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1 Efficacy and Safety of Glucarpidase for Routine EFFICACY AND SAFETY OF GLUCARPIDASE FOR ROUTINE USE AFTER HIGH DOSE METHOTREXATE IN PATIENTS WITH BONE SARCOMA Dr MARTHA PERISOGLOU UCL MD(RES) 1 DECLARATION I, Martha Perisoglou confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 ACKNOWLEDGEMENTS I feel privileged to have been able to work on and complete this doctoral thesis; I am deeply grateful to God and all who made this wonderful journey possible. I would like to express my sincerest appreciation and gratitude to the Richard Scowcroft Foundation for financially supporting my research. I would like to thank my supervisors Prof Jeremy Whelan and Prof John Hartley for their support, patience, guidance and constructive comments during the past years. I am particularly grateful to Janet Hartley for her mentorship, advice, care and friendship in the course of this task; Janet’s contribution has been invaluable. I would also like to thank Dr Joe Standing for his help with the pharmacokinetic analysis and Paul Bassett for his contribution in the statistical analysis of my data. I owe my deepest gratitude to all the patients and their families for their participation in the GLU 1 study; their attitude towards life and illness has been inspirational. Special thanks are due to my dearly beloved parents, Father Ioannis and Chrysanthi Perisoglou, and my siblings, Ellie, Maria, Giorgos and Manolis; without their love, prayers and constant presence I could not have completed this project. I am always grateful to my beloved husband Jonathan for his continuous support, encouragement and profound understanding, his endless humour, his love and belief in me. Last but not least, I would like to thank my son Timothy who spent many days in the company of others during the first two years of his life in order to allow me to complete this task. This work is dedicated to my parents. 3 ABSTRACT Background: High-dose methotrexate (HD-MTX) is an essential component of osteosarcoma treatment. Despite supportive measures MTX-related toxicity results in delays in subsequent chemotherapy administration and potentially reduced treatment efficacy. Alternative rescue regimens utilising glucarpidase in addition to folinic acid may be of benefit in reducing MTX-induced toxicity. Patients and methods: A double blind randomised crossover clinical trial, GLU 1, was designed and activated to determine the efficacy and safety of routine use of glucarpidase after HD-MTX. To establish the frequency of MTX-induced toxicity so that bespoke study endpoints and sample size could be determined, the medical records of 56 patients with bone sarcoma treated with HD-MTX between 2004 and 2005 at University College Hospital (UCH) were studied. Data were collected on MTX-related toxicity and treatment delays. In a separate review, similar data from 17 patients aged ≥ 40 years, and 25 patients aged < 40 years treated with HD-MTX between 2002 and 2007 at UCH were compared. A high performance liquid chromatography (HPLC) assay was validated for the evaluation of plasma MTX and DAMPA concentrations for trial participants. In GLU 1, patients were randomised to receive two HD-MTX courses with folinic acid rescue (cycle FA) followed by two HD- MTX courses with folinic acid and glucarpidase (cycle glu/FA), or cycle glu/FA first followed by cycle FA. The data of 16 patients enrolled up to the interim analysis of the trial were analysed. Results: MTX-related toxicity resulted in delays in half of subsequent chemotherapy cycles (58% in the ≥ 40 years group and 52% in the < 40 years group). In GLU 1, MTX toxicity resulted in delays in 43% of glu/FA cycles and 77% of FA cycles. The use of glucarpidase was not associated with a reduction in MTX AUC. The incidence and grade of MTX-induced toxicity were similar in glu/FA and FA although more 4 severe grades of mucositis were less frequent in glu/FA cycles. No glucarpidase toxicity was observed. Conclusions: Glucarpidase offers a promising addition for rescue from MTX toxicity and continued clinical evaluation to determine its most effective use is warranted. 5 CONTENTS 1. INTRODUCTION .............................................................................................22 1.1. Rationale and Background ........................................................................22 1.2. Osteosarcoma and Treatment of Osteosarcoma .......................................24 1.2.1. Osteosarcoma ....................................................................................24 1.2.2. Treatment of Newly Diagnosed Osteosarcoma ..................................27 1.2.3. Treatment of Relapsed Osteosarcoma ...............................................28 1.3. MTX and the Role of HD-MTX in Treatment of Osteosarcoma ..................28 1.3.1. Description and Use of MTX ...............................................................28 1.3.2. Mechanism of Action of MTX ..............................................................29 1.3.3. Half Life and Transport of MTX...........................................................29 1.3.4. Metabolism and Excretion of MTX ......................................................31 1.3.5. MTX Resistance .................................................................................32 1.3.6. Role of HD-MTX in Osteosarcoma .....................................................33 1.3.7. HD-MTX Induced Toxicity ...................................................................34 1.3.8. Role of Folinic Acid Rescue After HD-MTX ........................................39 1.3.9. Delays in Osteosarcoma Treatment Due to MTX Toxicity...................40 1.4. Glucarpidase (Voraxaze™) and its Rescue Role After HD-MTX ..............41 6 1.4.1. Mechanism of Action of Glucarpidase ................................................42 1.4.2. Clinical Studies with Glucarpidase ......................................................42 1.4.2.1. PK Study (Voraxaze™ Investigator’s Brochure, 2009). ................43 1.4.2.2. LV Interaction Study (Voraxaze™ Investigator’s Brochure, 2009). ....................................................................................................44 1.4.2.3. PD, NCI and Berlin Studies (Schwartz et al. 2004; Adamson et al. 2005; Buchen et al. 2005; Voraxaze™ Investigator’s Brochure, 2009). ..........................................................................................44 1.4.3. Adverse Effects Related to Glucarpidase ...........................................50 1.5. Aims ..........................................................................................................53 2. MATERIALS AND METHODS .........................................................................55 2.1. Review on MTX Related Toxicity and Resulting Delay in Subsequent Chemotherapy Administration ...................................................................55 2.2. GLU 1 Clinical Study: A Blind Randomised, Cross-Over, Phase II Clinical Trial, to Investigate the Efficacy and Safety of Glucarpidase For Routine Use After HD-MTX in Patients with Bone Sarcoma ...................................56 2.2.1. Study Objectives and Endpoints .........................................................56 2.2.2. Study Design ......................................................................................58 2.2.3. Patient Recruitment ............................................................................60 2.2.4. Study Assessments ............................................................................63 7 2.2.5. Study Medication and Treatment Plan ................................................65 2.2.5.1. Agents Used ................................................................................65 2.2.5.2. Prescription of MTX, Folinic Acid and Glucarpidase/Placebo .......66 2.2.5.3. Mandatory Assessments Prior to Each Chemotherapy Course ...66 2.2.5.4. Minimum Requirements Prior to Course M1 and GluM1 in Both Arms ............................................................................................67 2.2.5.5. Minimum Requirements Prior to Course M2 and GluM2 in Both Arms ............................................................................................67 2.2.5.6. Administration of MTX (GluM1, GluM2, M1 and M2 Courses) .........68 2.2.5.7. Glucarpidase Dose and Administration ........................................70 2.2.5.8. Folinic Acid Dose Calculation ......................................................70 2.2.5.9. MTX Induced Renal Failure and Delayed MTX Excretion ............71 2.2.6. MTX and DAMPA Pharmacokinetic Assessments ..............................71 2.2.6.1. Analysis of MTX Plasma Levels by Immunoassay .......................72 2.2.6.2. Analysis of MTX and DAMPA Plasma Levels by High Performance Liquid Chromatography ...............................................................72 2.2.7. Assessment of Anti-Glucarpidase Antibody Response .......................73 2.2.7.1. Background .................................................................................73 2.2.7.2. Blood Sampling Schedule............................................................73 8 2.2.7.3. Sampling Procedures ..................................................................74 2.2.8. Assessment of Glucarpidase and MTX Related Toxicity ....................74 2.2.8.1. Definitions ...................................................................................74 2.2.8.2. Expected Adverse Events............................................................77
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