Lomustine With and Without Reirradiation for First Progression of Glioblastoma: a Randomized Phase III Study

Обзор

Despite comprehensive multimodal treatment of newly diagnosed glioblastoma, almost all patients suffer from tumour relapse. Currently, no standard of care exists to treat these tumour relapses. Treatment options include repeated surgery (if feasible), systemic therapy (bevacizumab, lomustine, temozolomide re-challenge), reirradiation and best supportive care. Currently, the superiority of combined chemoradiation versus chemotherapy alone remains unproven. Given that lomustine is the standard chemotherapeutic agent for the treatment of recurrent glioblastoma in Europe and the unclear efficacy of reirradiation, we want to explore whether combining lomustine and reirradiation may be a better treatment than lomustine alone. The results of the prospective randomized trial proposed here should demonstrate a significant improvement in overall survival when lomustine is combined with reirradiation in patients with recurrent glioblastoma compared to lomustine alone without adversely affecting quality of survival. The trial will be stopped based on overall survival in a preplanned futility and efficacy interim analysis.

Вмешательства

• Препарат Lomustine
  Oral administration of Lomustine
• Лучевая терапия Reirradiation
  Given at least 6 months after the end of prior radiotherapy

Первичные конечные точки

• Overall Survival (OS) [Срок оценки: From the date of enrolment up to the date of death, assessed up to 40 months after first patient is enrolled]

Вторичные конечные точки (7)

• Progression Free Survival (PFS) [Срок оценки: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled]
• Health-related Quality of Life (HRQoL) [Срок оценки: From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled]
• Toxicity profile of lomustine plus reirradiation [Срок оценки: From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled]
• Neurocognitive functioning of lomustine pus reirradiation [Срок оценки: From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled]
• To transform self-reported quality of life data from the QLQ-C30 into health utility values, ready to be used in subsequent health economic analyses. [Срок оценки: From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled]
• Objective response (ORR) [Срок оценки: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled]
• Complete response (CRR) [Срок оценки: From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled]

Критерии участия

Критерии включения

• Before patient's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
• Patients with first progression or recurrent glioblastoma after standard chemoradiotherapy (any treatment other than use of nitroureas) having occurred at least 6 months after the end of prior radiotherapy
• Measurable disease according to RANO criteria with a maximum tumour diameter of 5 cm (local investigator assessment)
• In case of surgery for recurrence: fully recovered from surgery, confirmation of recurrence by histology, and patient fit for treatment as per local investigator assessment.
• Histologically proven diagnosis of glioblastoma, IDH wildtype per WHO 2021 classification and local assessment of tissue from diagnosis or recurrence
• Initial treatment of newly diagnosed glioblastoma by maximal safe resection and postsurgical concurrent conventionally fractionated or abbreviated (minimum 15 fractions) chemoradiotherapy with or without maintenance chemotherapy with temozolomide (patient must have received at least one dose)
• Stable or decreasing dose of steroids for 7 days prior to enrolment
• Age ≥ 18 years
• WHO Performance status of 0-2
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
• Patients of childbearing / reproductive potential must agree to use adequate birth control measures during the study treatment period and for at least 6 months after the last dose of study treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
• Non-sterile males must use contraception during treatment and for 6 months after the last dose.
• Non-sterile males must avoid sperm donation for the duration of the study and for at least 6 months after the last dose of study treatment.

Критерии исключения

• Any prior anticancer treatment for recurrent glioblastoma (except surgery)
• Significant reduction in thrombocyte and/or leukocyte counts as well as severe renal impairment according to investigator's opinion
• History or present acute leukaemia or any myeloid disease
• Known hypersensitivity to the active components or excipients of lomustine
• Known coeliac disease or wheat allergy
• Live attenuated vaccine in the 3 months prior to lomustine initiation
• Any serious or uncontrolled medical condition (e.g., infections, chronic alcoholism, drug addiction) or abnormality, in the judgment of the investigator that prohibits obtaining informed consent, safe participation and study completion
• Known contraindication to imaging tracer or any product of contrast media and Magnetic Resonance Imaging (MRI) contraindications
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 10 центров

• CHU d'Amiens - CHU Amiens Picardie - Site Sud — Amiens
• CLCC - Jean Perrin — Clermont-Ferrand
• CHRU de Lille — Lille
• CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer — Lyon
• Institut du Cancer de Montpellier — Montpellier
• CHU de Nice - Hôpital Pasteur — Nice
• Assistance Publique Hopitaux Paris- APHP - APHP Sorbonne Univ - Hopital la Pitie-Salpetrie — Paris
• Assistance Publique Hopitaux Paris- APHP - APHP Nord - Univ De Paris Cite - Hop. Saint Lou — Paris
• … и ещё 2 центра

Германия · 9 центров

• Univ. Knappschaft Krankenhaus Bochum — Bochum
• Universitaetsklinikum Koeln — Cologne
• Universitaetsklinikum Erlangen-Schwabachanlage — Erlangen
• Universitaetsklinikum - Essen — Essen
• Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital — Heidelberg
• Universitätsklinikum Leipzig-Klinik für Strahlentherapie und Radioonkologie — Leipzig
• Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern — Munich
• Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg — Regensburg
• … и ещё 1 центр

Бельгия · 6 центров

• AZORG — Aalst
• Cliniques Universitaires Saint-Luc — Brussels
• Universitair Ziekenhuis Gent — Ghent
• Grand Hopital de Charleroi - Site Les Viviers — Gilly
• U.Z. Leuven - Campus Gasthuisberg — Leuven
• Ziekenhuis aan de Stroom (ZAS) - ZAS Augustinus (previous GZA) — Wilrijk

Италия · 5 центров

• IRCCS-Ospedale Bellaria-Bologna — Bologna
• ULSS 9 Scaligera Veneto - Azienda Unita Locale Socio-Sanitaria N. 9-Mater Salutis Hospital — Legnago
• Istituto Clinico Humanitas — Milan
• IRCCS - Istituto Oncologico Veneto — Padova
• Azienda ospedaliero Univ Policlinico Umberto I — Roma

Австрия · 3 центра

• A.O Landeskrankenhaus - Innsbruck Universitaetsklinik — Innsbruck
• Kepler University Hospital - Neuromed campus — Linz
• Universitaetsklinikum Wien - AKH unikliniken — Vienna

Нидерланды · 3 центра

• Leiden University Medical Centre — Leiden
• Erasmus MC — Rotterdam
• ETZ Tilburg - ETZ - St. Elisabethziekenhuis — Tilburg

Испания · 3 центра

• Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Cata — Badalona
• ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia) — L'Hospitalet de Llobregat
• Hospital Universitario 12 de Octubre — Madrid

Норвегия · 2 центра

• Oslo University Hospital - Radiumhospitalet — Oslo
• St Olavs University Hospital - St. Olavs Hospital, Trondheim University Hospital — Trondheim

Швейцария · 2 центра

• Oncology Institute of Southern Switzerland (IOSI) - Ospedale San Giovanni — Bellinzona
• UniversitaetsSpital Zurich - Neurology Clinic — Zurich

Чехия · 1 центр

• Masaryk Memorial Cancer Institute — Brno

Дания · 1 центр

• Aarhus University Hospitals - Region Midtjylland - Aarhus University Hospital-Skejby — Aarhus

Публикации

• Preusser M, Kazda T, Le Rhun E, Sahm F, Smits M, Gempt J, Koekkoek JA, Monti AF, Csanadi M, Pitter JG, Bulbek H, Fournier B, Quoilin C, Gorlia T, Weller M, Minniti G; European Organisation for Research, Treatment of Cancer (EORTC) Brain Tumor Group. Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study PMID 38849943

Идентификаторы

NCT: NCT05904119 · EORTC-2227-BTG

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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