UKALL 2011 Trial - Northern Cancer Alliance

1 Children's Cancer Trials Team UKALL 2011 Trial United Kingdom National Randomised Trial For Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoma 2011 . Version 1st October 2013. Sponsor: University of Birmingham Sponsor Protocol Number: RG_09-072. CAS CODE: HM3009. Eudract Number: 2010-020924-22. ISRCTN Reference Number: ISRCTN64515327. Chief Investigator: Dr Nick Goulden Consultant Paediatric Haematologist Level 2 Camelia Botnar Laboratory Great Ormond Street Hospital Great Ormond Street London WC1N 3JH. UKALL 2011 Protocol TABLE OF CONTENTS.

2 Introductory 6. Chief Investigator Signature Page .. 12. Amendments .. 13. Trial Synopsis .. 15. Title .. 15. Trial Design .. 15. Aims .. 15. Objectives .. 15. Outcome Measures .. 15. Patient Population .. 16. Sample Size .. 16. Main Inclusion and Exclusion Criteria .. 16. Trial 17. Treatment Summary .. 18. Trial Schema .. 21. Schedule of Events for ALL patients .. 22. Schedule of Events for LBL patients .. 23. Abbreviations .. 24. 1. Background and Rationale .. 26. 26. Trial 28. Treatment stratification .. 29. Rationale for Use of 32. Rationale for Dexamethasone Randomisation.

3 33. Rationale for use of split dexamethasone in patients aged 10 and 34. Rationale for high dose methotrexate randomisation .. 35. Rationale for Pulses randomisation .. 36. High Risk Cytogenetics .. 37. 2. Aims, Objectives and Outcome Measures .. 38. Aims and Objectives .. 38. Aims .. 38. Objectives .. 38. Outcome Measures .. 39. Primary outcome measures .. 39. Secondary outcome measures .. 39. 3. Trial Design .. 40. Changes to treatment regimens compared to UKALL 2003 .. 40. Stratification of treatment in UKALL 2011 .. 40. Acute Lymphoblastic Leukaemia.

4 40. Lymphoblastic Lymphoma .. 41. Allocation of induction 42. Modification of Induction for High Risk Cytogenetics .. 42. Induction for Down's Syndrome patients (ALL and LBL) .. 43. Allocation of post-induction therapy in patients with ALL .. 43. UKALL2011 Protocol_version 1st October 2013 Page 1 of 201. UKALL 2011 Protocol Obtaining a Day 29 MRD result .. 43. Allocation of post-induction therapy (Day 29 MRD Result) .. 44. Obtaining a post consolidation MRD result (MRD Risk group only) .. 45. Allocation of post consolidation therapy (MRD Risk group only).

5 45. Allocation of post-induction therapy in LBL 46. Methotrexate and Pulses Randomisation (R2) .. 47. Special Categories .. 47. CNS Disease at Presentation (CNS3): .. 47. Traumatic or CNS2 LP at diagnosis .. 48. Testicular Disease at Diagnosis .. 48. High risk cytogenetics .. 48. Induction Failure .. 49. Duration of treatment .. 51. Frequency and duration of follow-up .. 51. 4. Eligibility .. 51. Inclusion Criteria .. 51. Exclusion Criteria .. 51. Trial entry/R1 (dexamethasone randomisation) .. 51. R2 (methotrexate and pulses randomisation).. 51. 5.

6 Screening and Consent .. 52. 52. Collection of diagnostic samples from LBL patients at diagnosis .. 53. Informed Consent .. 53. Stages of consent .. 54. 6. Trial Entry .. 56. Procedure for online patient registration and randomisation .. 56. Emergency randomisation .. 56. 7. Treatment Details .. 57. Risks of intrathecal therapy .. 57. General management of all treatment regimens .. 57. Administration of vincristine .. 58. Extravasation .. 58. Missed oral doses .. 58. Administration of intrathecal methotrexate .. 58. Trial Treatment .. 59. Investigational Medicinal Products (IMPs).

7 59. Non-Investigational Medicinal Products (NIMPs) .. 60. Determining weight for dosage calculations .. 61. Children (patients aged under 18 years) .. 61. Adults (patients aged 18 and above) .. 62. Regimen A Treatment Schedule .. 63. Summary of Regimen A Treatment .. 63. Regimen A: Induction Overview .. 63. Regimen A: Induction .. 64. Regimen A: Post-induction therapy .. 67. Regimen A: Consolidation .. 68. Regimen A: Standard Interim Maintenance .. 69. UKALL2011 Protocol_version 1st October 2013 Page 2 of 201. UKALL 2011 Protocol Regimen A: High Dose Methotrexate (Protocol M).

8 70. Regimen A: Delayed Intensification .. 72. Regimen A: Maintenance .. 74. Regimen B Treatment Schedule .. 79. Summary of Regimen B Treatment .. 79. Regimen B: Induction Overview .. 79. Regimen B: Induction .. 80. Regimen B: Post-induction therapy .. 83. Regimen B: Standard BFM Consolidation .. 84. Regimen B: Standard Interim Maintenance .. 85. Regimen B: High Dose Methotrexate (Protocol M) .. 86. Regimen B: Delayed Intensification .. 88. Regimen B: Maintenance .. 90. Regimen C Treatment Schedule .. 95. Summary of Regimen C Treatment .. 95. Regimen C: Induction Overview.

9 95. Regimen C: Induction .. 96. Regimen C: Post-induction therapy .. 99. Regimen C: Augmented BFM Consolidation .. 101. Regimen C: Capizzi Interim Maintenance .. 103. Regimen C: High dose methotrexate + asparaginase (Protocol M-A) .. 105. Regimen C: Delayed Intensification .. 107. Regimen C: Maintenance .. 109. Assessments .. 115. Routine Clinical and Laboratory Assessments during treatment .. 115. Sample Collection .. 115. Diagnosis .. 115. During induction .. 117. During Consolidation .. 118. Interim maintenance .. 119. During Delayed Intensification.

10 119. During Maintenance .. 120. MRD sample requirements .. 120. Quality of Life questionnaires .. 121. Dose Modifications .. 121. 121. Mercaptopurine (6-MP) and methotrexate (MTX) .. 122. Co-trimoxazole (trimethoprim and sulphamethoxazole) .. 124. Dose modifications for toxicity .. 125. Supportive treatment .. 130. Tumour Lysis .. 130. Antimicrobials .. 131. Antiemetics .. 131. Mouthcare .. 131. G-CSF .. 131. Patient Follow Up .. 131. Patient Withdrawal .. 131. UKALL2011 Protocol_version 1st October 2013 Page 3 of 201. UKALL 2011 Protocol Withdrawal from UKALL 2011 Trial treatment.