means better trials, with more precise questions and faster answers. The end result is acceleration, so that doctors can more quickly bring improved treatments to tomorrow's patients – and today's.