Monday, April 22, 2013

Making sense of the palifosfamide failure

By Suzie Siegel

Sarcoma specialists mourn the loss of palifosfamide, a promising new drug that could have improved the quality of life for their patients.

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

Ziopharm has reported that palifosfamide in combination with doxorubicin didn't show any significant difference from doxorubicin alone in a phase 3 clinical trial called PICASSO. Because FDA approval now appears impossible, the company has said it will no longer study its drug in sarcoma patients.

Dr. Charles Forscher
Soft-tissue 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. 

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.

Dr. Scott Schuetze
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 that 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 of the University of Michigan Comprehensive Cancer Center in Ann Arbor.  

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

Dr. Robin Jones
"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
Robert Maki, MD, PhD, medical director of the sarcoma program at Mount Sinai Medical Center in New York City, said an earlier,  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," Dr. Maki 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.

It also should have focused on subtypes of sarcoma that had shown response in previous studies, he said.

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," said 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.

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