Mifamurtide 4mg powder for dispersion for infusion vials

AbstractThe phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

Abstract licence: CC BY 4.0

Osteosarcoma is the most common primary malignant tumor of bone. The disease, however, is very rare with less than 2,000 expected patients at all age groups per year within the European Union and the United States of America. With multimodal therapy, which combines multiagent chemotherapy and complete resection of all macroscopically detectable tumors, about 60%–70% of patients with localized osteosarcoma can be cured. The prognosis, however, is still poor for patients with synchronous or metachronous metastatic or nonresectable primary disease, with reported 5-year event-free survival (EFS) rates of less than 30%. Overall, the EFS rate has been rather stable since the introduction of combination chemotherapy including doxorubicin, cisplatin, high-dose methotrexate with leukovorin rescue, and/or ifosfamide. Mifamurtide, a modulator of innate immunity, which activates macrophages and monocytes, which in turn release chemicals with potential tumoricidal effects, may help to control microscopic metastatic disease and has been safely given together with standard adjuvant chemotherapy to patients with high-grade osteosarcoma. Results of the recently published intergroup study 0133 trial from the Children’s Cancer and Pediatric Oncology Groups suggest that mifamurtide is a medicine that deserves further investigation in this orphan disease.

Abstract licence: CC BY-NC 3.0

PURPOSE Outcome of patients with localized osteosarcoma is challenging. The role of mifamurtide is still a matter of debate. Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)–positive patients. PATIENTS AND METHODS Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS). RESULTS From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% v 58.3%; P = .0139) not confirmed at multivariable analysis ( P = .0593). CONCLUSION In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.

Abstract licence: CC BY-NC-ND