John London wanted to scream in frustration. Penelope, his 4-year-old bike-riding, cupcake-baking daughter, was dying. And the goddamn doctors had nothing left to offer. After three years of chemotherapy, radiation, surgery and a bone marrow transplant, they suggested that John and his wife take Penelope home to enjoy their remaining time together. Instead, John began scanning hundreds of research abstracts from cancer conferences, seeking new treatments.
He spotted a case at the University of Vermont where a child with the same aggressive cancer as Penelope's—neuroblastoma, a cancer that originates in nerve tissue—went into remission after being treated with an anti-parasitic for an unrelated infection. The oncologist overseeing the case, Dr. Giselle Sholler, had followed up on the unexpected remission and had found that the anti-parasitic decreased tumor size in cell lines and mouse models by up to 75 percent.
John wanted the anti-parasitic for Penelope, but it was not approved for use in the U.S., and the manufacturer, Bayer, didn't have any: The U.S. Centers for Disease Control and Prevention (CDC) had stockpiled it for potential outbreaks of Chagas, a potentially deadly infectious disease mostly occurring in Latin America but increasingly seen in parts of the U.S.
Over two months, London enlisted a colleague to help him repeatedly call Bayer, the CDC and the U.S. Food and Drug Administration (FDA), which has the power to grant compassionate-use approval of unapproved drugs. Finally, he succeeded on all three fronts, and Sholler received the anti-parasitic to administer to Penelope. Six weeks later, she was running around a playground.
The Childhood Elephant
An estimated 2,000 children die of cancer each year, and the overall incidence of childhood cancer has been slowly increasing since 1975. Despite significant advances against certain pediatric cancers, including acute lymphoblastic leukemia, there are still some types of cancer for which there are few or no effective treatments. As John London found out, new drug development in the field is slow, often lagging way behind adult treatments, and few compounds are designed specifically for children. "I was on my own, as many parents are," London says. "The medical community had no interest."
That is in large part due to a practical reason: Childhood cancers make up less than 1 percent of all cancers diagnosed each year, according to the American Cancer Society. That 1 percent is not much of a market for drugmakers, who rack up an estimated $1.4 billion in out-of-pocket costs while bringing a novel drug to market. They would never recoup that treating the 700 children diagnosed with neuroblastoma annually, or the 100 diagnosed with diffuse intrinsic pontine glioma, a deadly brain tumor.
"The big elephant in the room is the cost of this type of research," says Raphaël Rousseau, director of pediatric oncology drug development at pharmaceutical giant Roche. Combined with the small potential market, that's led very few pharmaceutical companies to invest in developing drugs for pediatric cancer. Merck has one ongoing pediatric oncology trial. Pfizer is testing preclinical therapies only. Novartis leads the pack, with seven drugs in clinical trials for children's cancer.
Where Big Pharma is absent, government has stepped in. Most pediatric clinical trials are operated by the National Cancer Institute's (NCI) Children's Oncology Group (COG), which runs approximately 40 to 50 therapeutic trials across the country at any one time, according to Peter Adamson, chairman of the organization and a pediatric oncologist at the Children's Hospital of Philadelphia. Yet even with federal funding, pediatric cancer research receives only a fraction of the money that adult cancer research gets, and it's decreasing. In 2013, the NCI invested $185.1 million from a $4.79 billion budget in pediatric cancer research, the lowest amount since 2009.
"The options we have now to be explored are really blossoming, but the funds available to do the studies that need to be done are shrinking," says Richard O'Reilly, chairman of pediatric oncology at Memorial Sloan Kettering Cancer Center, in Manhattan. 'We don't want future generations to look back on this time and ask, 'What the hell were they doing?'"
Still, many oncologists interviewed by Newsweek are optimistic. Numerous initiatives are underway to spur new drug development for children's' cancers, including small nonprofit companies identifying and funding clinical trials for early compounds, and industry- and government-led efforts to develop new clinical trial designs that are more cost-effective. Best of all, there are promising drug therapies, thanks to the breakneck speed of advancing scientific research. The challenge is to make those potential drugs available to children.
Challenge Anger
The antibiotic kept Penelope's cancer at bay for six months before the disease came roaring back. With current therapies, less than 5 percent of children survive relapsed neuroblastoma. Penelope died just shy of her fifth birthday, in May 2007.
A month later, London walked into a dark, half-empty bar in Greenwich Village to meet another parent who had lost a child. The previous November, Scott Kennedy's son Hazen had died at the age of 5 from the same cancer as Penelope. London recognized him by the expression on his face. "It was like looking into a mirror," he says. Three beers later, the fathers had decided to solve children's cancer. "We want to make this an urgent, faster process that cuts right to the chase of the best and most hopeful treatments children can benefit from," Kennedy says.
Faster is a word often on the lips of parents of children with cancer. By some estimates, it takes an average of five years for promising laboratory results to move into clinical trials for pediatric cancer. Then there's an added delay: Drug development is not typically initiated for children until the drug has already made it into phase III clinical trials for adults.
For example, checkpoint inhibitors—drugs that activate the immune system to attack a tumor—are among the most promising cancer treatments. The first such drug, marketed by Merck, was approved to treat adult melanoma in September 2014. Yet clinical trials in children just began this May. It will be years before the same drug is approved for use in children. "It is one of our biggest challenges—getting access to high-priority drugs at an earlier time," says the COG's Adamson. "It has to do with risk aversion."
Companies want to measure the risks and the benefits of a drug in adults first, rather than exposing children to an unknown entity, says Roy Baynes, senior vice president for global clinical development at Merck, who led development of the company's checkpoint inhibitor, Keytruda. So the delay is necessary for safety reasons, he argues.
But Roche's Rousseau points out that children receive and tolerate chemotherapy at much higher doses than adults, and neither adult trials nor mouse studies can tell whether a drug will have long-term side effects on them. Therefore, "there is really no reason to wait," he says. "Preventing children from accessing the drug is nonsense."
London and Kennedy agree, which is why they founded a nonprofit, Solving Kids Cancer—which London initially funded with more than $4 million of his money—to identify, fund and manage small pilot clinical trials to bring promising treatments to clinical trials quickly. Over the past eight years, Solving Kids Cancer has helped bring 19 new drugs into clinical trials that might have otherwise never seen the light of day.
The first study they funded was a phase I trial for Nifurtimox, the anti-parasitic that gave Penelope an extra six months. Led by Sholler, the drug successfully completed phase I safety trials and is now in phase II at 13 cancer centers in the U.S. and Canada. Not long after the Nifurtimox trial, Sholler founded her own clinical trials network, the Neuroblastoma and Medulloblastoma Translational Research Consortium, now 24 hospitals strong. It's part of a growing trend of small trial networks trying to move promising drugs into the clinic more quickly. "We're smaller groups that can get studies open faster, in about a year," says Sholler. "We're really trying to bring new research forward."
Carrot or Stick?
At Roche Pharmaceuticals, the third-largest pharmaceutical company in the world, with $39.5 billion in revenue in 2014, Rousseau has another solution: Big Pharma needs to use its power for good.
If a drug shows promise in children while being developed for adults, companies typically pursue it in pediatrics for one of two reasons: the carrot or the stick. Under the Best Pharmaceuticals for Children Act of 2002 (reauthorized in 2007), drug companies that conduct FDA-requested pediatric studies can receive an additional six months of marketing exclusivity on an patented drug. For a drug that earns $1 billion per year, that's an extra $500 million—for a pediatric study that will cost just a fraction of that.
If that incentive doesn't work, there's the stick. Under the Pediatric Research Equity Act of 2003, the FDA can force a pharmaceutical company to test a new drug in a pediatric population. (However, many companies receive waivers if the condition they are treating is rare or not present in children, such as melanoma.)
Rousseau was a practicing pediatric oncologist and academic researcher for decades before joining Roche in 2009. Now he is trying to prove to large pharmaceutical companies that there is a sustainable model under which they can advance the development of drugs for children—and, though they won't make much money, they won't lose money.
The good news is that Roche is supporting him. In 2010, Rousseau formed a Pediatric Oncology Drug Development team there, which has since grown to 25 members. He's about to initiate a unique study design: a large, multinational, ongoing clinical trial that will test potential drugs in children with differing cancers at the same time, using the same facilities, rules and end points.
Rousseau has two Roche drugs ready to test in the trial. By doing the two together, instead of in two traditional, siloed clinical trials, he estimates the company will save $9 million. If he can reduce the cost of bringing a drug to trial, the patent incentive offered in both the U.S. and Europe might be enough to justify investment in pediatrics. "I'm convinced there is a way forward," he says. If he can prove it, he hopes other companies will follow suit.
But more than any other effort, it may be science—specifically, precision medicine—that will speedily identify effective drugs for children's cancer. This month, the NCI opened the Molecular Analysis for Therapy Choice (MATCH) trial that will analyze patients' tumors for mutations, and then match them with drugs targeting those mutations. As is typical, the MATCH trial has begun first in adults. But the pediatric version is not far behind, says Malcolm Smith, NCI associate branch chief for pediatric oncology. The NCI hopes to initiate it next year.
Many other teams around the country are working on similar efforts. Sholler, for example, now at Helen DeVos Children's Hospital in Grand Rapids, Michigan, has been running trials matching genetic signatures to treatments over the past three years. Her team recently published results showing that the technique stabilized or reduced tumors in eight of 14 children with neuroblastoma.
"Our goal is to make the drugs available to patients," Sholler says. "We try to give [families] more time with their children. Every year, every Christmas, every birthday, matters to a child."
This article is one in a series from Newsweek 's 2015 Cancer issue, exploring challenges and innovations in cancer treatment and research. The complete issue is available online and at newsstands.
