Sarcoma Alliance Examines Failure of Promising New Drug

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Sarcoma specialists mourn the loss of palifosfamide, which might have improved the quality of life for their patients.

Dr. Gina D'Amato of Georgia Cancer Specialists

It is such a shame that a great drug will not be approved.

With fewer side effects than standard chemo drugs, palifosfamide showed promise for people with soft-tissue sarcomas, a collection of rare cancers of connective tissue, said Sarcoma Alliance board member Gina D'Amato, MD. But the manufacturer recently stopped its research in sarcoma.

In a news release, Ziopharm reported that palifosfamide, in combination with doxorubicin, didn't show any significant difference from doxorubicin alone in a phase 3 clinical trial called PICASSO. In further statements, the company said FDA approval for sarcoma now appeared impossible.

"It is such a shame that a great drug will not be approved," said Dr. D'Amato, a sarcoma medical oncologist at Georgia Cancer Specialists in Atlanta.

Sarcoma patients have gotten the chemotherapy drug ifosfamide for years, often combined with doxorubicin (also known by its brand name Adriamycin). Palifosfamide was developed to be as effective as ifosfamide, but not as toxic, Dr. D'Amato said.

In the randomized PICASSO trial, doctors didn't know if they were giving patients palifosfamide or a placebo, said Charles Forscher, MD, medical director of Cedars-Sinai Medical Center's sarcoma program in Los Angeles.

Sometimes side effects give clues as to which patients are getting which drugs. But palifosfamide caused so few side effects that doctors couldn't tell which patients got the drug and which got saline injections, said Scott Schuetze, MD, PhD, director of the Connective Tissue Oncology Program and medical director of the Clinical Trials Office at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

He and other sarcoma oncologists say they await the full study results.

"The provisional results ... add to the evidence that doxorubicin alone could be considered standard systemic treatment for metastatic soft-tissue sarcoma," said Robin Jones, MD, who directs the Gilman Sarcoma Research Program at the Fred Hutchinson Cancer Research Center in Seattle.

Last year, he said, a "European trial of doxorubicin versus doxorubicin and ifosfamide showed NO significant difference in overall survival. However, the combination of doxorubicin and ifosfamide had significantly longer progression-free survival and higher response rate compared to doxorubicin alone."

Dr. Robert Maki, MD, PhD, medical director of the sarcoma program at Mount Sinai Medical Center in New York, said a smaller study of palifosfamide + doxorubicin showed a clear benefit, and the larger PICASSO trial was expected to do the same.

"With the failure of palifosfamide in this study, we continue to have no other option than to use ifosfamide, which causes significant side effects affecting the brain, kidney, bladder, and bone marrow," he said. "These side effects of ifosfamide appear to be worse in people over age 60."

Dr. D'Amato said: "This study was designed to show that doxorubicin + palifosfamide would improve the PFS [progression-free survival] by three months compared to doxorubicin. This is very difficult to do. Of course, hindsight is 20/20. They probably should have compared doxorubicin + ifosfamide vs doxorubicin + palifosfamide, and the endpoint should have been noninferiority, tolerability, Quality of Life (QoL). However, I suspect that the FDA encouraged the company to do the trial as the current design and not the latter."

"An even more ambitious design could have involved three randomized arms: doxorubicin + ifosfamide vs doxorubicin + palifosfamide vs doxorubicin," Dr. Jones said. He said it also should have focused on subtypes of sarcoma that had shown response in previous studies.

Another alkylating agent like ifosfamide, TH-302 (glufosfamide), is in clinical trials now, and it also is less toxic than ifosfamide, Dr. Maki said.

"The trial is still enrolling patients," says Dr. D'Amato, "so it will take some time before we have any answers as to whether TH-302 has a chance to be approved."

"We can still hold out hope for TH-302," Dr. Jones added.

The Sarcoma Alliance, based in Mill Valley, Calif., is a national nonprofit that provides information, guidance and support to people affected by sarcoma.

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