Pediatric Cancer Drugs in the Pipeline

The pediatric cancer drug pipeline may not be completely clogged, but much of the source material is languishing in the reservoir while little is pouring from the spigot to the patients who need it. “It's a stalled process,” said Gregory H. Reaman, MD, Chair of the Children's Oncology Group (COG) and Professor of Pediatrics at George Washington University School of Medicine and Children's National Medical Center. “There are many passionate, enthusiastic investigators in the labs, and the needs of children have never been greater, but there's no interest from pharmaceutical companies. They're not willing to devote the resources necessary to do clinical trials, and without their funding, there's not much we can do.” Is it the same old story of not enough patients to produce sufficient profit? “Yes,” he replied. “There are only 12,000 new cases of pediatric cancer each year. So not only is each type thus an orphan disease, but the whole population of children with cancer is an orphan.” Dr. Reaman explained that the only current clinical trials in children are those with drugs already approved for adult use, due to the possibility of bad effects showing up first in children. He added that the average time to move a drug from adult to pediatric approval is 13 years—of expensive preclinical studies, clinical trials, and uncertainty. That's a big financial risk for minimal eventual profit. Henry S. Friedman, MD, the James B. Powell, Jr. Professor of Neuro-Oncology at Duke University Medical Center, noted that by 2008, the market for cancer drugs will be a $60 billion endeavor—“and drugs for kids are a very small percentage of that,” he said. “In addition to the financial aspect, there are other disincentives in pediatric drug development.Figure: Gregory Reaman, MD: “There are many passionate, enthusiastic investigators in the labs, and the needs of children have never been greater, but there's no interest from pharmaceutical companies. They're not willing to devote the resources necessary to do clinical trials, and without their funding, there's not much we can do.”“There's lots of excellent work going on in laboratories all over the country right now, but it's almost impossible to translate that work to the clinical arena, because companies are concerned about the possibility of a child being harmed. But there's an irony here because in the past 30 years or so more progress has been made in childhood than in adult cancer. “It may be that their tumors are more treatable, but I think it's more social than biochemical,” Dr. Friedman continued. “When an adult has cancer, the person has a life that surrounds the disease—job, family, other obligations. That means you have to go easy on the dosages so he or she can carry on earning a living, taking care of children—all that. “But when a child gets cancer, that's all there is. Everything else falls away: school, soccer practice, Cub Scouts—everything. There is only one mission in life, and that is to cure the cancer, so you can give the maximum dose of very serious drugs and get on with it.” Malcolm Smith, MD, PhD, Associate Branch Chief in Pediatrics of the NCI Cancer Therapy Evaluation Program (CTEP), is more optimistic: “We are moving fairly rapidly into pediatric clinical evaluation and making progress in early phases,” he said. “While it's true that most of the targeted agents are still available only in preclinical or Phase I studies, there is a Phase III trial of rituximab, for example, in lymphoma and leukemia planned for late this year, and there are a number of agents available for clinical trial—most notably imatinib combined with chemotherapy for Philadelphia chromosome-positive ALL.” Drugs Used Now & Coming Along The main three new drugs in pediatric oncology are clofarabine (Clolar), teniposide (Vumon), and imatinib (Gleevec). Clofarabine treats newly diagnosed patients with leukemia. Imatinib, in addition to its original indications in chronic myelogenous leukemia, has now been approved for pediatric leukemias. And teniposide, a podophyllotoxin derivative, is approved for pediatric acute lymphoblastic leukemia, but hardly anyone uses it any more, Dr. Reaman said. The big challenge, said Dr. Smith, is deciding which compounds should go to Phase II and III trials.Figure: Keith L. Black, MD: “Cellular immunity overrides the major limitations of conventional therapy, and activated immune T-cells can cross the blood-brain barrier.” Results so far in about 80 adults with aggressive glioblastoma multiforme show an increase in two-year survival from 8% to 40%.“To do good studies, you need a group of patients with similar characteristics, as well as the same disease at the same stage,” he explained. “That means we can't do more than about one study every four years. So the critical need is to make good decisions about which agents to move forward.” One mechanism to aid that is the Pediatric Preclinical Testing Program, contracted through and funded by CTEP and directed by Peter Houghton, MD, Chair of Molecular Pharmacology and Director of the Solid Tumor Program Project Grant at St. Jude Children's Research Hospital. At about a dozen institutions, using xenografts and cellular models, this program systematically tests 10 to 12 new agents a year to try to predict which could go on to clinical trials. Antiangiogenics on the Horizon As in adult cancers, antiangiogenesis agents are creating rays of hope, albeit dim, for children. Cilengitide (EMD 121974) inhibits two receptor proteins that appear important in the angiogenic process. It is thought to target endothelial cells as well as the tumor itself and to trigger apoptosis. Preclinical studies have shown that the drug to be a potent inhibitor of angiogenesis, with activity in human melanoma, carcinoma, medulloblastoma, and glioblastoma cell lines. Bevacizumab (Avastin), approved for treating adult colorectal cancer, is a humanized monoclonal neutralizing antibody. In vitro it inhibits vascular endothelial growth factor (VEGF)-mediated tumor angiogenesis, and in adults, it produces objective response alone and in combination with cytotoxic drugs. Since VEGF is ubiquitous in human tumors, it stands to reason that VEGF-blocking agents can inhibit tumor growth in children as well. Treating Brain Tumors Brain tumors in children, glioblastoma multiforme (GBM) in particular, have been a very, very difficult problem, with only about 5% of children surviving at least two years. There is no spontaneous remission. “The best chance of finding an effective treatment will be a biologic agent,” predicted Keith L. Black, MD, Director of Neurosurgery at Cedars-Sinai Medical Center in Los Angeles. There are three major reasons conventional therapy fails, he explained: it does not reach the entire volume of the diffuse tumor; it is usually toxic to normal brain tissue; and it does nothing to limit resistance to the therapy. For 10 years Dr. Black has been working on a dendritic cell vaccine and has used it in 80 adults with aggressive GBM. “Cellular immunity is a new approach to treatment and overrides the major limitations of conventional therapy,” he said. “In addition, activated immune T-cells can cross the blood-brain barrier. We take cells from the tumor, strip out the proteins, and attach them to the patient's dendritic cells. Then we inject it subcutaneously.” The results so far show an increase in two-year survival from 8% to 40%. He also retrospectively analyzed survival and progression in 25 vaccinated GBM patients (13 with and 12 without subsequent chemotherapy). Vaccinated patients who received chemotherapy (mainly temozolamide) had significantly better time to progression and longer survival than did patients receiving either vaccination or chemotherapy alone. Dr. Black said he is now ready to try the vaccine in children in a slightly different form. “We'll start with 12 patients with inoperable brain stem glioma, so instead of using cells from the patient's own tumor, we'll purchase proteins and attach them to dendritic cells.”Figure: Henry S. Friedman, MD: “I don't know of one specific pediatric study that is so promising that I'd say it's a home run, but there's lots of research in novel pathways going on out there in the labs with very dedicated people doing it. Things will open up. I'm optimistic.”In addition, the problem of the blood-brain barrier may be diminishing. Data from an NCI-sponsored Phase I trial of 51 patients with GBM were presented at the Ninth Annual Meeting of the Society for Neuro-Oncology in Toronto late last year. The dose-escalation study was designed to determine the maximum tolerated dose (MTD) of cilengitide. Two patients had a complete response, three a partial response, and four had stable disease for more than six months. “These data, although from an early study in a small number of patients, are encouraging in the treatment of an aggressive malignant tumor for which there are few options,” said the principal investigator, L. Burt Nabors, MD, Associate Professor of Neurology at the University of Alabama at Birmingham. NCI is sponsoring a number of trials under a Cooperative Research and Development Agreement with Merck. One combines cilengitide with rituximab in patients with newly diagnosed GBM. Another uses cilengitide as a single agent for recurrent GBM. Another drug, gefitinib, approved for lung cancer, blocks EGFR proteins that are elevated in brain tumors and other tumors that metastasize to the brain. The Pediatric Brain Tumor Consortium is testing gefitinib in a Phase I trial in combination with radiation therapy in newly diagnosed gliomas, and a Phase II trial is evaluating gefitinib's activity in the first GBM relapse. Dr. Friedman has one of the largest brain tumor laboratories in the country. He uses human adult and pediatric central nervous system tumor cell lines and xenografts in rodents to define variables in the search for effective treatment: the chemotherapeutic profile of medulloblastoma, glioma, and ependyoma; mechanisms of resistance to classic alkylators; modulators designed to overcome or circumvent resistance; activity of signal-pathway inhibitors of EGFR and other targets; and therapeutic advantages of intrathecal and intratumoral drug delivery. Results that could lead to therapeutic advances include demonstration of: Marked activity of alkylating agents, particularly melphalan and cyclophosphamide. The role of abnormal drug transport and alterations in formation and repair of DNA in modulating therapeutic cytotoxicity. The profound activity of irinotecan, topotecan, irofulven, and karenitecin. Cytotoxic Agents for the Future Parsepril (PARP) is an oral agent that targets a pro-inflammatory, pro-necrotic nuclear enzyme, poly(ADP-ribose) polymerase. In experimental models PARP prevents oxidant-induced energy depletion and reduces pro-inflammatory signaling and gene expression. Karenitecin (BNP 1350) is a novel camptothecin that shows moderate efficacy in malignant melanoma and other cancers, but its use has been limited because of serious myelosuppression. Although camptothecins in general have antitumor activity, favorable metabolism, and reduced sensitivity to drug resistance, karenitecin is unfortunately turning out to be as toxic to children as it is to adults. Irinotecan, approved for recurrent metastatic colorectal cancer, is highly active in a broad spectrum of cell lines, especially in xenografts derived from pediatric tumors such as neuroblastoma, rhabdomyosarcoma, and peripheral neuroectodermal and CNS tumors. It inhibits topoisomerase I and sets up a chain of events that results in tumor cell death, and is now in Phase I and II trials for brain tumors. Irofulven (MGI 114) has demonstrated broad antitumor effects, especially when used in combination with irinotecan. It is one of a family of acylfulvenes and uses the rapid uptake of the drug in sensitive tumor cell types to cause apoptosis. The drug's developer is sponsoring mono- and combination therapy clinical trials in a variety of malignancies including glioblastoma multiforme. ABT-751, a cytotoxic agent that binds to the colchicine site of β-tubulin, is now being tested in four Phase I and four Phase II trials. Gene Modifiers Dr. Friedman noted the following promising gene-modifying agents for pediatric cancer: Depsipeptide is a histone deacetylase inhibitor isolated from a bacterium. In vitro it has potent activity against many human tumor cell lines, and in vivo it has been shown to inhibit the growth of xenograft tumors in mice. The agent was reasonably well tolerated in a Phase I study, and a trial in children with refractory solid tumors is underway at Stanford University School of Medicine. Decitabine has been granted orphan drug status in Europe and the United States and is well into Phase III trials for myelodysplastic syndrome (MDS). Its mechanism of action is thought to be correction of hypermethylation, an important mechanism for regulation of gene expression. A multicenter American trial of 152 patients follows a successful Phase II European trial of 121 patients, which achieved a 49% response rate with 16% having stable disease. The average duration of remission was nine months, with median survival of 22 months. Because dose-limiting toxicities of alkylating agents and anthracyclines make them poor choices for treating metastatic osteosarcoma, these patients are good candidates for new agents. In addition, recent studies have established a strong correlation between overexpression of HER2 and poor outcome in osteosarcoma. Regarding trastuzumab, a Phase II study of osteosarcoma patients, again at Stanford, will test the feasibility and safety of using trastuzumab in patients whose tumors overexpress HER2. It will be combined with cisplatin and doxorubicin, plus the cardioprotective agent dexrazoxane. A human-mouse chimeric anti-disaloganglioside monoclonal antibody, ch14.18, was the subject of a Phase I trial in 10 patients with refractory neuroblastoma and one with osteosarcoma. There was only one partial response and one patient had stable disease, but biologic activity was evident in the binding of the agent to tumor cells. In a study of 166 children with metastatic neuroblastoma treated with ch14.18, 37% had event-free survival for three years, and overall survival was nearly 57%. Cytoprotective Agents Amifostine ameliorates some of the toxicities of cytotoxic therapy, notably platinum compounds, by promoting the formation and survival of hematopoeitic progenitors, especially in MDS. It also decreases the incidence of granulocytopenia, reduces renal toxicity, and prevents mucositis in patients with osteogenic sarcoma. Small numbers of patients in Phase I and II trials with a variety of cancers have received amifostine. Several had a 50% or greater increase in absolute neutrophil and platelet counts. A small Italian study randomized 30 children with osteosarcoma being treated with cisplatin, carboplatin, and doxorubicin to amifostine or nothing. Vomiting was decreased, and granulocytopenia and leukopenia were significantly less frequent on the amifostine arm. Sometimes chemotherapy works almost too well and causes tumor lysis syndrome as tumor cells are destroyed. Uric acid contained within a tumor, when released at high levels, can overwhelm the kidneys and crystallize. Rasburicase (Elitek) increases the metabolism of uric acid by preventing it from crystallizing in the kidneys. It was tested in children with lymphoma and leukemia, found effective at controlling uric acid levels, and won FDA approval in 2002 for children with cancer. On the Bright Side Everyone interviewed for this article noted that treatments are sitting in laboratories waiting to be tried out, but the vehicles for testing—clinical trials—are not forthcoming. There are, however, ways out of the dilemma. “One way is to have a big presence in adult cancer,” Dr. Friedman said. “Then you have the leverage to convince companies to do pediatric trials. You can finesse your relationship with industry, but first you need to do lots of adult studies.” Accelerate Brain Cancer Cure (ABC2), founded in 2003 in Burlingame, Calif., funds translational research. Its President, John Reher, said that the organization is working with private industry, government, and academia to overcome the technical and economic barriers that drug companies erect to deter development of new therapies. To that end, the organization has established collaborations with Genentech, Duke University (which screens up to 12 new molecules a year at no cost to the companies that provide them), the University of California San Francisco, UCLA, and the University of Texas M. D. Anderson Cancer Center. Genentech conducts extensive brain cancer research, and once it identifies a promising therapy, ABC2 co-funds development to bring it to clinical trial. Genentech also is conducting a Phase III trial of erlotinib, which targets the HER1 pathway, for non-small cell lung cancer and pancreatic cancer. It also shows confirmed activity in glioblastoma, and ABC2 will fund Phase II trials for that indication. The Pediatric Brain Tumor Consortium, established in 1999 and sponsored by NCI, is a network of medical centers that evaluate promising treatments—difficult for a single institution. “No one center sees enough children with brain cancer to conduct clinical studies,” Dr. Smith noted. “The consortium, by involving a number of institutions in joint studies, will be able to evaluate new strategies as quickly as can be safely done.” As of early January, 511 patients have been accrued, 10 protocols opened, and three are in active development. “I don't know of one specific pediatric study that is so promising that I'd say it's a home run,” Dr. Friedman said. “But there's lots of research in novel pathways going on out there in the labs with very dedicated people doing it. Things will open up. I'm optimistic.” Dr. Reaman is too. “Activity in pediatric drug discovery is just beginning,” he said. “I'm filled with hope and expectation that people will realize that they have a moral and social obligation to devote time, expertise, and money to helping children with cancer.” The FDA Perspective “These two things could cause a paradigm shift in the way pediatric research is conducted—away from primary testing in adults with pediatric use as an afterthought. In the future, we will have validated and predictive nonclinical test results to use in simultaneous adult and pediatric studies, and we will be able to move high-priority agents right into international studies.” The Food and Drug Administration is doing its part, although at a bureaucratic pace. The 1998 pediatric rule, part of the FDA Modernization Act (FDAMA), requires manufacturers to assess the safety and efficacy of certain drugs and biological agents in children. The agency can require pediatric studies if a product is already used (off label) in substantial numbers of children and/or if a product would provide meaningful therapeutic benefit over existing treatments. In addition, FDAMA established economic incentives for manufacturers to conduct pediatric studies by extending market exclusivity for six months if companies provide information that the FDA determines is in the best interest of public health. If this sounds like too small a spur, it is. However, the agency is now in a transition phase, said Steven Hirschfeld, MD, Oncology Group Leader of the Office of Cellular Tissue and Gene Therapy for the Center for Biologics Evaluation and Research. 2 Major Trends “There are two major trends,” he said. “The first is awareness of the value of international collaboration. The number of children with cancer in all of western Europe is about the same as it is in the United States, so it will be beneficial to combine clinical trials. In fact, in the past 18 months, the number of these trials has increased.” The International Pediatric Oncology Working Group with representation from several regulatory agencies, professional organizations, cooperative groups, and NCI has met four times since September 2003 to discuss a global framework to facilitate and standardize international collaboration. The recommendations will be published later this year. The second trend is interest in and emergence of nonclinical models for testing pediatric cancer treatments. Dr. Hirschfeld said that NCI is putting forth a major national effort in predictive research: determining what will probably work in the clinical arena and what won't. “These two things could cause a paradigm shift in the way pediatric research is conducted—away from primary testing in adults with pediatric use as an afterthought,” he said. “In the future, we will have validated and predictive nonclinical test results to use in simultaneous adult and pediatric studies, and we will be able to move high-priority agents right into international studies.”

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