E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | Relapsed or refractory primary central neurvous system lymphoma. | |
E.1.1.1 | Medical condition in easily understood language | Cancer of the immune system that is located in the brain or spine and has return or not responded to previous treatment. | |
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 | E.1.2 | Level | PT | E.1.2 | Classification code | 10007953 | E.1.2 | Term | Central nervous system lymphoma | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | The first phase (Phase 1) of the study is to find the maximum safe dose (maximum Tolerated Dose) of thiotepa which is safe to give in combination with ifosphamide, etoposide and rituximab in patients with Primary Central Nervous System Lymphoma (PCNSL). The second phase (Phase 2) is to look at how effective the combinastion of drugs are in treating (PCNSL). We will assess this by determining the Overall response rate (Complete Response (CR) + Complete Response: unconfirmed (CRu) + Partial Response (PR)) after 2 cycles of TIER treatment, as assessed by the ‘International Workshop to Standardise Baseline Evaluation and Response Criteria for Primary CNS Lymphoma'. | |
E.2.2 | Secondary objectives of the trial | To determine: The Toxicity of the TIER treatment using common terminology criteria for adverse events (CTCAE) version 4 The Complete response rate after 2 cycles of TIER The 2 year progression free survival (PFS) The 2 year event free survival (EFS) The 2 year overall survival (OS) The proportion of patients proceeding to high-dose therapy and autologous stem cell transplant (HDT-ASCT) The rate of successful stem cell harvest for patients proceeding to transplant Exploratory Outcome Measures Analysing the MRI scans to look for MRI-based prognostic and response parameters Analysing the Pathobiological features of relapsed/refractory primary central nervous system lymphoma cases | |
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives | Blood sample collection, as detailed in main protocol. Analysis of ctDNA at Royal Marsden Institute of Cancer Research. | |
E.3 | Principal inclusion criteria | • Age ≥ 16 years of age • Histologically confirmed* CD20+ Diffuse Large B-Cell Lymphoma (DLBCL) confined to the central nervous system • Relapsed or refractory primary central nervous system lymphoma (PCNSL) according to the following definition : o one or two prior chemotherapy regimen(s), of which at least one regimen contained high-dose methotrexate at a dose of >1g/m2. • ECOG performance status 0,1 or 2 (or 3 if attributed to lymphoma) • Adequate organ function o Bone marrow: platelets >80 x109/L, neutrophils >1 x109/L, haemoglobin >80 g/L o Hepatic: bilirubin <1.5 x upper limit of normal (ULN) (unless isolated unconjugated hyperbilirubinaemia attributable to Gilbert’s syndrome) o Renal: eGFR ≥40ml/min (Cockcroft-Gault) o Cardiorespiratory (as judged by the Local Investigator): clinically relevant cardiac or pulmonary function tests must be performed if there is a previous history of significant cardiac or pulmonary impairment • Able to comply with the scanning requirements of the study • Valid Informed consent | |
E.4 | Principal exclusion criteria | • Evidence of Systemic lymphoma • Active infection requiring intravenous antimicrobials • Chemotherapy for lymphoma within 4 weeks registration • Whole-brain radiotherapy within 6 months of registration • Relapse within 1 year of a Thiotepa-based autologous stem cell transplant • Prior therapy with the R-IE (Rituximab – ifosphamide and etoposide) regimen with the last year • Evidence of HIV or Hepatitis C infection • Hepatitis B infection* • Serum albumin <25g/l • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry) • Competent pPatients and competent patients with partners of childbearing potential not willing to use effective contraception during and for 12 months after therapy | |
E.5 End points |
E.5.1 | Primary end point(s) | Phase I Maximum Tolerated Dose (MTD) of thiotepa in combination with ifosphamide, etoposide and rituximab (TIER) Phase II Overall response rate (Complete Response (CR) + Complete Response: unconfirmed (CRu) + Partial Response (PR)) after 2 cycles of TIER treatment, as assessed by the International Workshop to Standardise Baseline Evaluation and Response Criteria for Primary CNS Lymphoma | |
E.5.1.1 | Timepoint(s) of evaluation of this end point | The phase I outcome will be measured after the required number of patients have completed 1 cycle of TIER treatment as per the 3+3 design. The phase II outcome will be measured after 28 patients have completed 1 cycle of TIER treatment at the maximum tolerated dose of thiotepa. | |
E.5.2 | Secondary end point(s) | • Toxicity of TIER using common terminology criteria for adverse events (CTCAE) version 4 • Complete response rate after 2 cycles of TIER • 2 year progression free survival (PFS) • 2 year event free survival (EFS) • 2 year overall survival (OS) • Rate of successful stem cell harvest • Proportion of patients proceeding to high-dose therapy and autologous stem cell transplant (HDT-ASCT) | |
E.5.2.1 | Timepoint(s) of evaluation of this end point | Analysis will be predominantly descriptive, with p-values given where appropriate for information only •The number and proportion of patients experiencing toxicity, will be reported with 95% confidence intervals (CIs) •The number of patients achieving complete response as assessed by the International Workshop to Standardise Baseline Evaluation and Response Criteria for PCNSL after 2 cycles of TIER will be reported as a proportion of the total number of patients registered •Time to event outcomes will be assessed using the method of Kaplan and Meier with point estimates presented at 6, 12 and 24 months with 95% CIs and median survival time •The rate of successful stem cell harvest and proportion of patients proceeding to HDT-ASCT will be reported with 95% CIs | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description | Determine the MDT of thiotepa in comination with R-IE | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 | The trial involves single site in the Member State concerned | No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | LVLS plus 6 months for final data cleaning. | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |