FDA panel rejects mifamurtide for osteosarcoma in children

Trial design was flawed, and despite a potential increase in overall survival, there are unanswered questions.

Issue: June 1, 2007

The FDA Oncologic Drugs Advisory Committee voted 12-2 that data on the investigational drug mifamurtide do not demonstrate the drug's efficacy in treating patients with nonmetastatic, resectable osteosarcoma when added to combination chemotherapy.

"Where we are now is where we were years ago," committee member Gregory Reaman, MD, professor of pediatrics at George Washington University in Washington and chair of the Children's Oncology Group, said at the meeting. "There are compelling data and early clinical evidence of activity, but not enough to say that this should be approved and be part of the standard of care for patients with nonmetastatic, resectable osteosarcoma."

The FDA will make a final ruling, and often follows the advice of its panels.

The committee's recommendation is based on the results of INT-0133, a phase-3 trial. Although the results showed a seeming increase in disease-free and overall survival, the original study design was not meant for evaluation in a regulatory setting. The factorial design of the study was intended to independently evaluate both the clinical advantage of mifamurtide (Junovan, IDM Pharma) and the benefit of adding ifosfamide (Mitoxana, ASTA Medica) to treatment. A potential interaction between these interventions, however, undermined the ability to interpret the data.

In a further analysis of previously published data, along with additional follow-up data, researchers found that in the study arm of children who received ifosfamide and mifamurtide, there was a negative but not statistically significant interaction. In the study arm of children who received only the standard chemotherapy and mifamurtide, however, the drug sponsors claimed that benefit was evident.

"Mifamurtide had a clear effect, but there was a pretty big interaction with ifosfamide, which means you can't interpret these results in the usual way," committee member Stephen George, PhD, professor of biostatistics at Duke University Medical Center, said at the meeting. "It's unfortunate that this study design was used. In a regulatory setting, this study is difficult to interpret."

Osteosarcoma

Osteosarcoma affects children and young adults mainly in the femur, tibia and humerus. The disease has orphan status, with less than 1,000 cases diagnosed yearly in the United States. There has been no change in clinical outcome for patients with the disease in the past 20 years.

Mifamurtide is used to prevent recurrence of osteosarcoma and improve long-term survival when combined with surgery and chemotherapy. It works by stimulating the immune system to kill tumor cells.

"There is no doubt that mifamurtide does interact with ifosfamide," committee member Lee Helman, MD, scientific director for clinical research at the Center for Cancer Research of the NCI, said at the meeting. "It was an unexpected finding. Given the data that we have, however, it would be unethical not to do another study that would answer the question."

INT-0133

INT-0133 is the largest and longest randomized, controlled trial ever conducted in young adults and children with osteosarcoma. The clinical development of mifamurtide began in 1986 with phase-1/phase-2 studies in adults with the disease who failed prior therapy. The maximum tolerated dose was established at 4 mg/m² to 6 mg/m².

In a phase-2 study, mifamurtide demonstrated biological activity and an increase in relapse-free survival in patients with recurrent osteosarcoma. The results of this trial led the NCI and the Children's Oncology Group to begin the phase-3 clinical study, INT-0133.

The study was a multicenter, open label, randomized, factorial, four-parallel treatment group study. It was conducted at 178 sites. Enrollment began in 1993 and ended in 1997. Researchers enrolled 793 patients: 678 who had nonmetastatic resectable disease and 115 who had metastatic or unresectable disease. The mean age of the patients was 14. Most of the primary tumor sites were at the femur or tibia.

The patients with nonmetastatic, resectable osteosarcoma were the focus of the original investigation and were the only patients included in the efficacy data. All patients were included for safety data.

The patients were stratified and randomly assigned prior to any therapy to one of four groups. The study was designed to test neoadjuvant ifosfamide in addition to adjuvant mifamurtide. Mifamurtide was the only investigational drug. Ifosfamide was already marketed to treat osteosarcoma.

All patients received chemotherapy with methotrexate, doxorubicin and cisplatin. In regimen A, the patients received chemotherapy alone or chemotherapy plus mifamurtide. Patients in regimen B received chemotherapy and ifosfamide or chemotherapy and ifosfamide with mifamurtide.

Mifamurtide was associated with significantly increased disease-free survival. The six-year probability of surviving without a relapse was 66% in patients who received the drug compared with 57% in patients who did not receive the drug. The FDA's analysis of this data, however, did not support these findings.

Added to chemotherapy

Adding mifamurtide to chemotherapy also had a clinically meaningful and statistically significant increase in overall survival among patients with non-metastatic resectable osteosarcoma, according to the researchers. The six-year survival probability was 77% in patients who received mifamurtide compared with 66% in patients who did not.

The phase-1/phase-2 studies provide the primary safety evidence. The most common grade-1 or grade-2 adverse events included chills, fever, fatigue, nausea, tachycardia and headache. The phase-3 study only collected data on grade-3 and grade-4 toxicities. The only potentially serious adverse effect associated with mifamurtide in this trial was hearing loss. Reports of death and treatment discontinuations were attributed to the disease and not treatment.

Eugenie Kleinerman, MD, professor and head of the division of pediatrics at The University of Texas M.D. Anderson Cancer Center, presented tolerability and benefit/risk data on mifamurtide, as a witness on behalf of the drug's sponsor.

Kleinerman said that the agent has 20 years of data showing minimal adverse effects in children, and the drug could potentially save the lives of about 50 children per year, assuming approximately 600 cases of osteosarcoma are diagnosed per year.

"Although I recognize that this is typically not the responsibility of the FDA, my hope is that effort will be made to ascertain the activity of this agent because of the unmet clinical need, the rarity of the disease, the lack of improvement in patient outcome in more than 20 years, and the fact that this was the largest clinical trial for newly diagnosed osteosarcoma in the world," Kleinerman told Hem/Onc Today. "I don't want to lose the opportunity to have this agent available to treat patients with osteosarcoma. Saving this drug requires a collaborative effort."

Unmet need

There have been many advances in treating childhood cancers, but there still remains a substantial need for improvement, according to Ian Lewis, MD, a pediatric and adolescent oncologist at St. James University Hospital in the United Kingdom. Lewis spoke about this unmet need at the meeting on the sponsor's behalf.

"It's clear that we've reached the limit of survival in patients with osteosarcoma with the currently available conventional chemotherapy," Lewis said. "Data show no change in survival since 1987."

The pediatricians on the advisory committee all agreed that there is no question about the need for better treatment for osteosarcoma. Reaman said that it is important that they do what is best for children, but it is as equally important to measure what is good for children using objective evidence.

The survival data are compelling, committee member Peter Adamson, MD, chief of the division of clinical pharmacology at the Children's Hospital of Philadelphia, said at the meeting. However, it is challenging to believe the evidence given the underlying problem with the trial and the obvious interaction with ifosfamide, which makes the overall survival data difficult to interpret.

"It comes down to where we are with overall survival and the adequacy of that data," Adamson said. "Although I agree that having 80% of survival data available at five years is excellent, there are still events that occur after five years, potentially resulting in significant changes to the curves that could affect conclusions. We need to be really certain that we are confident in this survival analysis, and I have not reached that level of certainty." – by Emily Shafer