Osteosarcoma - FDA's Oncologic Drugs Advisory Committee (ODAC) voted 12 to 2 that the data in the NDA do not provide substantial evidence of effectiveness of L-MTP-PE
- From: J <nexsw@nvalid,anon>
- Date: Sat, 22 Sep 2007 07:05:03 -0400
http://www.biospace.com/news_story.aspx?NewsEntityId=67694
IDM Pharma, Inc. (IDMI) Receives Not Approvable Letter for Mifamurtide
(L-MTP-PE) for the Treatment of Osteosarcoma
8/27/2007
IRVINE, Calif., Aug. 27 /PRNewswire-FirstCall/ -- IDM Pharma, Inc.
announced today that it received a not approvable letter from the U.S.
Food and Drug Administration (FDA) after completing the review of the new
drug application (NDA) for the investigational drug mifamurtide
(L-MTP-PE), formerly known as Junovan, for the treatment of non-metastatic
osteosarcoma, a rare and often fatal bone tumor that typically affects
children and young adults.
The FDA has requested data from additional clinical trials to demonstrate
the benefit of L-MTP-PE. Additionally, the FDA has requested information
or clarification with respect to other sections of the NDA.
"We continue to strongly believe in the overall survival benefit and
safety profile of L-MTP-PE for the treatment of osteosarcoma and are
committed to obtaining regulatory approval to provide L-MTP-PE to the
critically ill children and young adults who have not had a new treatment
option in more than 20 years," said Timothy P. Walbert, President and
Chief Executive Officer of IDM Pharma, Inc. "In anticipation of a not
approvable letter from the FDA, in July we announced our intent to amend
the current NDA with additional survival data with the goal of bringing
L-MTP-PE to market as quickly as possible. While the FDA has asked for
data from additional clinical trials, we believe that this decision was
made in context of the lack of complete data in the submitted NDA and that
capturing supplemental data will overcome the need for additional trials
and further confirm the overall survival benefit of L-MTP-PE in
osteosarcoma and provide evidence for approvability."
The Company will continue working with the cooperative groups and
investigative sites involved in the study to collect vital status
(information on whether the subjects remain alive or have died) on
patients who participated in the Phase 3 clinical trial and for whom
complete data were not available at the time of filing of the NDA in
October 2006. When the additional follow up data have been collected, the
Company will analyze the data and expects to submit an amendment to the
NDA to the FDA by the first quarter of 2008. In addition to collecting
supplemental Phase 3 data, the Company will address the other points
raised in the FDA action letter.
"While we believe the evidence demonstrating the overall survival benefit
of L-MTP-PE exists, we commend IDM Pharma for their continued investment
in and commitment to working with investigators to collect the most recent
data available," said Matthew Alsante, executive director, Sarcoma
Foundation of America. "As the survival in children with osteosarcoma has
not improved in the last twenty years, gaining approval of investigational
agents with demonstrated improvement in survival is critical."
Conference Call Details
The Company will be holding a conference call on Monday, August 27, 2007
at 4:30 p.m. ET. A webcast of the call will be accessible through the
Company's website at http://www.idm-pharma.com. A replay of the call will
be available on the website for 30 days.
Dial-In Information: U.S. Dial-In: (800) 289-0529 International Dial-In:
913-981-5523 Passcode (both U.S. and International): 4467870
About the mifamurtide (L-MTP-PE) NDA
The L-MTP-PE NDA includes efficacy and safety data from 678 patients with
non-metastatic resectable osteosarcoma, 332 of whom received L-MTP-PE, and
from 115 patients with metastatic or unresectable osteosarcoma, 39 of whom
received L-MTP-PE, in the controlled Phase 3 trial conducted by the
Pediatric Oncology Group (POG) and the Children's Cancer Group (CCG), now
the Children's Oncology Group (COG), sponsored by the Cancer Therapy
Evaluation Program (CTEP) of the National Cancer Institute. Also included
are safety and efficacy data from 51 patients with metastatic osteosarcoma
treated in earlier Phase 2 studies. The biological effects and safety of
L-MTP-PE are further supported by data from 7 other Phase 1 and 2 clinical
studies performed under IND, in which an additional 197 patients received
at least one dose of L-MTP-PE.
L-MTP-PE stimulates the innate immune system (the body's first line of
defense) to kill tumor cells. When administered in combination with
chemotherapy and after tumor resection to osteosarcoma patients in the
Phase 3 trial, L-MTP-PE provided a significant improvement in Disease Free
Survival (DFS) (p = 0.0245) and Overall Survival (OS) (p = 0.0183). At 6
years, the probability of survival when L-MTP-PE is combined with adjuvant
chemotherapy is 77% (95%CI: 72-83%) compared to 66% (95%CI: 59-73%)
without L-MTP-PE, a clinically meaningful finding in a pediatric
population where the longer the survival, the greater the chance the
patient is cured of cancer.
Treatment with L-MTP-PE was generally well tolerated in all phases of
study. Adverse events were mild to moderate in severity and included
chills, fever, nausea, vomiting, myalgia, headache, tachycardia (fast
heart rate), hypo- and hypertension, fatigue and shortness of breath, all
of which are consistent events with the activation of monocytes and
macrophages by L-MTP-PE and the flu-like symptoms that follow cytokine
release.
L-MTP-PE was granted orphan drug status in the United States in 2001. The
NDA for L-MTP-PE was submitted to the FDA in October 2006 and was accepted
on December 26, 2006.
In May 2007, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 12
to 2 that the data in the NDA do not provide substantial evidence of
effectiveness of L-MTP-PE in the treatment of patients with
non-metastatic, resectable osteosarcoma receiving combination
chemotherapy.
IDM Pharma also is seeking marketing approval from the European Medicines
Agency (EMEA) for the use of L-MTP-PE, or MEPACT as it is known in Europe.
L-MTP-PE was granted orphan drug status in Europe in 2004. The Marketing
Authorization Application (MAA) for L-MTP-PE was submitted to the EMEA on
November 1, 2006 and accepted for review on November 27, 2006. The EMEA
application is currently under review and the Company continues to work
closely with the regulatory body to ensure it has the information needed
to approve L-MTP-PE
About Osteosarcoma
About 3% of all childhood cancers are osteosarcoma. Because osteosarcoma
usually develops from osteoblasts, it most commonly affects children and
young adults experiencing their adolescent growth spurt. Boys and girls
have a similar incidence rate until later in their adolescence, when boys
are more commonly affected. While most tumors occur in larger bones, such
as the femur, tibia, and humerus, and in the area of the bone that has the
fastest growth rate, they can occur in any bone. The most common symptom
is pain, but swelling and limited movement can occur as the tumor grows.
Osteosarcoma is an orphan disease with fewer than 1,000 new cases
diagnosed in the U.S. each year. A similar incidence of the disease exists
in Europe. According to the Children's Oncology Group, the survival of
children with osteosarcoma has remained at 60-65% since the mid-1980s. The
standard treatment for osteosarcoma is tumor resection with combination
chemotherapy before and after surgery.
About IDM Pharma
IDM Pharma is focused on the development of innovative cancer products
that either destroy cancer cells by activating the immune system or
prevent tumor recurrence by triggering a specific adaptive immune
response. IDM Pharma is dedicated to maximizing the full therapeutic and
commercial potential of each of its innovative products to address the
needs of patients and the physicians who treat these patients.
For more information about the company and its products, visit
http://cancer.iu.edu/osteosarcoma/patients/intreatment/surgery/limbsalvage.php
Limb-salvage Surgery
Limb-salvage surgery has become the standard of care, except in situations
where it may compromise the outcome.
In 80-90% of patients, a doctor may perform a limb-salvage surgery where
the bone that has cancer is removed and the limb (usually an arm or leg)
is saved from amputation. The challenge for the surgeon is to remove the
entire tumor while still preserving the nearby tendons, nerves, and
vessels. The bone that is removed is replaced by filling the gap with a
bone graft (healthy bone taken from another part of your body) or special
metal rod called an endoprosthesis.
Most patients can walk with the help of crutches within 2 days after
surgery. However, recovery depends on the location of the tumor and the
surgery. Most patients can walk without crutches within 2 weeks. Some
patients with more complex reconstruction and those with bone grafts (as
opposed to metal implants) may need to continue use of crutches for up to
6 to 12 weeks. Every patient undergoes some type of rehabilitation or
physical therapy.
Quick Facts
Osteosarcoma [OS-tee-oh-sar-KO-muh] is the most common type of bone cancer
in children and adolescents, although cancer in young people is rare in
general. Osteosarcoma is most common between the ages of 10 and 25 when
the bones are rapidly growing. In the US 400 new cases of osteosarcoma are
diagnosed per year. Osteosarcoma is potentially curable by combining
chemotherapy (medications that kill cancer cells) with surgical removal of
the tumor.
What is Osteosarcoma?
Osteosarcoma is the most common bone cancer in children and adolescents,
and the third most common cancer in adolescence. Not all bone cancers are
osteosarcomas. Osteosarcoma is a bone tumor that can occur in any bone,
but most frequently occurs in the long bones of the arms and legs near the
growth plates. The most common sites are the thigh bone above the knee,
the shin bone below the knee, and the upper arm bone. Other tumor
locations are the skull or jaw and hip bones. At the time of diagnosis
15-20% of patients have detectable metastases that have spread to the
lungs or other bones. Metastases are collections of cancerous cells that
have spread and are growing at a location different from the original
tumor site.
In the US 400 new cases of osteosarcoma are diagnosed per year. Most
diagnoses are made during adolescence, between ages 10 and 19, and rarely
in young children below five years of age. Osteosarcoma occurs more
frequently in males than females.
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What are the risk factors for Osteosarcoma?
The exact cause of osteosarcoma is unknown and cannot be prevented because
it is associated with random genetic mutations or changes of the bone
forming cells (oteoblasts). However, risk factors (things that increase
the chance of getting cancer) may exist. It is rare, but several diseases
can be passed down from grandparents to parents to children that make the
individual, and in some cases other family members, more likely to develop
many types of cancer, including osteosarcoma. These diseases include
retinoblastoma, Li Fraumeni syndrome, Rothmund-Thomson syndrome, Paget's
disease, and Werner's syndrome. The only known environmental risk factor
is exposure to radiation, as in previous radiation therapy for some other
type of cancer.
More information about these diseases .
What do we know about the biology of osteosarcoama?
Osteosarcoma biology remains a challenge to researchers all over the
world. It is not yet well understood what specifically causes a normal
bone cell to become a cancer cell. The chromosomes in osteosarcoma cells
have complex abnormalities that are different in each tumor. Due to these
changes errors occur in important sequences of events, called "pathways",
which control normal cell growth and also tumor cell growth. Important
pathways controlled by the RB and p53 genes for example lose their ability
to control cell growth which is a major step in the process leading to
cancer.
Understanding the differences between normal bone cells and osteosarcoma
cells has been a high priority in recent osteosarcoma research, with the
goal of designing drugs that specifically attack the cancer cells and
leave the normal cells alone. In addition to much needed improvements in
therapeutic agents, an understanding of the biology of osteosarcoma is
also needed to develop better ways to predict and follow the response of
each individual's tumor to chemotherapy. This would allow treatment to be
customized and individualized to each person for the best possible
treatment for their particular cancer.
What Are Symptoms of Osteosarcoma?
Common signs of osteosarcoma include pain or swelling in or around bones
that does not go away. These symptoms might be worse at night or when
exercising.
It is important to realize that pain and swelling in arms and legs are
common in young people. They result more often from sport injuries than
osteosarcoma. However, if pain or swelling in bones persists, a doctor
needs to be seen.
How is Osteosarcoma Diagnosed?
Imaging studies are performed first to scan the body for possible
osteosarcomas. First an x-ray is taken of the site where symptoms are
occurring. This is followed by a CT scan and/or MRI scan to determine the
extent of the tumor and to look for skip metastases (more than one tumor
site in the same bone). A helical CT scan of the chest and radionucleotide
bone scan of the entire body are used to search for sites to which the
cancer may have spread. Abnormal areas found on the bone scan should be
imaged subsequently using CT scan or MRI.
Biopsy is the best method to diagnose osteosarcoma after the initial
imaging studies have been performed. Biopsy allows for identification of
cancerous cells under the microscope. It is recommended that biopsies be
performed by the surgeon who will perform the operation to remove the
osteosarcoma. Once the osteosarcoma has been confirmed by the biopsy,
chemotherapy is begun to try to shrink the tumor before surgically
removing it.
Once the diagnosis of osteosarcoma has been confirmed by a pathologist,
the oncologist will evaluate the results and assign a stage to the tumor.
Staging means assessing the progress of the tumor, which helps determine
how aggressive the cancer is, whether it has spread, and if so, how
extensive it is. Localized low-grade tumors are stage I, localized
high-grade tumors are stage II, and metastatic tumors are all stage III.
Stages I and II are subdivided into categories A (intracompartmental) and
B (extracompartmental).
This is based on the Musculoskeletal Tumor Society Staging system,
described by Wolf and Enneking, Orthop Clin North Am 27:473-481, as given
in the latest World Health Organization publication on soft tissue and
bone pathology and genetics. Stage III lesions cannot be A, because by
definition they have extended out of the primary site's "compartment".
How is Osteosarcoma Treated?
Osteosarcoma treatment has progressed greatly over the past thirty years.
The standard treatment for patients with conventional osteosarcoma
consists of the combination of chemotherapy and surgery, and in some cases
radiation.
See: Resources for Teens or Parents
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