Clinical trial NCT03763422: Trial in Low Grade Glioma Patients: Wait or Treat
Official title: IDH Mutated 1p/19q Intact Lower Grade Glioma Following Resection: Wait Or Treat? IWOT - a Phase III Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Low-grade Glioma
Temozolomide
Phase III
Wait or Treat
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Cooperative Trials Group for Neuro-Oncology (COGNO)
First posted: 2018-12-04
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The 1635-EORTC-BTG study - Wait or Treat - concerns patients that represent a clinically favorable group of patients with IDHmutated astrocytoma (oligo-symptomatic), without a need for immediate post-operative treatment. It will establish whether early adjuvant treatment with radiotherapy and adjuvant temozolomide in resected IDHmutated astrocytoma will improve outcome, and whether benefits of early treatment outweigh potential side-effects of that, such as deterioration in neurocognitive function or Quality of Live, seizure activity and Patient Reported outcome compared to active surveillance.


Eligibility criteria: Inclusion Criteria:

* Histologically WHO grade II (diffuse) or III (anaplastic) astrocytoma, IDHmt without 1p/19q co-deletion (local diagnosis)
* Time since diagnostic surgery or first resection ≤ 6 months
* No need for immediate radiotherapy followed by chemotherapy
* Having seizures only, without functional deficits due to the tumor (but the presence of functional deficits due to the resection is allowed)
* Patients for whom by local judgment an active surveillance policy is a realistic management alternative
* The patient is at least 18 years of age on day of signing informed consent
* WHO PS 0-2
* Adequate hematological, renal, and hepatic function, as follows:

  * Absolute neutrophil count ≥ 1.5 x 10\*9/L
  * Platelets ≥ 100 × 10\*9/L
  * Serum creatinine ≤ 1.5 times upper limit of laboratory normal (ULN)
  * Total serum bilirubin ≤ 1.5 × ULN
  * AST and ALT ≤ 2.5 × ULN
  * Alkaline phosphatase of ≤ 2.5 × ULN
* Presence of at least one paraffin block from the initial diagnosis for pathology review and translational research. If a representative formalin-fixed, paraffin-embedded (FFPE) block is not available, the collection of optimally 36, minimally 24 x 5 µm, unstained slides is required.
* At the time of randomization presence only of a non-enhancing tumor on T1 weighted contrast enhanced MR images; some faint non-nodular enhancement or enhancement that can be ascribed to the surgical resection or peri-operative ischemia is allowed. Preoperative enhancement is allowed provided this area is resected as shown on postoperative imaging
* Ability to take oral medication
* Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test done within 72 hours prior to randomization
* Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as defined by the investigator, during RT and TMZ treatment and for at least 6 months after the last TMZ cycle. A highly effective method of birth control is defined as those which result in low failure rate (i.e., less than 1 percent per year) when used consistently and correctly
* Women who are breast feeding must agree to discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment
* Male patients should be advised not to father a child and not to donate sperm up to 6 months after receiving the last dose of TMZ, and to seek advice on cryoconservation of sperm prior to treatment start
* Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments
* Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria:

* Presence of signs of increased intracranial pressure after surgery
* Requirement of steroids for control of tumor symptoms
* Presence of uncontrolled seizures after surgery, defined as having both:

  * persistent seizures interfering with everyday life activities AND
  * failed three lines of anti-epileptic drug regimen, including at least one combination regimen
* Presence of contra-indications for radiotherapy
* Hypersensitivity to dacarbazine (DTIC), to the active substance or to any of the excipients used for TMZ capsules
* Prior chemotherapy, or prior radiotherapy to the brain
* Pregnancy or breastfeeding
* Known HIV, chronic hepatitis B, or hepatitis C infection
* Inability to take oral medication (e.g., frequent vomiting, partial bowel obstruction)
* Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, coronary artery disease, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
* Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with PSA of less than or equal to 0.1 ng/mL). Other cancers for which the subject has completed potentially curative treatment more than 3 years prior to study entry are allowed
* Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Primary outcomes:
measure: Next intervention free survival (FIFS)
timeFrame: From the date of randomization until initiation of second treatment or death whichever occurs first assessed up to 11.5 years as of first patient in (FPI)
Secondary outcomes:
measure: First intervention free survival (FIFS)
timeFrame: from the date of randomization until initiation of preferably RT/TMZ or any other first therapeutic intervention (second surgery, RT, chemotherapy) or death (any cause) whichever occurs first assessed up to 11.5 years as of first patient in
measure: Progression Free Survival (PFS)
timeFrame: From the date of randomization until the date of first objective progression or the date of patient's death whichever occurs first assessed up to 11.5 years as of first patient in
measure: Overall Survival
timeFrame: From the date of randomization up to the date of death up to 1 year after first progression or start of second treatment in early treatment arm or first treatment in active surveillance arm assessed up to 11.5 years as of first patient in
measure: Seizure activity
timeFrame: The IWOT Seizure Control Composite Score Index can be completed up to 4 weeks before or after the planned assessment. A time window of 8 weeks is therefore available for each assessment. Assessed up to 11.5 years after FPI
measure: Safety profile: CTCAE
timeFrame: The collection period will start from randomization and up to start of second treatment for patients in the early treatment arm and from randomization to first treatment, for patients in active surveillance arm. Assessed up to 11.5 years after FPI
measure: Translational research
timeFrame: tissue and blood at randomization and new tissue at repeated surgical interventions if patient consented for translational research.Assessed up to 11.5 years after FPI
measure: HRQoL related to seizures
timeFrame: From randomization until progression assessed up to 11.5 years as of FPI
Other outcomes:
Locations:
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital - University of Queensland
state: Brisbane, QLD
city: Randwick - Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital - Crown Princess Mary Cancer Centre
state: New South Wales
city: Wollongong
country: Australia
facility: Illawarra Cancer Care Centre - Wollongong Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy (Melbourne)
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: West-Australia
city: Vienna
country: Austria
facility: Universitaetskliniken der Uni Wien - Universitaetsklinikum Wien - AKH uniklinieken
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Wilrijk
country: Belgium
facility: Gasthuiszusters van Antwerpen - GasthuisZusters Antwerpen - Sint-Augustinus
city: Aarhus
country: Denmark
facility: Aarhus University Hospitals - Aarhus University Hospital-Skejby
city: Bron
country: France
facility: CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer
city: Lille
country: France
facility: CHRU de Lille
city: Marseille
country: France
facility: Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone (APHM)
city: Paris
country: France
facility: Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere
city: Strasbourg
country: France
facility: Institut de Cancerologie Strasbourg Europe (formar Paul Strauss)
city: Bologna
country: Italy
facility: AUSL Bologna - Ospedale Bellaria
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Clinico Humanitas
city: Milano
country: Italy
facility: IRCCS - Istituto Neurologico Carlo Besta
city: Padova
country: Italy
facility: IRCCS - Istituto Oncologico Veneto
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino - Ospedale San Giovanni - Dipartimento Neuroscienze
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Leidschendam
country: Netherlands
facility: Haaglanden Medisch Centrum (HMC) - Haaglanden MC - locatie Antoniushove
city: Maastricht
country: Netherlands
facility: Maastro Clinic - Maastricht Radiation Oncology
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Tilburg
country: Netherlands
facility: ETZ Tilburg - St. Elisabethziekenhuis TweeSteden
city: Utrecht
country: Netherlands
facility: UMC-Academisch Ziekenhuis Utrecht
city: Barcelona
country: Spain
facility: Hospital Clinic Universitari de Barcelona
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - Hospital Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 De Octubre
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland (IOSI)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Zürich
country: Switzerland
facility: UniversitaetsSpital Zurich
city: Dundee
country: United Kingdom
facility: NHS Tayside - Ninewells Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: NHS Lothian - Western General Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Centre for Oncology NHS Trust - Clatterbridge NHS -Wirral
Study officials:
affiliation: EORTC Study Coordinator
name: Martin Van den Bent
role: PRINCIPAL_INVESTIGATOR
References: