Phase 1 Clinical Trial for ALK-Driven Childhood Cancers

A pill designed to zero in on abnormal genes that drive specific cancers has produced encouraging early results in children with an uncommon but aggressive type of lymphoma, and in children with a rare form of neuroblastoma. A phase 1 clinical trial of the drug crizotinib achieved remissions, with minimal side effects, for 10 of the children participating in a clinical study carried out by the multicenter Children's Oncology Group (COG). Children's Hospital of Philadelphia researcher Yael Mossé, MD, led the trial. It was the result of nearly two decades of work by collaborating researchers.


Phase 1 Clinical Trial for ALK-Driven Childhood Cancers 

Yaël P. Mossé, MD: Neuroblastoma is a cancer of childhood. It's the most common cancer we see in children who are under the age of one. And other than brain tumors, it's the most common solid cancer that we see in children. There have been some recent progress as we've intensified the treatment and also become a bit smarter about how we give that treatment. But still today in the year of 2012, half of children with the aggressive form of this disease suffer a relapse. That is what fuels my research. In our lab we are dedicated to making discoveries that will impact the clinic. And we have been focused on the rare families where neuroblastoma is inherited, knowing from other diseases like breast cancer that these families can teach us about what drives the cancer. And in 2008, we made the discovery that these families all have abnormalities in the DNA of this gene we now call ALK, which stands for anaplastic lymphoma kinase. It's a gene that when it's turned on, it allows the tumor to grow. And so fortunate for us, it allows us the opportunity to think of ways to turn it off.

John M. Maris, MD: That was found to be the cause of why certain children developed neuroblastoma. But, also, was found to be mutated in the actual tumor cancer cells and, therefore, perhaps was an Achilles' heel, something that was making the cancers grow abnormally and, therefore, can be targeted with the new treatment. If it is a mutation that is making the cancer cell want to grow and divide and keep on spreading, then one can figure out a way to take that "on" switch for a cancer cell and turn it off.

Yaël P. Mossé, MD: Of the eight patients with lymphoma who went on, seven of the eight have had substantial benefit from this drug and their symptoms cleared within days or a couple of weeks of starting this pill. And now all of these patients remain without any evidence of active disease. For the IMT patients, I can say that they've all benefited in one form or the other. They've had either tumor shrinkage or some objective response and all of these have been patients who remain on treatment with the drug. And then for neuroblastoma, the eight who had an ALK mutation that we know of, five of those did not respond. All five of those patients were treated at lower doses. Of the three others with a known ALK mutation, one of them remains on the drug after being on it for ten months and has disease that has been quiet and the patient has excellent quality of life, and the other two are patients who have had complete responses. We think this is very promising for kids who historically have had very few options and little hope. This is a first. It's a first for children who have this rare form of childhood cancer to be able to take a pill, twice a day, and turn off their cancer.

John M. Maris, MD: The integration of this precision type of medicine into frontline therapy is a shining example of the power of modern cancer research.

Yaël P. Mossé, MD: We're now moving into an era where the goal is to make a big difference for a small group of patients rather than making a small difference for a big group of patients. In the past, we made a small difference by giving drugs that are poison for all the cells in our body and aren't selective for the cells that are really the ones responsible for causing the cancer. Now, we're moving into an era where the goal is to specifically, first and foremost, discover what are those cells fueling the cancer. And for a subset of patients it's ALK. And we can now provide very specific tailored therapy, indeed personalized medicine, to improve our chance of curing these patients.

Related Centers and Programs: Cancer Center