Brain Re-Irradiation Or Chemotherapy: a phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma

INTERVENTION: Trade Name: Lomustine medac Product Name: Lomustine Pharmaceutical Form: Capsule INN or Proposed INN: Lomustine CAS Number: 13010‐47‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Product Name: Procarbazine Pharmaceutical Form: Capsule INN or Proposed INN: Procarbazine CAS Number: 366‐70‐1 Other descriptive name: N‐(1‐Methylethyl)‐4‐[(2‐methylhydrazinyl)methyl]benzamide hydrochloride Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Trade Name: Vincristine Product Name: Vincristine Pharmaceutical Form: Injection INN or Proposed INN: Vincristine CAS Number: 2068‐78‐2 Other descriptive name: 22‐Oxovincaleukoblastine sulfate salt, Leurocristine sulfate salt, VCR, Vincristine sulfate Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐ CONDITION: Recurrent Glioblastoma ; MedDRA version: 20.0 Level: PT Classification code 10018336 Term: Glioblastoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: The principal research question is to assess the number of patients alive in the re‐irradiation arm at 9 months post‐start of treatment. Overall survival will be defined as the time from randomisation to the date of death from any cause. OS rates in the chemotherapy arm will also be assessed for calibration purposes only and not for direct statistical comparison. Primary end point(s): The primary outcome measure is overall survival rate at 9 months. Secondary Objective: Secondary endpoints will assess Health Related Quality of Life (HRQOL), using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ‐C30) and Brain Cancer module (BN20) questionnaires, which will be completed by participants. Additionally, HRQOL will be also assessed by a one‐off semi‐structured interview in a participant/caregiver subset of 15 participants or until data saturation.; Other secondary endpoints include Dexamethasone use, anti‐epileptic drug use, radiological response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).; ; Timepoint(s) of evaluation of this end point: The assessment of the primary endpoint is based on the 9‐month overall survival rates i.e. the number and proportion of patients alive in the re‐irradiation arm at 9 months post‐start of treatment. Overall survival is defined from randomisation to the date of death from any cause and survival data will be collected at all standard follow‐up visits. SECONDARY OUTCOME: Secondary end point(s): Health Related Quality of Life (HRQOL); ; Questionnaires to be completed by participants include the European Organisation for Research and Treatment of Cancer (EORTC) Quality of life questionnaire core 30 (QLQ‐C30) and Brain Cancer module (BN20). These will be completed independently by participants at clinic visits at baseline and at 6 weekly intervals post start of treatment up to 48 weeks post‐start of treatment.; ; In addition HRQOL will be evaluated through one‐off semi‐structured qualitative interviews in patient/carer subset (n 15 or until data saturation). This will include HRQOL before/ during treatment, experience of treatment and what matters most to patients/carers.; ; Dexamethasone use; ; Dexamethasone use will be defined by the dose and frequency of dexamethasone received. Data on dexamethasone use, including dose, any change in dose including the date of change will be collected at baseline and then on a 6 weekly basis post start of treatment. ; ; Anti‐epileptic drug use; ; Anti‐epileptic drug use will be defined by the type, dose and frequency of anti‐epileptic received. Data on anti‐ epileptic use including name of anti‐epileptic drug(s), dose, any change in dose including the date of change will be collected at baseline and then on a 6 weekly basis post start of treatment. ; ; Radiological response rate; ; Participants will be assessed for response to treatment at 12 weeks post start of treatment and then at 12 weekly intervals up to 48 weeks post start of treatment or until progression. Radiological response to treatment will be assessed via MRI imaging in accordance with Response Assessment in Neuro‐Oncology (RANO) criteria.; ; Acute and late toxicities; ; Assessment of toxicities will take place at 6 weekly intervals post start of treatment up to 48 weeks or until progression. They will be evaluated according to the current NCI‐CTCAE criteria and include all AEs. Acute toxicities will be defined as those occurring up to 12 weeks post end of treatment. Late toxicities will be defined as those occurring after 12 weeks post end of treatment. The end of treatment will be the date of the last radiotherapy dose or the final chemotherapy cycle. The period of collection of acute toxicity data will differ between arms due to different treatment lengths, but the overall period of data collection for toxicities will be the same for both treatment arms. ; ; Participant reported toxicities will be captured via the EORTC QLQ‐C30 and QLQ‐BN20 at baseline and every 6 weeks from the start of treatment up to 48 weeks or until progression.; ; Progression free survival (PFS); ; Progression‐free survival is defined as the time from randomisation to the first documented evidence of disease progression or death (from any cause). PFS includes radiological progression assessed in accordance with RANO criteria and non RANO evaluable progression where RANO assessment is not possible (e.g. clinical progression in a patient who is too unwell for further imaging).; ; Overall survival (OS) ; ; Overall survival is calculated as the time from randomisation to date of death from any cause, or date last known to be alive. Patients not known to have died at the time of analysis will be censored at the date last known to be alive. Date of death or date last known to be alive will be collected throughout the trial, and from sites at the end of the trial for all participants not known to have died prior to the end of follow up. ; Timepoint(s) of evaluation of this end point: Health Related Quality of Life HRQOL; Evaluated at each follow up time point ; ; Dexamethasone use; Evaluated at 6, 12 and 18 weeks post start of treatment and overall at the end of follow up. Evaluated over treatment period for the re‐irradiation arm.; ; Anti‐epileptic use; Evaluated at 6, 12 and 18 weeks post start of treatment and overall at end of follow up.; ; Radiological response rate; Evaluated at baseline, 12, 24, 36 and 48 weeks post start of treatment; ; Acute and late toxicities; Acute toxicities evaluated within 12 weeks of treatment, late toxicities >12 weeks following treatment and overall; ; PFS; Evaluated 48 weeks post start of treatment, presented for 6, 9 and 12 months post start of treatment and overall; ; OS; Evaluated at end of trial INCLUSION CRITERIA: • Histologically proven diagnosis of GBM with consistent molecular pathology, based on original pathology. • First recurrence of GBM, with contrast enhancing disease, following primary treatment (or following surgery alone for first recurrence of GBM; i.e. no previous systemic therapy or re‐irradiation for recurrence permitted). • The MRI scan that reveals recurrence must be reviewed by the local multi‐disciplinary meeting, including agreement of a Consultant Neuro‐Radiologist that imaging changes are in keeping with recurrence and not pseudo‐progression. • Randomisation must be performed within 21 days of the MRI that confirms recurrence. Outside of 21 days, an updated MRI is required to confirm eligibility and serve as a contemporaneous baseline scan to assess response to further treatment. Please see section 9 Assessments for further details for achieving this. • =6 months since completion of primary radiotherapy (where the interval since radiothe