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Uncertain Road for Potential Ewing Sarcoma Therapy

Posted Nov 16 2010 12:00am

Uncertain Road for Potential Ewing Sarcoma Therapy

At the 2010 American Society of Clinical Oncology annual meeting , Dr. William Tap of UCLA’s Jonsson Comprehensive Cancer Center described the case of a young patient with Ewing sarcoma , who, as part of a phase I clinical trial , had been treated with an investigational monoclonal antibody , AMG 479. The antibody blocks the activity of a growth factor receptor known as the type 1 insulin-like growth factor receptor, or IGF-1R.

Eight days after the first treatment, the patient’s tumors began to shrink. Three years later, continuing to receive the drug, the patient was still cancer free. Eleven other patients in the trial had tumors in the Ewing family of sarcomas. A second patient experienced some tumor shrinkage but had to leave the trial because of a bone marrow disorder. The remaining 10 patients, Dr. Tap explained, “did not respond to AMG 479 therapy.”

This experience is almost identical to what has been seen in early human trials of other IGF-1R inhibitors, all monoclonal antibodies, in patients with Ewing and other sarcomas: some good responses—including partial tumor shrinkage and sustained periods of stable disease, in addition to a handful of patients with complete tumor eradication—but little more.

In a rare cancer where you have a targeted therapy that you know only a subset of patients are going to respond to, you need big international studies.

—Dr. Lee Helman

“The extent of activity in Ewing sarcoma is nearly identical to what was seen with trastuzumab (Herceptin) in breast cancer when it first went into phase II testing,” said Dr. Laurence Baker of the University of Michigan, who, as director of the Southwest Oncology Group, has been involved in a number of trials testing new treatments for sarcomas.

But Ewing sarcoma affects only 400 to 500 mostly younger patients a year in the United States, in stark contrast with the comparatively vast population of patients who develop breast cancer. And, unlike trastuzumab, which has overexpression of the protein HER2 as a biomarker to identify patients who are most likely to respond to the drug, no such biomarker yet exists for the IGF-1R inhibitors under investigation.

That reality has raised doubts in some corners about whether these agents can complete the often perilous journey to the clinic. Those doubts have even caused one large pharmaceutical company to halt development of its IGF-1R inhibitor.

Nevertheless, the drugs deliver “an unbelievable benefit in some patients,” stressed Dr. Lee Helman, the scientific director of NCI’s Center for Cancer Research , who has been at the forefront of efforts to develop new therapies for Ewing and other sarcomas, including the IGF-1R inhibitors. But, he conceded, “it’s clear we still have a lot of work to do.”

Inching Forward

A phase II clinical trial called SARC 011 was designed to help answer some of the most pressing questions about these agents, including biomarkers that may identify patients who should receive them. Launched by its namesake, the nonprofit Sarcoma Alliance for Research through Collaboration , the trial involved the monoclonal antibody known as R1507, which had been manufactured by Roche. But, in December 2009, while the trial was in progress, Roche announced it was halting development of R1507.

The decision had immediate repercussions. The SARC 011 trial would have to be halted prematurely, at a time when enrollment of an “enrichment cohort”—a group of  patients who, based on data accumulated in the trial, the investigators suspected may be more likely to respond to the drug—was at six patients, when the target was 30. Also, a planned phase II trial combining R1507 with chemotherapy, already approved by the FDA to proceed, would have to be scrapped.

The company’s decision “has been a source of frustration,” Dr. Helman admitted. “I have a patient who has been on [R1507] for the last year,” he said. “She’s back in school and she’s doing well.” Whether this particular agent will resurface, he said, is unknown.

In total, SARC 011 enrolled 321 patients, 135 of whom had Ewing sarcoma. In pursuing the trial, SARC had reached out to other companies developing IGF-1R inhibitors to see if any would support a large international phase II trial but let the SARC investigators control the study, explained the group’s president, Denise Reinke, an oncology nurse at the University of Michigan. They found a partner in Roche.

“Accrual was incredibly brisk,” she explained. “The trial opened in December 2007, and by December 2008 we had 220 patients on the study, and 75 were Ewing patients.”

In order to get a sufficient number of patients for such a rare cancer—enough to supply the statistical power needed to get a good indication of the drug’s efficacy as a single agent—an international trial was needed. “In a rare cancer where you have a targeted therapy that you know only a subset of patients are going to respond to, you need big international studies,” Dr. Helman said.

The rarity of the disease also makes it important to ensure that trials testing new treatments are designed to answer the most important scientific questions, he added, which makes collaboration all the more important.

The SARC 011 trial has concluded and the research team has a manuscript with the most up-to-date findings, Reinke said. In the meantime, with Roche’s exit from this drug class and trials testing IGF-1R inhibitors in more common cancers (including lung and colorectal cancer ) failing to show survival improvements, some researchers are putting a lot of eggs in the SARC 011 basket. The trial’s results “are likely to be pivotal to the future of this family of targeted therapies in sarcoma,” wrote Dr. David Olmos and his colleagues from the Royal Marsden NHS Foundation Trust in London earlier this year.

The Broader Landscape

We don’t understand what is different about those patients who have responded, so [developing biomarkers] is really one of the next critical steps.

—Dr. Suman Malempati

As for the future of these agents, there is near-unanimous consensus about what needs to happen. “We don’t understand what is different about those patients who have responded, so [developing biomarkers] is really one of the next critical steps,” said Dr. Suman Malempati of Doernbecher Children’s Hospital/Oregon Health & Science University, who has been involved in two early-phase trials of an IGF-1R inhibitor called cixutumumab , which is being developed by Imclone under a Cooperative Research and Development Agreement with NCI.

The drugs also need to be tested in combination with cytotoxic therapies, Dr. Baker stressed. “Everything we know suggests that most [targeted therapies] are better in combination than alone,” he said. Based on lab and animal model studies, Dr. Baker continued, “there’s every reason to believe that, if these agents can be combined with chemotherapy, they will have good synergy.”
Testing IGF-1R inhibitors in combination with other therapies should provide “an entrée with indication of how to go forward,” agreed Dr. Jeffrey Toretsky of Georgetown University’s Lombardi Comprehensive Cancer Center. Based on the results in human trials to date, he continued, “I just wouldn’t know how to incorporate them as a single agent into current therapy.”

One combination trial of an IGF-1R inhibitor in sarcoma is moving ahead. Dr. Malempati is leading a pilot study, sponsored by the Children’s Oncology Group (COG), that will test the addition of cixutumumab with or without temozolomide to a multidrug chemotherapy regimen in patients with rhabdomyosarcoma . COG is also in discussions with Pfizer to conduct trials of its IGF-1R inhibitor figitumumab in patients with Ewing sarcoma, said the group’s chair, Dr. Gregory Reaman, which they hope can include a combination therapy trial.

But the onus isn’t all on monoclonal antibodies that target IGF-1R. Several companies also have IGF-1R-targeted small-molecule drugs that may make their way into early human trials. Because they tend to be less specific for their intended targets, small molecules can be a double-edged sword, explained Dr. Malempati. Weaker specificity can be advantageous, he said, “because you may be able to inhibit other processes that aid the cancer.” However, he continued, “it also means that you can have more off-target side effects.” (See the box below.)

Regardless of what kind of agent is used to inhibit its activity, the extent of the therapeutic advantage to be gained by targeting IGF-1R is unclear, Dr. Toretsky believes. But, he continued, enough has been accomplished to date that further research on these agents “needs to be done so that we can fully vet their potential.”

Carmen Phillips

So a Small Molecule Meets a Fusion Protein…

In October 2010, Dr. Toretsky received a nearly $4.4 million grant from NCI, under the American Recovery and Reinvestment Act , to further the development of a small molecule inhibitor that he hopes will prove useful in Ewing sarcoma. The compound, however, doesn’t target IGF-1R. Rather, it targets a fusion protein, EWS-FLI1—the product of a chromosomal translocation in which parts of the EWS and FLI1 genes are fused together—that is present in many Ewing sarcoma tumors and appears to be an important driver of the disease.

Still in the preliminary stages , this approach is highly novel in targeted therapy because the small molecule Dr. Toretsky and his colleagues are investigating is the first to block a fusion protein from adhering to another protein that it requires to drive tumor formation.

“We knew we would have to find critical partners of the fusion in order for it to work,” Dr. Toretsky explained. They eventually found that partner, the protein RNA helicase A (RHA). They then mined an NCI library of 3,000 small molecules to see if any would bind to EWS-FLI1. They were successful, and fortunate, because the same molecule also blocked the fusion protein from binding to RHA. Working with chemists at Lombardi, they developed an analog of this molecule that was a more potent inhibitor of the proteinprotein binding, called YK-4-279.

“The NCI grant provides support for pharmacokinetics, toxicology, and, assuming our studies indicate that it’s a reasonable thing to do, filing of an Investigational New Drug application with the FDA to begin human trials,” Dr. Toretsky explained. The research takes time, but it can’t move fast enough.

“I’m getting two to three e-mails a week from families of patients with Ewing,” he said.


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