MADRID, Spain, March 22 /PRNewswire/ -- PharmaMar announces today that Aplidin(r), the novel marine anti-tumour agent, has entered Phase I clinical trials for paediatric solid tumours and haematological malignancies, as anticipated at the business review day on 28 January 2004. The rationale to start this trial was made following promising results from Phase I studies in adults with advanced solid tumours and non-Hodgkin's lymphomas, together with preclinical data supporting its potential for the treatment of haematological malignancies. Aplidin was 3-10 times more selective towards leukaemia and lymphoma cells than towards normal haemopoyetic cells in preclinical studies.
The trial is expected to recruit 35 to 41 patients with solid tumours and leukemias, including acute lymphoblastic leukaemia (ALL), in a European multicentre study. The primary endpoint of the study is to determine the recommended dose for Phase II trials. Secondary endpoints include safety at the recommended dose, pharmacokinetic parameters and efficacy.
Aplidin will be administered as a 3-hour intravenous infusion, every two weeks. The first cohort of patients will be treated at a starting dose of 4.0 mg/m2, equivalent to 80% of the proposed recommended dose for the selected dosing schedule for adult Phase II trials. Doses will be escalated based on the toxicity in the previous dose.
For ethical reasons, when conducting trials in children, potential benefit should be maximised whilst also minimising the risk of significant toxicities. This approach has been determined in accordance with CPMP guidelines on paediatric oncology.
Aplidin was granted Orphan Drug designation in Europe for ALL in 2003. Leukemias make up approximately 25% of cancers in children and young adults under the age of 20. Approximately 75% of all childhood leukemias are ALL. In 2004, about 3,940 new cases of ALL in children will be diagnosed in Europe.
Commenting on the trial, Dr M. A. Izquierdo, Director of Clinical Development at PharmaMar, said: "Aplidin is our second anti-cancer agent in development. It is currently in several Phase II trials in adults for a variety of solid tumours, with further Phase II trials in adults with haematological malignancies due to commence later this year. The efficacy demonstrated in the clinic to date, together with its favourable side-effect profile, has encouraged us to develop Aplidin as a potential treatment for children."
Aplidin (Ref 1) is a cyclodepsipeptide derived from the marine tunicate Aplidium albicans. Aplidin is a multifactorial apoptosis inducer agent, characterized by a low haematological toxicity and a high specificity towards tumour cells. Aplidin is currently in Phase II trials for melanoma and non-Hodgkin's lymphoma, colorectal, renal, lung (NSCLC and SCLC), head and neck pancreatic carcinomas. Further Phase II trials in other solid and haematological tumours are planned for 2004.
Mechanism of action
Aplidin induces rapid and persistent activation of apoptosis combined with blocking of cell division in the G1/G2 phase of the cell cycle in tumour cells. It also inhibits the secretion of vascular endothelial growth factor (VEGF), a crucial protein involved in the vascularization and growth of a number of tumours, and the expression of the VEGF receptor 1 (VEGFR1).
1. Aplidin(r) is the registered trademark of Aplidin.
PharmaMar is a biopharmaceutical company, advancing cancer care through the discovery and development of innovative marine-derived medicines. PharmaMar's clinical portfolio currently includes Yondelis (TM) in phase II/III clinical trials (co-developed with OrthoBiotech Products L.P.), designated Orphan Drug for STS by the EMEA in 2001 and Orphan Drug for ovarian cancer in 2003; Aplidin(r), in phase II, designated Orphan Drug for acute lymphoblastic leukaemia in 2003; Kahalalide F in phase II and ES-285 in phase I clinical trials.
PharmaMar, based in Madrid, Spain, is a subsidiary of the Zeltia Group (Spanish stock exchange: ZEL.MC; Bloomberg: ZEL SM; Reuters: ZEL.MC). PharmaMar can be found on the Web at http://www.pharmamar.com