Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.

Abstract

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.

Mifamurtide for the treatment of nonmetastatic osteosarcoma

“…Due to rapid mononuclear phagocytosis of the liposome transporter, L-MTP-PE has very rapid clearance from the blood only approximately 0.5% of L-MTP-PE remains in the plasma at the 5-min time point compared with 93% when administrated as the free form [35]. In humans, there is no evidence of accumulation of either liposomes or free MTP-PE after L-MTP-PE 4-mg treatment twice a week for 9 week [36]. The half-life of free MTP-PE can be estimated as 3-6 h from dog and rat studies.…”

Prevention of experimental endotoxin shock by a monocyte activator

“…The muramyl derivative MTP-PE has been studied mostly with respect to its anticancer activity (8,14,15,23,29). Two studies have shown prophylactic efficacy in viral infection models of influenza virus or human immunodeficiency virus (5,19).…”

“…The monocyte-activating properties of MTP-PE have been successfully used in experimental cancer models and in the treatment of cancer patients (15,20). Completed phase I trials have demonstrated that MTP-PE is a safe drug with only minor side effects (8,23,29).…”

Adjuvants for a New Generation of Vaccines

“…The lipophilic MDP analogues tested were potent in the induction of uveitis (17) , and administering them in liposomes aggravated this activity. While the use of the lipophilic MTP-PE in cancer patients (16) ethically is justifiable, the safety of this formulation in widely used adjuvants is questionable.…”

“…Certain individuals, particularly those of the HLA-B27 haplotype , genetically are predisposed to develop one or more components of Reiter's complex (15); this can happen when they are exposed to small amounts of bacterial products or given certain drugs such as levamisole hydrochloride. Some Reiter's symptoms (an influenza-like syndrome and generalized joint discomfort) can be produced by injection of 1 mg or more of muramyl peptide analogues into humans ( 16) . If an adjuvant is to be used in millions of people, some genetically predisposed, it might produce or exacerbate Reiter's symptoms (the most serious is anterior uveitis) .…”