1. Mepact® (mifamurtide) Fulfilling an unmet need in osteosarcoma treatment
Prescribing information can be found at end of the presentation

2. Osteosarcoma Second most common type of primary bone cancer1
Disease of children and young adults2
Most common between ages of years2
Accounts for >10% of all solid tumours in adolescents aged years3
More common in males than females3
Incidence: per 100,000 population in Europe3
Estimated 1,135 new cases every year in Europe1
Osteosarcoma is the second most common type of primary bone cancer [Stiller 2013/P688/Table 2]. It is a disease of children and young adults [Meyers 1997/P973/Abstract] and is most common between ages of years [Meyers 1997/P974/Fig 1]. Osteosarcoma accounts for >10% of all solid tumours in adolescents aged years [ESMO 2012/Pvii100/Col1/Para 2/L2-4].
Osteosarcoma is more common in males than females (the male:female ratio is approximately 1.4:1) [ESMO 2012/Pvii100/Col1/Para 2/L4-5].
The incidence is per 100,000 population in Europe [ESMO 2012/Pvii100/Col1/Para 2/L2]. There are an estimated 1,135 new cases every year in Europe [Stiller 2013/P688/Table 2].
References
1. Stiller CA, Trama A, Serraino D et al. Descriptive epidemiology of sarcomas in Europe: Report from the RARECARE project. European Journal of Cancer 2013;49:
2. Meyers PA and Gorlick R. Osteosarcoma. Pediatric Clinics of North America 1997;44(4):
3. The ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012; 23(7): vii100-vii109
1. Stiller CA et al. Eur J Cancer 2013;49:
2. Meyers PA, Gorlick R. Pediatr Clin North Am 1997;44(4):
3. Bone sarcomas: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23(7): vii100-vii109.

3. Osteosarcoma Most common sites are ends of long bones1
Approximately half of tumours begin around the knee
Around 20% of newly diagnosed patients have detectable lung metastases1
Almost all patients have subclinical microscopic metastases
Death from osteosarcoma is almost always the result of progressive pulmonary metastases
Relapse rate in newly diagnosed patients can be as high as 30%2
Most recurrences occur as lung metastases1
Osteosarcoma is usually found in the metaphysis of a long bone, the most frequent primary site is the distal femur, followed by the proximal tibia and proximal humerus [Meyers 1997/P975/Clinical Presentation/Para 2/L1-4]. Approximately half of tumours begin around the knee [Meyers 1997/P975/Clinical Presentation/Para 2/L4-5].
Around 20% of newly diagnosed patients have detectable lung metastases [Meyers 1997/P975/Clinical Presentation/Para 2/L16-17]. Almost all patients have subclinical microscopic metastases [Meyers 1997/P975/Clinical Presentation/Para 2/L8-9] and death from osteosarcoma is almost always the result of progressive pulmonary metastases [Meyers 1997/P977/L1-2].
Relapse rate in newly diagnosed patients can be as high as 30% [Grimer 2005/P85/Col2/Para 1/L7-8] and most recurrences occur as lung metastases [Meyers 1997/P982/Patients Who Present With Metastatic Disease/Para 1/L3-4].
References
Meyers PA and Gorlick R. Osteosarcoma. Pediatric Clinics of North America 1997;44(4):
Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncology 2005;6:85-92.
Meyers PA, Gorlick R. Pediatr Clin North Am 1997;44(4):
2. Grimer RJ. Lancet Oncol 2005:6:85-92.

4. Minimal improvement in osteosarcoma survival since 1980s
Historical:
Surgery alone
Introduction of chemotherapy
Attempted refinement of chemotherapy
Long term survival in localised high-grade osteosarcoma increased substantially from 10-20% when surgery as a single treatment was the only option, up to 50-60% in the mid 1980s following the introduction of chemotherapy in However, since then no substantial further improvement has been observed and a plateau has been seen for more than two decades [Anninga 2011/P2432/Col1/Para 1/L8-12].
Results of the cooperative group trial conducted by the Children's Oncology Group suggest that the addition of ifosfamide to multi-agent chemotherapy did not enhance overall survival or event free survival, but the addition of Mepact to multi-agent chemotherapy increased 6-year overall survival from 70% to 78% (p=0.03) for localised disease compared to chemotherapy alone [Meyers 2008/P633/Abstract/Results/L2-4].
References
Anninga JK, Gelderblom H, Fiocco M et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47(16):
Meyers PA, Schwartz CL, Krailo MD et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children's Oncology Group. J Clin Oncol. 2008;26(4):633-38
Adapted from: 1. Anninga JK et al. Eur J Cancer 2011;47(16): 4

5. Minimal improvement in osteosarcoma survival since 1980s
Before the 1970s patients underwent amputation and no chemotherapy
Long term overall survival was <20%1
By the mid 1980s long term overall survival up to 50-60%1
Some studies showed better rates, but overall little significant improvement for over three decades1
Meta-analysis of chemotherapy studies showed1:
5 year overall survival of 60% with 2-drug regimen compared with 66% for 3-drug regimen (p=0.04)
No benefit of a fourth drug
Most investigators agree treatment has reached a plateau2
Before the 1970s when patients underwent amputation with no chemotherapy the long term overall survival was <20%. By the mid 1980s, following the introduction of chemotherapy, long term overall survival was up to 50-60% [Anninga 2011/P2432/Col1/Para 1/L8-12 & Fig1]. Some studies showed better rates, but overall there has little significant improvement for over three decades [Anninga 2011/P2432/Col1/Para 1/L11-12 & Fig1].
A meta-analysis of chemotherapy studies showed a 5 year overall survival of 60% with a 2-drug chemotherapy regimen compared with 66% for 3-drug regimen (p=0.04) [Anninga 2011/P2439/Discussion/Para 2/L5-6]. There was no benefit of adding a fourth drug [Anninga 2011/P2440/Col1/Para 1/L2-6].
Most investigators agree that treatment has reached a plateau [Meyers 2009/P1035/Col2/Para 1/L6-10].
References
Anninga JK, Gelderblom H, Fiocco M et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47(16):
Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther 2009;9:
1. Anninga JK et al. Eur J Cancer 2011;47(16):
2. Meyers PA. Expert Revs Anticancer Ther 2009;9:

6. Significant unmet need in osteosarcoma treatment
Today, long-term (5-year) survival for localised disease is 50-60%1
Continuing improvements in survival have been seen for many childhood cancers, but the news is less positive for osteosarcoma2
No improvement in past 30 years despite the introduction of multi-agent chemotherapy1
Therefore, improving overall survival for osteosarcoma patients represents a significant unmet need
Today, long-term (5-year) survival for localised disease is 50-60% [Anninga 2011/P2432/Col1/Para 1/L8-11]. Continuing improvements in survival have been seen for many childhood cancers, but the news is less positive for osteosarcoma [Gatta 2005/P3742/Abstract/Results/L2-4 and & P3745/Table2]. No improvement in osteosarcoma treatment has been seen in the past 30 years despite the introduction of multi-agent chemotherapy [Anninga 2011/P2432/Col1/Para 1/L11-12 & Fig1].
Therefore, improving overall survival for osteosarcoma patients represents a significant unmet need.
References
Anninga JK, Gelderblom H, Fiocco M et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47(16):
Gatta G, Capocaccia R, Stiller C et al. Childhood Cancer Survival Trends in Europe: A EUROCARE Working Group Study. J Clin Oncol 2005;23:
1. Anninga JK et al. Eur J Cancer 2011;47(16):
2. Gatta G et al. J Clin Oncol 2005;23:

7. The potential role of immunotherapy in osteosarcoma
Immunotherapy is a treatment strategy which upregulates the body’s immune response to cancer cells and thus increases tumouricidal activity1
There is a growing body of evidence to support immunotherapy as an effective treatment in osteosarcoma1
Postoperative infection after endoprosthetic surgery has been shown to improve survival outcome which suggested a role for infection-induced anti-tumour immune response2
Immunotherapy is a treatment strategy which works by upregulating the body’s immune response to cancer cells and therefore increases the capacity for tumouricidal activity [Mori 2006/P693/Abstract/Para 1/L15-25]. There is a growing body of evidence to support immunotherapy as an effective treatment option in osteosarcoma [Mori 2006/P693/Introduction/Para 2/L1-11]. One of the current theories posits that postoperative infection after endoprosthetic surgery improves survival outcome which suggests a role for infection-induced anti-tumour immune response. Jeys et al report a 10 year survival of 84.5% in patients who developed a deep infection versus 62.2% in the non-infected group (p=0.017) [Jeys 2007/P /Results Prognostic Factors/Para 2/L1-5].
References
Mori K, Rédini F, Gouin F et al Osteosarcoma: Current status of immunotherapy and future trends (Review). Oncology Reports. 2006;15:
Jeys LM, Grimer RJ, Carter SR et al. Post operative infection and increased survival in osteosarcoma patients: are they associated? Ann Surg Oncol Oct;14(10):
Mori K et al. Oncology Reports 2006;15:
Jeys LM et al. Ann Surg Oncol. 2007;14(10):

8. The evidence for immunotherapy in osteosarcoma
Potential strategies targeting the host immune system include:
Immune modulation (interferon-α1, muramyl tripeptide phosphatidyl ethanolamine MTP-PE2)
Cellular therapy (cytotoxic T-cells, primed dendritic cells3)
Study results cannot be extrapolated across immunotherapeutic agents:
Immunotherapy with interferon-α as an adjuvant therapy has been evaluated following initial encouraging results1 however preliminary data from the EURAMOS-1 trial concluded that there is no evidence to support interferon-α in this setting4
Mepact has demonstrated a proven benefit on overall survival2
There is evidence to support immunotherapy as a potential treatment strategy in osteosarcoma. Included in these strategies are immunomodulation - using agents such as interferon-α [Müller 2005/P475/Abstract/L9] and MTP-PE [Meyers 2008/Col1/L3-9] and cellular therapy, for example cytotoxic T-cells [Mori 2006/P693/Abstract/Para 1/L15-19]. The results with immunotherapeutic agents cannot be extrapolated across all agents. A study by Müller et al showed a potential role for interferon as an adjunctive treatment to chemotherapy [Müller 2005/P475/Abstract/L9] however the subsequent EURAMOS-1 study disputes this. EURAMOS-1 is a large scale, randomised control trial which aimed to optimise treatment strategies for resectable osteosarcoma based on histological response to pre-operative chemotherapy. The preliminary data concluded that there is no evidence of a beneficial effect with the addition of interferon-α [Bielack 2013/Abstract/Conclusions]. The addition of Mepact to multi-agent chemotherapy increased 6-year overall survival from 70% to 78% (p=0.03) for localised disease compared to chemotherapy alone [Meyers 2008/P633/Abstract/Results/L2-4].
References
Müller C et al. Interferon-α as the only adjuvant treatment in high-grade osteosarcoma: Long term results of the Karolinska Hospital series. Acta Oncologica 2005;44:
Meyers PA et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children's Oncology Group. J Clin Oncol 2008; 26(4):
Mori K, Rédini F, Gouin F et al Osteosarcoma: Current status of immunotherapy and future trends (Review). Oncology Reports. 2006;15:
Bielack S et al. MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization. J Clin Oncol 31, 2013 (suppl; abstr LBA10504)
Müller C et al. Acta Oncologica 2005;44:
Meyers PA et al. J Clin Oncol 2008; 26(4):
Mori K et al. Oncology Reports 2006;15:
Bielack S et al. J Clin Oncol 31, 2013 (suppl; abstr LBA10504)

9. Introduction - What is Mepact?
Mepact (mifamurtide) is L-MTP-PE, a liposomal formulation of Muramyl Tripeptide Phosphatidyl Ethanolamine (MTP-PE)1
Liposomal formulation facilitates uptake by tissue macrophages after i.v. infusion
A potent activator of macrophages
L-MTP-PE was initially developed as an immunostimulant with significant anti-tumour effects in preclinical models1,2
MTP-PE is a synthetic analog of muramyl dipeptide (MDP)3
The smallest natural immune stimulatory component of the mycobacterium cell wall1
Mepact (mifamurtide) is L-MTP-PE, a liposomal formulation of Muramyl Tripeptide Phosphatidyl Ethanolamine (MTP-PE) [Nardin 2006/P123/Abstract/L4-6]. L-MTP-PE was initially developed as an immunostimulant with significant anti-tumour effects in preclinical models [Nardin 2006/P123/Abstract/L7] [Fidler 1981/P1680/Abstract/L17-21].
MTP-PE is a synthetic molecule derived from muramyl dipeptide (MDP) the minimal peptidoglycan motif common to both Gram-positive and Gram-negative bacteria [Nardin 2006/P123/Col2/Para2/L1-3]. MDP was discovered in the search to replace heat-killed mycobacteria in Freund's complete adjuvant as an immunostimulant [Fidler 1981/P1680/Col2/Para1/L2-4].
Fidler and colleagues developed a liposomal formulation that, when injected intravenously, distributes primarily in the liver, spleen, and lungs, where it is phagocytosed by monocytes and macrophages [Nardin 2006/P123/Col2/Para3/L13-16].
The liposomal formulation facilitates uptake by tissue macrophages after i.v. infusion [Nardin 2006/P124/Col1/Para1/L5-7]. Like MDP, MTP-PE activates in vitro monocytes and macrophages [Nardin 2006/P124/Col2/Para2/L1-2]. This activation is measured by increased tumouricidal activity and secretion of cytokines and proinflammatory factors [Nardin 2006/P123/Col2/Para3/L2-4]. This was ascribed to the lipophilic properties of MTP-PE, resulting in higher cell uptake via passive transfer through the cytoplasmic membrane, with increased availability for an intracellular receptor [Nardin 2006/P123/Col2/Para3/L7-10].
Formulation of MTP-PE into these phospholipids vesicules improves activation of macrophage and monocyte tumouricidal properties in vitro, and prolongs its presence in the lungs [Nardin 2006/P124/Col1/Para1/L5-8]. In vitro, both free and liposomal MTP-PE are potent activators of monocytes and macrophages. Increased tumouricidal activity on melanoma and sarcoma cell lines has been measured with murine alveolar macrophages or peritoneal macrophages after treatment with this molecule [Nardin 2006/P124/Col2/Para2/L1-6].
References
Nardin A, Lefebvre M-L, Labroquere K et al. Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma. Current Cancer Drug Targets 2006;6:
Fidler IJ, Sone S, Fogler WE et al Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc. Natl Acad. Sci. USA. 1981;78:
Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
1. Nardin A. et al. Current Cancer Drug Targets. 2006;6:
2. Fidler IJ. et al. Proc. Natl Acad. Sci. USA. 1981;78:
3. Mepact SmPC, March

10. Mepact is well studied and characterised
Extensive supporting data at the time of Marketing Authorisation submission (November 2006)
Administered to more than 700 patients in clinical trials1
More than 100 pre-clinical studies1
86 pharmacology studies, 12 pharmacokinetic studies and 20 toxicology studies were submitted as part of the EMA dossier1
Extensive clinical development program
18 Phase I and II studies were submitted as part of EMA dossier1
There is extensive clinical data supporting Mepact. At the time of Marketing Authorisation submission (November 2006) Mepact has been administered to more than 700 patients in clinical trials [EMA Report/P48/Para4/L1] and there were more than 100 pre-clinical studies including 86 pharmacology studies, 12 pharmacokinetic studies and 20 toxicology studies, which were all submitted as part of the EMA dossier [EMA Report/P12/Para8/L1-2].
The extensive clinical development program included18 Phase I and II studies, which were also submitted as part of EMA dossier [EMA Report/P21/Para8/L1-3].
References
EMA Assessment Report for Mepact. Procedure No. EMEA/H/C/ Last accessed 9th July 2013
EMA Assessment Report for Mepact EMEA/H/C/ 10

11. Mepact is well studied and characterised
Robust Phase III clinical data1
Leading paediatric cooperative study group (COG*) clinical trial
One of the largest studies ever completed
Consistent, significant and long-term survival benefit
Almost one third reduction in relative risk of death with an absolute risk reduction of 8% (p=0.03)1
Favourable benefit/risk profile2
Granted Orphan Medicinal Product Status in 20043
One of most studied paediatric oncology drugs
Mepact is one of most studied paediatric oncology drugs. The Phase III study is one of the largest studies ever completed in osteosaroma. It was undertaken by a leading paediatric cooperative study group (Children’s Oncology Group – COG). The results show consistent, significant and long-term survival benefit with almost a one third reduction in relative risk of death with an absolute risk reduction of 8% (p=0.03) [Meyers 2008/P637/Para2/L2-5]. There was also a favourable benefit/risk profile [Meyers 2009/P1-045/Para3/L1-11].
Mepact was granted Orphan Medicinal Product Status in 2004 [EMA/P1/Para1].
In countries where it is possible to create Data on File, the following data from the Mepact Clinical Overview Addendum (13 May 2013) may be used:
As of March 2013
Total patient experience in clinical trials = 1,023 patients [P13/Table5-1]
In addition, patient prescribing since marketing authorisation = approximately 415 patients [P14/Table5-2]
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther 2009;9:
EMA Committee for Orphan Medicinal Products. Public summary of positive opinion for orphan designation of muramyl tripeptide phosphatidyl ethanolamine for the treatment of osteosarcoma. EMEA/COMP/373/04. Last accessed 9th July 2013
* COG – Children’s Oncology Group
Meyers PA et al. J Clin Oncol. 2008;26:
2. Meyers PA. Expert Revs Anticancer Ther 2009;9:
3. EMA. EMEA/COMP/373/04 11

12. Mepact development pathway
In pre-clinical models, Mepact was proven to be an immunostimulant with significant anti-tumour effects1
Anti-tumour effects are macrophage mediated
Direct (activated macrophage tumour killing)
Indirect (cytokine mediated, activation of immune cells)
Liposomal formulation facilitates uptake by tissue macrophages after i.v. injection1
Particularly in lungs, nasopharynx, spleen, liver2
Following pre-clinical models, results in dogs stimulated additional interest in Mepact3
Comparable model for human osteosarcoma
In pre-clinical models, Mepact was proven to be an immunostimulant with significant anti-tumour effect. The anti-tumour effects are macrophage mediated both directly (activated macrophage tumour killing) and indirectly (cytokine mediated, activation of immune cells) [Nardin 2006/P123/Abstract/L8-11].
Liposomal formulation facilitates uptake by tissue macrophages after i.v. injection [Nardin 2006/P123/Col2/Para3/L13-16] with distribution particularly to the lungs, nasopharynx, spleen, liver [Murray 1989/P1923/Fig5].
Following pre-clinical models, results in dogs (which are a comparable model for human osteosarcoma) stimulated additional interest in Mepact [Meyers 2009/P1035/Col2/Para2/L1-5]
References
Nardin A, Lefebvre M-L, Labroquere K et al. Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma. Current Cancer Drug Targets. 2006;6:
Murray JL, Kleinerman ES, Cunningham JE et al. Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol. 1989;7:
Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther 2009;9:
1. Nardin A et al. Current Cancer Drug Targets. 2006;6:
2. Murray JL et al. J Clin Oncol. 1989;7:
3. Meyers PA. Expert Revs Anticancer Ther 2009;9:

13. In a pre-clinical mouse model, Mepact was shown to be most effective when administered 3 days post-surgery*
Day 10
P<0.001
P<0.01
p=0.2
Day 3 post-surgery
Initiation of
Mepact Therapy
Day 7 post-surgery
Day 10 post-surgery
This graph is adapted from Fidler 1986/P171/Fig3.
In this model, metastases are well established by the time of surgical removal of the local tumour [Fidler 1986/P170/Col1/Para4/L1-3]. Treatment with Mepact has significant therapeutic benefit, but the degree of success depends upon the timing of the first treatment. Delay in start of treatment can lead to less therapeutic benefit and indicates that tumour burden is an important factor in the timing of treatment initiation [Fidler 1986/P172/Col1/Para3/L5-8]. The data also suggest that macrophage mediated destruction of large tumour burdens may not be feasible [Fidler 1986/P172/Col2/Para1/L1-3].
References
Fidler IJ. Optimisation and limitations of systemic treatment of murine melanoma metastases with liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Immun Immunother. 1986;21:
* No final conclusions can be made on the impact on humans
Adapted from: Fidler IJ. Cancer Immun Immunother. 1986;21:

14. In a pre-clinical study of canine osteosarcoma Mepact was shown to improve survival compared to placebo*
p < vs placebo liposomes
Mepact 2mg/m2 twice weekly x 8 weeks, n=14
Placebo liposomes
(same schedule), n=13
Cumulative Propprtion Surviving (%) 20 40 60 80
100
Days Post Surgery
200
400
600
800
1000
This graph is adapted from MacEwen 1989/P937/Fig2. The dosages can be found at P936/Para4/L6-11.
Canine osteosarcoma is a spontaneous malignancy in dogs characterized by micrometastasis to pulmonary and extra pulmonary tissues [MacEwen 1989/P935/Abstract/L1-4]. Median survival time is 3-4 months with death due to metastases [MacEwen 1989/P935/Abstract/L7-9]. 14 dogs were treated with liposomal MTP-PE and 13 with empty liposomes, median survival time was 222 days compared with 77 days (p<0.002) – the animals all had amputations [MacEwen 1989/P935/Abstract/L14-22]. In the Mepact group, 4 dogs were still alive and free of metastases more than a year post surgery [MacEwen 1989/P935/Abstract/L22-25] and 2 dogs alive >2 years post surgery [MacEwen 1989/P937/Para1/L4-5]. Interestingly, in the placebo group all 13 dogs died of metastatic disease [MacEwen 1989/P937/Para1/L6-7].
References
MacEwen EG, Kurzman ID, Rosenthal RC et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome encapsulated muramyl tripeptide. J Natl Cancer Inst. 1989;81:
* No final conclusions can be made on the impact on humans
Adapted from: MacEwen EG. et al. J Natl Cancer Inst. 1989; 81:

15. Phase I studies determined maximum tolerated dose and optimal biological dose
Maximum Tolerated Dose 1,2,3 is 4-6 mg/m2
Patients received doses from mg/m2
Optimal Biological Dose 3
Induction of monocyte mediated tumouricidal activity
Within hours of administration
Wide range of doses assessed
Optimal range between mg/m2
Doses above 2 mg/m2 provide little increased effect
Similarity to other biologicals (IFN) that activate monocytes/ macrophages
Recommendation for future studies to be conducted using Optimal Biological Dose3
A number of published Phase I studies at doses up to 12 mg/m2 established:
the maximal tolerated dose to be 4-6 mg/m2 [Murray 1989/P1915/Abstract/Col2/L1], [Creaven 1990/P492/Summary/L7-8], [Kleinerman 1989/P4665/Abstract/L9].
the biologically active dose to be in the range of 0.5-2mg/m2 [Kleinerman 1989/P4665/Abstract/L10].
A wide range of doses were assessed and it was demonstrated that the optimal biological dose of 2 mg/m2 induces monocyte mediated tumouricidal activity within hours of administration. Doses above 2 mg/m2 provide little increased effect [Kleinerman 1989/P4667/Fig1A and P4668/Fig2A]. This effect is similar to other biologicals (IFN) that activate monocytes/ macrophages [Kleinerman 1989/P4668/Col2/Par2/L1-11].
The recommendation was for future studies to be conducted using Optimal Biological Dose [Kleinerman 1989/P4669/Col1/Par3/L6-8]
An excellent overview of all the early Phase I and II studies can be reviewed in Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Reviews Anticancer Therapy 2009;9:
References
1. Murray JL, Kleinerman ES, Cunningham JE et al. Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol. 1989;7:
2. Creaven PJ, Cowens W, Brenner DE et al. Initial trial of the macrophage activator muramyl tripeptide-phosphatidylethanolamine encapsulated in liposomes in patients with advanced cancer. J Biol Res Mod 1990;9:
3. Kleinerman ES, Murray JL, Snyder JS et al. Activation of tumouricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide ethanolamine. Cancer Research. 1989;49:
1. Murray JL et al. JCO 1989;7:
2. Creaven PJ et al. J Biol Res Mod,1990;9:492-8.
3. Kleinerman ES et al. Cancer Res 1989;49:

16. Phase I study determined optimal biological dose
0.05–0.50 mg/m2
0.55–2.0 mg/m2
2.1–6.5 mg/m2 20
*p=<0.05
Change in cytotoxicity (%) 10 **
**p=<0.005 * * *
Time (hr) post administration of Mepact
A Phase I studies established the biologically active dose to be in the range of 0.5-2mg/m2 [Kleinerman 1989/P4665/Abstract/L10].
A wide range of doses were assessed and it was demonstrated that the optimal biological dose of 2 mg/m2 induces monocyte mediated tumouricidal activity within hours of administration. Doses above 2 mg/m2 provide little increased effect [Kleinerman 1989/P4667/Fig1A and P4668/Fig2A]. This effect is similar to other biologicals (IFN) that activate monocytes/ macrophages [Kleinerman 1989/P4668/Col2/Par2/L1-11].
The recommendation was for future studies to be conducted using Optimal Biological Dose [Kleinerman 1989/P4669/Col1/Par3/L6-8]
References
1. Kleinerman ES, Murray JL, Snyder JS et al. Activation of tumouricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide ethanolamine. Cancer Research. 1989;49:
The optimal biological dose of 2 mg/m2 induces monocyte mediated tumouricidal activity within hours of administration
Doses above 2 mg/m2 provide little increased effect
Patients with an initial monocyte-mediated cytotoxic activity <35% (20 of 28 patients)
Adapted from Kleinerman ES et al. Cancer Res 1989;49:

17. *principal site of metastatic disease in osteosarcoma2
Mepact shown to be taken up by macrophages in lungs, nasopharynx, spleen and liver1
spleen
lungs*
nasopharynx
liver
*principal site of metastatic disease in osteosarcoma2
This graph is adapted from Murray 1989/P1923/Fig5.
In this Phase I study in 28 patients with metastatic cancer refractory to standard therapy patients received doses of L-MTP-PE given at mg/m2 [Murray 1989/P1915/Abstract/L1-4]. Treatment was well tolerated [Murray 1989/P1915/Abstract/L12-13] and there was no evidence of cumulative toxicity [Murray 1989/P1919/Col1/Para1/L1-2]. The maximum tolerated dose was 6 mg/m2 [Murray 1989/P1915/Abstract/Col2/L1].
Clear evidence for in situ activation of tumourical properties with monocyte production of IL-1 and acute phase reactants found [Murray 1989/P1922/Col2/Para3/L8-11].
Dose limiting side effects were chills (80% of patients), fever (70% of patients), fatigue (malaise seen in 60%), nausea (55%), vomiting and headache [Murray 1989/P1915/Abstract/L14-15 and P1922/Col2/Para3/L3-5].
In the majority of cases side-effects were experienced with initial doses of Mepact only [Murray 1989/P1923/Fig5].
Radio-labelled liposome uptake in liver, spleen, lung and nasopharynx [Murray 1989/P1922/Col2/Para3/L7]. The principal site of metastatic disease in osteosarcoma is the lung [Meyers 1997/P975/Para3/L13].
The lack of antitumour activity observed was not unexpected since preclinical studies have indicated that macrophage activation is only effective against minimal disease [Murray 1989/P1924/Col2/Para3/L1-6].
References
Murray JL, Kleinerman ES, Cunningham JE et al. Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol. 1989;7:
Meyers PA and Gorlick R. Osteosarcoma. Pediatric Clinics of North America 1997;44(4):
Biodistribution study of a patient receiving 1 mg of Mepact in radio-labelled liposomes
Figure adapted from: 1. Murray J et al. J Clin Oncol. 1989;7:
2. Meyers PA, Gorlick R. Pediatr Clin North Am 1997;44(4):

18. Mepact induces inflammatory macrophage infiltration into lung metastases1
Pre-Mepact
Post-Mepact
A Phase II study demonstrated that liposomal MTP-PE has a biological effect in the lung (5 of 9 patients) [Kleinerman 1992/P211/Summary/L23-24]. 5 patients with osteosarcoma showed histological changes in the characteristics of their pulmonary tumours following liposomal MTP-PE treatment. Peripheral fibrosis surrounded the tumour with inflammatory cell infiltration and neovascularisation present. In contrast, chemotherapy results in a central necrosis with viable peripheral tumour cells present and no inflammatory response [Kleinerman 1992/P214/Col1/Para1/L11-21].
The photo shows immunohistological staining of lung lesions before and after Mepact treatment (the brown-black areas are inflammatory macrophages).
Observations are reiminiscent of the ‘walling off’ seen in the appearance of pulmonary tuberculosis lesions where slow necrosis proceeds from the outside, replacing the lesion with fibrous tissue [Kleinerman 1992/P219/Col1/Para3/L1-4].
References
1. Kleinerman ES, Raymond AK, Bucana CD et al. Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide. Cancer Immunol Immunother. 1992;34:
Photographs kindly supplied by E Kleinerman
1. Kleinerman ES et al. Cancer Immunol Immunother. 1992;34:

19. Measured immunological effects
Activation of macrophages1
Induction of tumouricidal monocytes2
Elevated levels:
IL-12,3
IL-61,3-7
IL-123
C-reactive protein (CRP)1,4,7
Increased levels of β2-microglobulin6
Leukocytosis8
IL-24
IL-83,7
TNF-1,3,4,7
Neopterin4,6-8
Multiple studies have provided evidence for the biological effect of Mepact in patients.
Activation of marcophages [Kleinerman 1992/P1310/Col1/L5-6]
Induction of tumouricidal monocytes [Kleinerman 1989/P4665/Abstract/L7-8]
Elevated levels of:
IL-1 [Kleinerman 1989/P4665/Abstract/L11], [Mepact SmPC/Section5.1/Para3/L4]
IL-2 [Sculier 1993/P276/Summary/L7-9]
IL-6 [Mepact SmPC/Section5.1/Para3/L4], [Kleinerman 1992/P1310/Abstract/Col2/L1-2], [Frost 1990/P160/Summary/L3-4], [Sculier 1993/P276/Summary/L7-9], [Liebes 1992/P694/Col1/L37], [Asano 1993/P286/Summary/L14]
IL-8 [Mepact SmPC/Section5.1/Para3/L4], [Asano 1993/P288/Col2/Para2/L1-2]
IL-12 [Mepact SmPC/Section5.1/Para3/L4]
TNF- [Mepact SmPC/Section5.1/Para3/L4], [Kleinerman 1992/P1310/Abstract/Col2/L1-2], [Sculier 1993/P276/Summary/L7-9], [Asano 1993/P286/Summary/L14]
Increased levels of:
C-reactive protein (CRP) [Kleinerman 1992/P1310/Abstract/Col2/L10-11], [Sculier 1993/P276/Summary/L7-9], [Asano 1993/P286/Summary/L14-15]
neopterin [Sculier 1993/P276/Summary/L7-9], [Liebes 1992/P694/Col1/L34-35], [Asano 1993/P286/Summary/L14-17], [Landmann 1994/P1/Abstract/L9-10]
β2-microglobulin [Liebes 1992/P694/Col2/L1-2]
Leukocytosis [Landmann 1994/P5/Col2/Para1/L1-2 and P6/Fig2A]
References
1. Kleinerman ES, Jia S-F, Griffin J et al. Phase II study of liposomal muramyl tripeptide in osteosarcoma: The cytokine cascade and monocyte activation following administration. J Clin Onco. 1992;10:
2. Kleinerman ES, Murray JL, Snyder JS et al. Activation of tumouricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide ethanolamine. Cancer Research 1989;49:
3. Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
4. Sculier JP, Gerain J, Body JJ et al. A pilot study on a muramyltripeptide lipophilic derivative entrapped into liposomes in patients with advanced non-small-cell lung cancer. Drug Invest. 1993;6:
5. Frost H, Murray JL, Chaudri HA et al. Interleukin-6 induction by a muramyltripeptide derivative in cancer patients. J Biol Response Modifiers. 1990;9:
6. Liebes L, Walsh CM, Chachoua A et al. Modulation of monocyte function by muramyl tripeptide phosphatidylethanolamine in a phase II study with patients with metastatic melanoma. J Natl Cancer Inst. 1992;84:
7. Asano T, Kleinerman ES. Liposome encapsulated MTP-PE: A novel biologic agent for cancer therapy. J Immunother. 1993;14:
8. Landmann R, Obrist R, Denz H et al. Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide. Biotherapy. 1994;7:1-12
1. Kleinerman ES et al. J Clin Onco. 1992;10:
2. Kleinerman ES et al. Cancer Research 1989;49:
3. Mepact SmPC, March
4. Sculier JP et al. Drug Invest. 1993;6:
5. Frost H et al. J Biol Response Modifiers. 1990;9:
6. Liebes L et al. J Natl Cancer Inst. 1992;84:
7. Asano T. Kleinerman ES. J Immunother. 1993;14:
8. Landmann R et al. Biotherapy. 1994;7:1-12.

20. Immunological effects following Mepact infusion
Time of Peak Increase
TNF-
1-2h1
IL-2*
2h2
IL-6
2-3h1
IL-8
C-reactive protein
24h1
Neopterin
MTA (monocyte tumourcidal activity)
72-96h3
The times of peak elevation of cytokines and monocytes following infusion of Mepact provides evidence for the biological effect of Mepact in patients.
Elevated levels of:
TNF- [Asano 1993/P290/Table1]
IL-2 [Sculier 1993/P283/Fig4] (serum level of soluble of IL-2 receptors measured)
IL-6 [Asano 1993/P290/Table1]
IL-8 [Asano 1993/P290/Table1]
C-reactive protein [Asano 1993/P290/Table1]
Neopterin [Asano 1993/P290/Table1]
Monocyte tumourcidal activity [Murray 1989/P1921/Fig4]
References
1. Asano T, Kleinerman ES. Liposome encapsulated MTP-PE: A novel biologic agent for cancer therapy. J Immunother. 1993;14:
2. Sculier JP, Gerain J, Body JJ et al. A pilot study on a muramyltripeptide lipophilic derivative entrapped into liposomes in patients with advanced non-small-cell lung cancer. Drug Invest. 1993;6:
3. Murray JL, Kleinerman ES, Cunningham JE et al. Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol. 1989;7:
* Serum level of soluble of IL-2 receptors measured
1. Asano T. Kleinerman ES. J Immunother. 1993;14:
2. Sculier JP et al. Drug Invest. 1993;6:
3. Murray J et al. J Clin Oncol. 1989;7:

21. Potential multiple pathways for Mepact
Mepact i.v.
Liver & Spleen Macrophages
Monocytes in lung vessels
Activated AM
PMN, DC activation?
Cytotoxicity
TNF-α, IL-6, IL-8, neopterin
Secondary effects?
DC maturation
NK activation
PMN recruitment
This figure is adapted from Nardin 2006/P127/Fig3.
Direct and indirect cellular targets of intravenous administration of Mepact. Tumouricidal macrophages are elicited in lungs, liver and spleen. They secrete cytokines and chemokines that may directly affect the micrometastasis, and increase the recruitment and activation of other cells, including dendritic cells, granulocytes, NK cells [Nardin 2006/P127/Fig3 Commentary]
References
Nardin A, Lefebvre M-L, Labroquere K et al. Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma. Current Cancer Drug Targets. 2006;6:
Inhibition of metastasis
TNF: Tumour Necrosis Factor
IL-6: Interleukin 6
IL-8: Interleukin 8
PMN: Polymorphonucleocytes
DC: Dendritic cells
NK: Natural Killer Cells
AM: Alveolar macrophages
Adapted from:
Nardin A. et al. Current Cancer Drug Targets. 2006;6:

22. Anti-tumour activity of Mepact is mediated by activation of the host immune system1-5
Mepact enters the macrophage where it is broken down to Muramyl Di-Peptide (MDP) which then binds to the NOD-2 receptor [Nardin 2006/P123/Col2/Para3/L13-16] and [Strober 2006/P11/Fig2] . Intracellular pathways are activated which induce cytotoxic function and result in the secretion of numerous cytokines [Mepact SmPC/Section5.1/Para3/L3-4] and [Kleinerman 1989/P4665/Abstract/L11], which along with other recruited and activated immune cells eradicate the micro-metastases [Nardin 2006/P127/Fig3 Commentary] and [Fidler 1981/P1683/Col2/Para1/L1-3].
References
1.Nardin A, Lefebvre ML, Labroquère K et al. Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma. Current Cancer Drug Targets. 2006;6:
2.Strober W, Murray PI, Kitani A et al. Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Rev Immunol. 2006;6:9-20
3.Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
4. Kleinerman ES, Murray JL, Snyder JS et al. Activation of tumouricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide ethanolamine. Cancer Research. 1989;49:
5.Fidler IJ, Sone S, Fogler WE et al. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc. Natl Acad. Sci. USA. 1981;78:
Adapted from:
1. Nardin A et al. Current Cancer Drug Targets. 2006;6:
2. Strober W et al. Nature Rev Immunol. 2006;6:9-20.
3. Mepact SmPC, March
4. Kleinerman ES et al. Cancer Res. 1989;49:
5. Fidler IJ et al. Proc. Natl Acad. Sci. USA. 1981;78:

23. Mepact is given in conjunction with chemotherapy1
Mepact is given in conjunction with chemotherapy [Mepact SmPC/Section4.1/L3]. Almost all patients have subclinical microscopic metastases at diagnosis [Meyers 1997/P975/Clinical Presentation/Para 2/L8-9]. Mepact is added to adjuvant chemotherapy with the aim of eradicating micro-metastases [Fidler 1981/P1683/Col2/Para1/L1-3].
References
1. Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
2. Meyers PA, Gorlick R. Osteosarcoma. Pedr Clin North Am 1997;
3. Fidler IJ, Sone S, Fogler WE et al. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc. Natl Acad. Sci. USA. 1981;78:
The following paper sets out the current treatment of bone sarcomas:
The ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012; 23(7): vii100-vii109
1. Mepact SmPC, March
2. Meyers Ps & Gorlick R. Ped Clin North Am 1997;44:85-92.
3. Fidler IJ. et al. Proc. Natl Acad. Sci. USA. 1981;78:

24. Mepact administration
Supplied as lyophilised powder
Liposome suspensions are formed after hydration of lyophilisate
48 Doses over 36 weeks
2mg/m2
One hour i.v. infusion
First 12 weeks:
Twice weekly
Total 24 doses
Next 24 weeks:
Once weekly
Total 24 infusions
Examples only – replace with vial and pack shots appropriate to your market
Mepact is supplied as a white to off-white homogeneous lyophilised powder in 50mL glass vials [Mepact SmPC/Sections 3 and 6.5]. It consists of the active ingredient and two synthetic phospholipids 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt [OOPS] and 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine [POPC] [Mepact SmPC/Section 6.1]. One vial contains 4 mg mifamurtide [Mepact SmPC/Section 2]
The recommended dose of mifamurtide for all patients is 2 mg/m2 body surface area. It should be administered as adjuvant therapy following resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks [Mepact SmPC/Section 4.2/Para2].
References
Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
Mepact SmPC, March

25. The Children’s Oncology Group Phase III study of Mepact
National Cancer Institute sponsored Children’s Oncology Group (COG) study1,2
Designed and conducted independently of corporate sponsor
enrollment
follow-up
One of the largest studies completed in osteosarcoma
Newly diagnosed patients (enrolled n=793*; age <31)2
662 non-metastatic resectable disease
115 with more metastatic or unresectable disease
Independently analysed and published survival benefit2
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008; 26:
The Mepact phase III National Cancer Institute sponsored Children’s Oncology Group (COG) study is one of the largest studies completed in osteosarcoma. Patients were enrolled from [Meyers 2005/P2005/Col1/Para3/L1-4] and [Meyers 2008/P634/Col1/Para2/L1-3] and followed up until 2007.
Patients recruited had newly diagnosed osteosarcoma. The study enrolled 793 patients aged < patients were considered ineligible with 777 entering the study:
662 non-metastatic resectable disease
115 with more advanced disease (metastatic or unresectable) [Meyers 2008/P634/Col2/Para3/L8-10].
Patient Selection
Study patients had to have histologically confirmed, highgrade, intramedullary osteosarcoma. Initial surgery was specified as biopsy only, but patients who had primary ablative surgery, typically amputation, were eligible. Patients who received any prior chemotherapy or radiation were ineligible. Patients with clinically detectable metastatic disease were eligible at Children’s Cancer Group institutions but ineligible at paediatric Oncology Group institutions. Patients had to have adequate renal function, as defined by serum creatinine <1.5 normal or creatinine clearance more than 40 mL/min/m2; adequate hepatic function, as defined by bilirubin <1.5 normal and AST or ALT <2.5 normal; and adequate cardiac function, as defined by fractional shortening on echocardiogram >29% or ejection fraction by radionuclide angiography >50%. Approval from the institutional review board (IRB) was required at every institution before enrollment. Informed consent was obtained from all patients or their guardians, and the appropriate IRB-approved written informed consent was signed [Meyers 2005/P2005/Col2/Para1].
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
* 777 patients entered the study. 16 were ineligible for treatment
Meyers PA. et al. J Clin Oncol. 2005;23:
Meyers PA. et al. J Clin Oncol. 2008;26:

26. The COG Phase III study Objectives
The study posed two questions in a 2 x 2 factorial design
To compare overall survival and event free survival of a three drug chemotherapy regimen of cisplatin, doxorubicin and high-dose methotrexate with a four drug regimen using these agents with ifosfamide
Whether the addition of Mepact to chemotherapy would improve overall survival or event free survival
The study posed two questions in a 2 x 2 factorial design:
To compare overall survival and event free survival of a three drug chemotherapy regimen of cisplatin, doxorubicin and high-dose methotrexate with a four drug regimen using these agents with ifosfamide
Whether the addition of Mepact to chemotherapy would improve overall survival or event free survival
[Meyers 2008/P634/Col1/Para2/L5-13]
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
Meyers PA et al. J Clin Oncol 2008;26:

27. The COG Phase III study Factorial design
Induction
Maintenance
3 drugs
Cisplatin
Doxorubicin
High-Dose Methotrexate
CIS, DOX, HDMTX
Without Mepact (A-)
With Mepact (A+)
Ifosfamide
4 drugs
IFOS, CIS, DOX, HDMTX
Without Mepact (B-)
With Mepact (B+)
Regimen A
Regimen B
The factorial design is valuable in clinical trials research by enabling two (and occasionally more) treatment issues to be evaluated simultaneously in the same study/with same participants (in a cost effective way). The simplest and most commonly used approach is the 2 x 2 factorial where patients are randomised to one of four options. In principle this enables the merits of both treatments to be evaluated without increasing the required number of patients, by making available two analyses of results.
The Mepact study has a 2 x 2 factorial design with two factors where each factor creates a separate question to be addressed. The two factors are:
the chemotherapy factor (two different chemotherapy regimens of either 3- or 4-drug regimens)
the Mepact factor (with or without Mepact).
Patients were randomly assigned at study entry to one of four treatment arms. There were two chemotherapy arms:
a 3-drug regimen A (cisplatin, doxorubicin and high-dose methotrexate)
a 4-drug regimen B (ifosfamide, cisplatin, doxorubicin and high-dose methotrexate)
and within these regimens patients were randomly assigned to receive Mepact or not.
There were four treatment arms:
A- Regimen A without Mepact
A+ Regimen A with Mepact
B- Regimen B without Mepact
B+ Regimen B with Mepact.
This study was designed to compare results from either:
those patients who received Mepact (A+/B+) vs those who did not receive Mepact (A-/B-)
those patients on 3-drug chemotherapy regimen A (A+/A-) vs those on 4-drug chemotherapy regimen B (B+/B-).
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
During induction phase Regimen A patients received 2 doses of cisplatin (CIS) and Regimen B patients received 2 courses of ifosfamide (IFOS)
During maintenance therapy all patients received doxorubicin (DOX) and high-dose methotrexate (HDMTX) plus:
Regimen A: 2 doses of cisplatin
Regimen B: 3 courses ifosfamide + 4 doses cisplatin
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

28. The COG Phase III study Design overview
RANDOMI
SATION
INDUCTION
D E F I N I T I V E S U R G E R Y H I
STOLOG
CAL
EVALUAT ON
MAINTENANCE A
Cisplatin
Doxorubicin
HDMTX
Cisplatin, Doxorubicin, HDMTX A-
Cisplatin, Doxorubicin, HDMTX, Mepact
Ifosfamide, Cisplatin, Doxorubicin, HDMTX, Mepact A+ B- B
Ifosfamide
Doxorubicin
HDMTX
Ifosfamide, Cisplatin, Doxorubicin, HDMTX
This diagram has been adapted from Meyers 2005/P2005/Fig1.
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
Methodology
This multi-center, randomised, open-label study was conducted in three phase: induction therapy, surgery, maintenance therapy.
Within 30 days of a new diagnosis of high-grade osteosarcoma, patients were randomly assigned to one of four treatment groups and received 10 weeks of neoadjuvant induction therapy with one of two chemotherapy regimens. In the induction phase, Regimen A consisted of cisplatin, doxorubicin and high-dose methotrexate and Regimen B consisted of ifosfamide, doxorubicin and high-dose methotrexate.
Definitive surgery was performed between Weeks 10 to 11, during which patients received no study medication. Beginning at Week 12, patients in Regimen A received maintenance therapy that consisted of cisplatin, doxorubicin and high-dose methotrexate with (A+) or without (A-) Mepact. Maintenance therapy for patients in Regimen B consisted of ifosfamide, cisplatin, doxorubicin and high-dose methotrexate with (B+) or without (B-) Mepact.
Regimen A consisted of four courses of cisplatin 120 mg/m2 over 4 hours combined with doxorubicin 75 mg/m2 administered as a 72-hour continuous infusion administered twice during induction at weeks 0 and 5 and twice during maintenance at weeks 12 and 17. An additional two courses of doxorubicin without cisplatin were administered at weeks 22 and 27. HDMTX 12 g/m2 with a maximum dose of 20 g was administered as a 4-hour infusion followed by leucovorin administration at 10 mg (not adjusted to body-surface area) beginning 24 hours from initiation of methotrexate infusion and continuing until the serum methotrexate level was less than 1x10-7 mol/L (100 nmol/L). Serum methotrexate levels and renal function were monitored daily, and hydration, alkalinisation, and leucovorin doses were specified in the event of delayed methotrexate excretion. HDMTX was administered 12 times, four times during induction at weeks 3, 4, 8, and 9 and eight times during maintenance at weeks 15, 16, 20, 21, 25, 26, 30, and 31. To maintain dose-intensity of doxorubicin, the protocol specified that, if there was a delay greater than 1 week between the first and second of each pair of HDMTX administrations, the second was omitted.
Regimen B included ifosfamide 1.8 g/m2/d with mesna uroprotection for 5 days; a total dose of 9 g/m2 was administered five times, twice during induction at weeks 0 and 5 and three times during maintenance at weeks 17, 27, and 35. The first four courses of ifosfamide were to be administered with doxorubicin. Cisplatin 120 mg/m2 was administered four times, all during maintenance, at weeks 12, 22, 32, and 38. The first two courses of cisplatin were scheduled to be administered with doxorubicin. Doxorubicin and methotrexate were administered at the same doses and in the same weeks as Regimen A.
Total doses of cisplatin, doxorubicin, and HDMTX were the same in the two arms (cisplatin 480 mg/m2, doxorubicin 450 mg/m2, and HDMTX 144 g/m2). Timing of doxorubicin and HDMTX was the same in both arms. Patients assigned to Regimen B received ifosfamide during induction to maximise its effect on tumour response. Thus, from the perspective of evaluating tumour necrosis, Regimen B could be considered a substitution of ifosfamide for cisplatin.
Patients assigned to receive Mepact in the maintenance phase received twice weekly injections for 12 weeks followed by once weekly injections for an additional 24 weeks. The starting dose of Mepact was 2 mg/m2. The dose could be escalated twice (to 2 mg/m2 + 1 mg and then to 2 mg/m2 + 2 mg) until signs of biologic activity were seen, defined as fever, chills or an increase in the C-reactive protein. Mepact treatment was not interrupted for delays in chemotherapy.
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26: B+ 20 27 36
Weeks
Regimens A and B: Doxorubicin x 6 ea (25 mg/m2/day x 3), Cisplatin x 4 ea (120 mg/m2), and Methotrexate x 12 ea (12 g/m2)
Regimen B only: Ifosfamide x 5 ea (1.8 g/m2/day x 5)
HDMTX = High-Dose Methotrexate;
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

29. Dose schedule: induction phase
The COG Phase III study
Dose schedule: induction phase
Week
Regimen A
Regimen B
CIS + DOX
IFOS + DOX 1 2 3
HDMTX 4 5 6 7 8 9
10-11
SURGERY
Drug doses
Cisplatin: 120 mg/m2 four hours infusion
Doxorubicin: 75 mg/m2 72 hour continuous infusion
High-dose methotrexate: 12 g/m2 (max 20 g) four hour infusion followed by leucovorin 10 mg (fixed dose) 24 hours after start HDMTX continuing until serum high dose methotrexate < 1 x 10-7 mol/L (100 nmol/L)
Ifosfamide: 1.8 g/m2 for five days (total dose 9 g/m2 (with mesna uroprotection)
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
CIS: cisplatin; DOX: doxorubicin; HDMTX: high-dose methotrexate; IFOS: ifosfamide
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

30. Dose schedule: maintenance phase
The COG Phase III study
Dose schedule: maintenance phase
Drug doses
Cisplatin: 120 mg/m2 four hours infusion
Doxorubicin: 75 mg/m2 72 hour continuous infusion
High-dose methotrexate: 12 g/m2 (max 20 g) four hour infusion followed by leucovorin 10 mg (fixed dose) 24 hours after start HDMTX continuing until serum high dose methotrexate < 1 x 10-7 mol/L (100 nmol/L)
Ifosfamide: 1.8 g/m2 for five days (total dose 9 g/m2 (with mesna uroprotection)
Mepact: 2 mg/m2, with an additional 1 mg or 2 mg (maximum) at subsequent dosing according to patient biologic activity
Week
Regimen A-
Regimen B-
Regimens A+ and B+ 12
CIS + DOX
Mepact twice weekly 13
(for 12 weeks) 14 15
HDMTX 16 17
IFOS + DOX 18 19 20 21 22
DOX 23
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
CIS: cisplatin; DOX: doxorubicin; HDMTX: high-dose methotrexate; IFOS: ifosfamide
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

31. Week 31 = end of treatment for Regimen A-
The COG Phase III study
Dose schedule: maintenance phase cont.
Drug doses
Cisplatin: 120 mg/m2 four hours infusion
Doxorubicin: 75 mg/m2 72 hour continuous infusion
High-dose methotrexate: 12 g/m2 (max 20 g) four hour infusion followed by leucovorin 10 mg (fixed dose) 24 hours after start HDMTX continuing until serum high dose methotrexate < 1 x 10-7 mol/L (100 nmol/L)
Ifosfamide: 1.8 g/m2 for five days (total dose 9 g/m2 (with mesna uroprotection)
Mepact: 2 mg/m2, with an additional 1 mg or 2 mg (maximum) at subsequent dosing according to patient biologic activity
Week
Regimen A-
Regimen B-
Regimens A+ and B+ 24
Mepact once weekly 25
HDMTX
(for 24 weeks) 26 27
DOX
IFOS + DOX 28 29 30 31
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
Week 31 = end of treatment for Regimen A-
CIS: cisplatin; DOX: doxorubicin; HDMTX: high-dose methotrexate; IFOS: ifosfamide
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

32. Regimens A+ and B+ Mepact treatment continued until
The COG Phase III study
Dose schedule: maintenance phase cont.
Drug doses
Cisplatin: 120 mg/m2 four hours infusion
Doxorubicin: 75 mg/m2 72 hour continuous infusion
High-dose methotrexate: 12 g/m2 (max 20 g) four hour infusion followed by leucovorin 10 mg (fixed dose) 24 hours after start HDMTX continuing until serum high dose methotrexate < 1 x 10-7 mol/L (100 nmol/L)
Ifosfamide: 1.8 g/m2 for five days (total dose 9 g/m2 (with mesna uroprotection)
Mepact: 2 mg/m2, with an additional 1 mg or 2 mg (maximum) at subsequent dosing according to patient biologic activity
Week
Regimen A-
Regimen B-
Regimens A+ and B+ 32
CIS
Mepact once weekly 33
(for 24 weeks) 34 35
IFOS 36 37 38
Full details of scheduling and dosing can be found in Meyers 2005 and on the following slides [Meyers 2005/P2005-6/Treatment]
References
1. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
2. Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol 2008;26:
Week 38 = end of treatment for Regimen B-
Regimens A+ and B+ Mepact treatment continued until
week 47
CIS: cisplatin; DOX: doxorubicin; HDMTX: high-dose methotrexate; IFOS: ifosfamide
1. Meyers PA et al. J Clin Oncol 2005;23:
2. Meyers PA et al. J Clin Oncol 2008;26:

33. According to Treatment Regimen Overall Survival Probability (%)
The COG Phase III study
Results
According to Treatment Regimen
Treatment Regimen
Event-Free Survival
Probability (%)
Overall Survival Probability (%)
4 years
6 years
All patients 66 64 81 74
All patients on 3-drug chemotherapy
Regimens A- and A+ 65 63 80 73
All patients on 4-drug chemotherapy
Regimens B- and B+ 67 82 75
All patients who did not receive Mepact
Regimens A- and B- 61 78 70
All patients who received Mepact
Regimens A+ and B+ 69 84
The 2005 publication by Meyers et al is an intermediate analysis. The 2008 paper reports overall survival and event-free survival, the 2005 paper only event-free survival [Meyers 2005/P2004/Abstract/Results] and [Meyers 2008/P633/Abstract/Results]. In 2005 the study could not be analysed for survival because the first analysis of survival was planned after half of the anticipated deaths estimated from a priori probability. In 2005, half the predicted number of deaths had not occurred [Meyers 2009/P1044/Col2/Para4/L5-8].
The table shows event free survival and overall survival for the four treatment arms which can be compared within the factorial analysis. The two questions to be addressed by this study were:
Whether a 3-drug chemotherapy regimen of cisplatin, doxorubicin and high-dose methotrexate differs in terms of event-free survival and overall survival from a 4-drug regimen using these agents with ifosfamide
Whether the addition of Mepact to chemotherapy would improve overall survival or event free survival.
The chemotherapy regimens, either 3-drug or 4-drug, resulted in similar event-free and overall survival.
Both event-free survival and overall survival were improved in patients who received Mepact compared with those who did not. The addition of Mepact to chemotherapy improved 6-year overall survival to 78%, compared to 70% with chemotherapy alone (p=0.03) [Meyers 2008/P633/Abstract/Results/L3-4]. Six-year event-free survival was improved from 61% for chemotherapy alone to 67% for those patients who received Mepact (p=0.08) [Meyers 2008/P635/Col2/Para1/L6-11].
The hazard ratio for 6-year overall survival with the addition of Mepact was 0.71 (95% CI, ) [Meyers 2008/P635/Col2/Para2/L16-18].
The hazard ratio for 6-year event-free survival with the addition of Mepact was 0.80 (95% CI, 0.62 to 1.0) [Meyers 2008/P635/Col2/Para1/L9-11].
The clear conclusion is that the addition of Mepact to chemotherapy resulted in improved overall survival and event-free survival.
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: A Randomised, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther 2009;9:
3-drug and 4-drug chemotherapy resulted in similar event-free (63 vs. 64%) and overall survival (73 vs. 75%)
Both event-free survival and overall survival were improved in patients who received Mepact compared with those who did not (61 vs. 67% and 70 vs. 78%, respectively)
Adapted from: 2. Meyers PA. et al. J Clin Oncol. 2008;26:

34. The effect of Mepact with chemotherapy compared to chemotherapy alone on overall survival
Overall survival: HR = 0.71, which translates to an almost one third reduction in the risk of death (absolute risk reduction 8%, p=0.03) vs. chemotherapy alone [Meyers 2008/P637/Col2/Para2/L2-5].
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
Overall survival: HR = 0.71, which translates to an almost one third reduction in the risk of death (absolute risk reduction 8%, p=0.03) vs. chemotherapy alone
Adapted from: Meyers PA et al. J Clin Oncol. 2008;26:

35. The effect of Mepact with chemotherapy compared to chemotherapy alone on event-free survival
The addition of Mepact resulted in improved event-free survival of 67% compared with 61% for chemotherapy alone (p=0.08) HR = 0.80 [Meyers 2008/P635/Col2/Para1/L6-11].
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
The addition of Mepact resulted in improved event-free survival of 67% compared with 61% for chemotherapy alone (p=0.08) HR = 0.80
Adapted from: Meyers PA et al. J Clin Oncol. 2008;26:

36. Results of the Mepact with our without multi-agent chemotherapy on overall survival
The addition of Mepact to chemotherapy:
Improved 6-year overall survival from 70% to 78% (p=0.03)
Improved 6-year event-free survival from 61% to 67% (p=0.08)
Reduced the risk of death by almost one third (relative risk=0.71, absolute risk reduction 8%)
There are clear messages from the results of this study.
The addition of Mepact to chemotherapy:
Improved 6-year overall survival from 70% to 78% (p=0.03) [Meyers 2008/P633/Abstract/Results/L3-4]
Improved 6-year event-free survival from 61% to 67% (p=0.08) [Meyers 2008/P635/Col2/Para1/L6-11].
Reduced the risk of death by almost one third (relative risk=0.71, absolute risk reduction 8%) [Meyers 2008/P637/Col2/Para2/L2-5].
References
Meyers PA, Schwartz CL, Krailo MK et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the Children’s Oncology Group. J Clin Oncol. 2008;26:
Meyers PA. et al. J Clin Oncol. 2008;26:

37. COG Phase III study: adverse events consistent with high dose chemotherapy
Received at least one dose of any study drug
Grade III-IV Adverse Event (%)
No Mepact
Received Mepact A- B- A+ B+
Stomatitis 54 37 49 43
Abdominal Pain 2 4 3
Constipation
Diarrhoea 6
Nausea and Vomiting 21 14
Central Nervous System 5
Skin 8
Infection 28 20 23
Hearing loss* 10 16
Mood 1
This table is adapted from EMA Report/P41-42/Table12.
Only grade III and IV toxicities were collected in the phase III study. Analyses of the adverse events indicate that the most frequent events are typically associated with chemotherapy, including stomatitis, nausea and vomiting, abnormal liver enzymes, low blood counts and infections [EMA Report/P41/Para4]. The only adverse event that occurred at significantly higher frequency in the Mepact group was objective hearing loss: 7% in those patients who did not receive Mepact (n=24) compared to 12% for those who did receive Mepact (n=39) (p=0.0478) [EMA Report/P42/Para2].
In the phase III study there were 148 deaths reported in the patients in the primary analysis group, mostly due to progressive disease. No deaths were attributed to Mepact [EMA Report/P42/Para4].
Five instances of potential allergic reaction to Mepact were reported, including 2 cases of urticaria, one erythema multiform, one grade IV allergic reaction and one bronchospasm. In four cases, reactions occurred late in the maintenance treatment. Except for urticaria, Mepact was discontinued. [EMA Report/P42/Para5].
During the phase III study, three patients experienced two pleural effusions and one pericardial effusion. Although rare, pericardial and pleural effusions have been previously reported with Mepact during prior phase I-II studies. In toxicological studies, pericarditis was recorded. The aetiology of effusion could be related to the immune stimulation of Mepact [EMA Report/P42/Para6].
Two episodes of seizure and painful spasms of extremities could be related to neurotoxicity of Mepact. One convulsion, one muscle spasm and one leukoencephalopathy were also recorded during phase I-II protocols including Mepact [EMA Report/P42/Para7]. One case of cardiac grade II arrhythmia was reported during the phase III study. No other rhythm abnormality was recorded during phase I-II protocols. However, tachycardia and bradycardia were commonly registered during all studies. They were frequently associated with initial febrile reaction [EMA Report/P42/Para8].
References
EMA Assessment Report for Mepact. Procedure No. EMEA/H/C/ Last accessed 9th July 2013
Adverse events reported in >2% of patients
* within the range of Cisplatin reported effect
Ototoxicity has occurred in up to 31% of patients treated with a single dose of cisplatin 50 mg/m2
Cisplatin Summary of Product Characteristics, August 2012
Adapted from: EMA Assessment Report for Mepact EMEA/H/C/

38. COG Phase III study: adverse events consistent with high dose chemotherapy cont.
Received at least one dose of any study drug
Adverse Event (%)
No Mepact
Received Mepact A- B- A+ B+
White blood cells 23 27 17 31
Neutrophils 48 43 45 50
Platelets 32 26 29
Haemoglobin 8 11
SGOT 28 40 35
SGPT 61 51 53
Bilirubin 10 7 9
Glucose 2 6
Potassium 5
This table is adapted from EMA Report/P43-44/Table13.
Only grade III and IV toxicities were collected in the phase III study. Analyses of the adverse events indicate that the most frequent events are typically associated with chemotherapy, including stomatitis, nausea and vomiting, abnormal liver enzymes, low blood counts and infections [EMA Report/P41/Para4].
References
EMA Assessment Report for Mepact. Procedure No. EMEA/H/C/ Last accessed 9th July 2013
Adverse events reported in >2% of patients
SGOT - serum glutamic oxaloacetic transaminase (often referred to as AST: aspartate aminotransferase)
SGPT - serum glutamic pyruvic transaminase (often referred to as ALT: alanine aminotransferase)
Adapted from: EMA Assessment Report for Mepact EMEA/H/C/

39. Mepact adverse event profile
Very Common Side Effects (>1/10)
Anaemia
Anorexia
Headache, dizziness
Tachycardia
Hypertension, hypotension
Dyspnoea, tachypnoea, cough
Vomiting, diarrhoea, constipation, abdominal pain, nausea
Hyperhidrosis
Myalgia, arthralgia, back pain, pain in extremity
Fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain
Selected Common Side Effects (>1/100 to <1/10)
Sepsis
Leukopenia
Thrombocytopenia
Granulocytopenia
Hypokalaemia
Vertigo
Tinnitus
Hearing loss
Mepact SmPC Adverse Events can be found in Section 4.8
References
Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
Please refer to Summary of Product Characteristics (SmPC) for full list of adverse events
Mepact SmPC, March

40. Mepact contraindications
Hypersensitivity to the active substance or to any of the excipients
Concurrent use with ciclosporin or other calcineurin inhibitors
Concurrent use with high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors)
Contraindications [Mepact SmPC/Section4.3]
Hypersensitivity to the active substance or to any of the excipients.
Concurrent use with ciclosporin or other calcineurin inhibitors
Concurrent use with high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors)
Special warnings and precautions for use [Mepact SmPC/Section4.4]
Respiratory distress
In patients with a history of asthma or other chronic obstructive pulmonary disease, consideration should be given to administration of bronchodilators on a prophylactic basis. Two patients with pre-existing asthma developed mild to moderate respiratory distress associated with the treatment. If a severe respiratory reaction occurs, administration of MEPACT should be discontinued and appropriate treatment initiated.
Neutropenia
Administration of Mepact is commonly associated with transient neutropenia, usually when used in conjunction with chemotherapy. Episodes of neutropenic fever should be monitored and managed appropriately. Mepct may be given during periods of neutropenia, but subsequent fever attributed to the treatment should be monitored closely. Fever or chills persisting for more than 8 hours after administration of Mepact should be evaluated for possible sepsis.
Inflammatory response
Association of Mepact with signs of pronounced inflammatory response, including pericarditis and pleuritis is uncommon. It should be used with caution in patients with a history of autoimmune, inflammatory or other collagen diseases. During Mepact administration, patients should be monitored for unusual signs or symptoms, such as arthritis or synovitis, suggestive of uncontrolled inflammatory reactions.
Cardiovascular disorders
Patients with a history of venous thrombosis, vasculitis or unstable cardiovascular disorders should be closely monitored during Mepact administration. If symptoms are persistent and worsening, administration should be delayed or discontinued. Haemorrhage was observed in animals at very high doses. These are not expected at the recommended dose, however monitoring of clotting parameters after the first dose and once again after several doses is recommended.
Allergic reactions
Occasional allergic reactions have been associated with Mepact treatment, including rash, shortness of breath and grade 4 hypertension. It may be difficult to distinguish allergic reactions from exaggerated inflammatory responses, but patients should be monitored for signs of allergic reactions.
Gastrointestinal toxicity
Nausea, vomiting and loss of appetite are very common adverse reactions to Mepact Gastrointestinal toxicity may be exacerbated when Mepact is used in combination with high dose, multi-agent chemotherapy and was associated with an increased use of parenteral nutrition.
References
Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
Please refer to Summary of Product Characteristics (SmPC) for full list of adverse events
Mepact SmPC, March

41. Mepact EMA licensed indication
Mepact is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis
Mepact is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis [Mepact SmPC/Section4.1].
References
Mepact Summary of Product Characteristics, March Last accessed 9th July 2013
Mepact SmPC, March

42. MEPACT® Prescribing Information
Please refer to Summary of Product Characteristics (SmPC) before prescribing
Insert Local Prescribing Information and replace TPI GmbH (below)with LOC company name
© 2013 – Takeda Pharmaceuticals International GmbH