Phase III Trial of Anaplastic Glioma Without 1p/19q Loss of Heterozygosity (LOH)

Brain and Central Nervous System Tumors Clinical Trial

— CATNON  

Official title:

Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma. The CATNON Intergroup Trial.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00626990
• Other study ID #: EORTC-26053-22054
• Secondary ID: NCIC CTG CEC.1RT
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 2007
• Est. completion date: December 2029

Study information

• Verified date: August 2023
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether giving temozolomide during and/or after radiation therapy is more effective than radiation therapy alone in treating anaplastic glioma.

PURPOSE: This randomized phase III trial is studying giving temozolomide during and/or after radiation therapy to see how well it works compared to radiation therapy alone in treating patients with anaplastic glioma.

Description:

OBJECTIVES:

Primary

• To assess whether concurrent radiotherapy with daily temozolomide improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma.

• To assess whether adjuvant temozolomide improves survival as compared to no adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma.

Secondary

• To assess whether concurrent and adjuvant temozolomide prolongs progression-free survival and neurological deterioration-free survival in patients with non-1p/19q deleted anaplastic glioma.

• To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma, including late effects on cognition.

• To assess the impact of concurrent and adjuvant temozolomide on the quality of life of patients with non-1p/19q deleted anaplastic glioma.

OUTLINE: This is a multicenter study. Patients are stratified according to institution, World Health Organization (WHO) performance status (0 vs > 0), age (≤ 50 vs > 50), presence of 1p LOH only (yes vs no), presence of oligodendroglial elements (yes vs no), and O6-methylguanine-DNA methyltransferase promoter methylation status (methylated vs unmethylated vs indeterminate). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients undergo radiotherapy* once daily, 5 days a week, for 6.5 weeks (total of 33 fractions).

• Arm II: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy).

• Arm III: Patients undergo radiotherapy* once daily, 5 days a week for 6.5 weeks (total of 33 fractions). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses.

• Arm IV: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses.

• Patients must begin radiotherapy within 8 days after randomization and within 7 weeks after surgery.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients complete quality-of-life questionnaires, including EORTC core quality of life questionnaire (QLQ-C30) version 3, EORTC brain cancer module (BCM20), and the Mini Mental Status Exam at baseline, 4 weeks after the completion of radiotherapy, and then every 3 months for 5 years.

Tissue samples are collected at baseline for histology review, 1p/19q analysis, methylation status of the O6-methylguanine-DNA methyltransferase promoter, and isocitrate dehydrogenase mutation analysis.

After completion of study treatment, patients are followed every 3 months.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 751
• Est. completion date: December 2029
• Est. primary completion date: September 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Anaplastic oligodendroglioma

• Anaplastic oligoastrocytoma

• Anaplastic astrocytoma

• Newly diagnosed disease

• Prior surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression

• Absence of combined 1p/19q loss

• Tumor material available for central 1p/19q assessment, central O6-methylguanine-DNA methyltransferase promoter methylation status assessment, isocitrate dehydrogenase mutation analysis, and central pathology review

• Patients must be on a stable or decreasing dose of steroids for at least two weeks prior to randomization

PATIENT CHARACTERISTICS:

• WHO performance status 0-2

• Absolute Neutrophil Count (ANC) = 1.5 x 10^9 cells/L

• Platelet count = 100 x 10^9 cells/L

• Bilirubin < 1.5 x upper limit of normal (ULN)

• Alkaline phosphatase < 2.5 x ULN

• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 x ULN

• Serum creatinine < 1.5 x ULN

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No known HIV infection or chronic hepatitis B or hepatitis C infection

• No other serious medical condition that would interfere with follow-up

• No medical condition that could interfere with oral medication intake (e.g., frequent vomiting or partial bowel obstruction)

• No other prior malignancies except for any malignancy which was treated with curative intent more than 5 years prior to registration and adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix

• No prior or concurrent malignancies at other sites except for surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer

• No psychological, familial, sociological, or geographical condition that would potentially hamper compliance with the study protocol and follow-up schedule

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior chemotherapy, including carmustine-containing wafers (Gliadel®)

• No prior radiotherapy to the brain

• No concurrent growth factors unless vital for the patient

• No other concurrent investigational treatment

• No other concurrent anticancer agents

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

Drug:
• temozolomide
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.

Genetic:
• DNA methylation analysis
O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.

Other:
• laboratory biomarker analysis
Prognostic factor analyses

Procedure:
• adjuvant therapy
Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.
• quality-of-life assessment
Quality of Life analysis will also be used to assess neurological deterioration free progression

Radiation:
• radiation therapy
Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Austin-Repatriation Medical Centre	Heidelberg
Australia	Royal Hobart Hospital	Hobart
Australia	St Vincent'S Hospital	Melbourne
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Alfred Hospital	Prahran
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales
Belgium	ZNA Middelheim	Antwerpen
Belgium	Cliniques Universitaires St. Luc	Brussels
Belgium	Universitair Ziekenhuis Brussel	Brussels
Belgium	Clinique Notre-Dame	Charleroi
Belgium	Algemeen Ziekenhuis Sint Lucas	Gent
Belgium	U.Z. Gasthuisberg	Leuven
Canada	Tom Baker Cancer Centre	Calgary
Canada	London Regional Cancer Center	London
Canada	Allan Blair Cancer Centre	Saskatoon
Canada	University Health Network - Oci / Princess Margaret Hospital	Toronto
Canada	Cancercare Manitoba	Winnipeg
France	Assistance Publique - Hôpitaux de Marseille - C.H.U. De La Timone	Marseille
France	C.H.U. de Nancy - Hopital St Julien	Nancy
France	Centre Antoine Lacassagne	Nice
France	Chu Pitie-Salpetriere AP-HP	Paris
France	Centre Eugene Marquis	Rennes
France	Institut Gustave Roussy	Villejuif
Germany	Klinikum Bamberg	Bamberg
Germany	Universitaetsklinikum Bonn	Bonn
Germany	Medizinische Hochschule Hannover	Hannover
Germany	UniversitaetsKlinikum Heidelberg	Heidelberg
Germany	Universitaetskliniken Regensburg	Regensburg
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Ospedale Bellaria	Bologna
Italy	Istituto Scientifico H.S. Raffaele	Milano
Italy	Azienda Ospedaliera San Giovanni Battista Di Torino-Universita Di Torino	Torino
Netherlands	Academisch Medisch Centrum - Universiteit van Amsterdam	Amsterdam
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam
Netherlands	Medisch Centrum Haaglanden - Westeinde	Den Haag
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Maastro Clinic - Maastricht Radiation Oncology	Maastricht
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen
Netherlands	Erasmus MC - Daniel den Hoed Cancer Center	Rotterdam
Spain	Hospital Clinic Universitari	Barcelona
Spain	ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)	Barcelona
Switzerland	Hopital Cantonal Universitaire De Geneve	Geneve
Switzerland	Universitaetsspital	Zurich
United Kingdom	University Hospitals Bristol NHS Foundation Trust - Bristol Haematology And Oncology Centre	Bristol
United Kingdom	Addenbrookes Hospital	Cambridge
United Kingdom	Cheltenham General Hospital	Cheltenham
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Devon And Exeter Hospital	Exeter
United Kingdom	St. James'S University Hospital	Leeds
United Kingdom	Christie NHS Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust - City Hospital campus	Nottingham
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Royal Marsden Hospital	Sutton
United Kingdom	Clatterbridge Centre for Oncology NHS Trust	Wirral
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Akron City Hospital - Summa Health System	Akron	Ohio
United States	Lehigh Valley Hospital	Allentown	Pennsylvania
United States	McFarland Clinic	Ames	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Summa Barberton Hospital	Barberton	Ohio
United States	UPMC - Heritage Valley Health System - The Medical Center	Beaver	Pennsylvania
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachussets General Hospital Cancer Center	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Western Reserve University	Cleveland	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Oncology Associates PC	Fort Wayne	Indiana
United States	Parkview Hospital	Fort Wayne	Indiana
United States	University of Florida	Gainesville	Florida
United States	University of Texas Medical Branch	Galveston	Texas
United States	Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Cancer Centers of the Carolinas - Eastside	Greenville	South Carolina
United States	Cancer Centers of the Carolinas - Faris Road	Greenville	South Carolina
United States	Cancer Centers of the Carolinas - Greer Radiation Oncology	Greer	South Carolina
United States	Penn State M.S. Hershey Medical Center	Hershey	Pennsylvania
United States	Md Anderson Cancer Center	Houston	Texas
United States	Methodist Hospital	Houston	Texas
United States	Saint Vincent Oncology Center	Indianapolis	Indiana
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Gundersen Lutheran	La Crosse	Wisconsin
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University Of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Southwest General Health Center Ireland Cancer Center	Middleburg Heights	Ohio
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	State University of New York Upstate Medical University	New York	New York
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	UHHS-Chagrin Highlands Medical Center	Orange Village	Ohio
United States	Florida Hospital	Orlando	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Arizona Oncology Services Foundation	Phoenix	Arizona
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Highland Hospital	Rochester	New York
United States	University of Rochester - James P. Wilmot Cancer Center	Rochester	New York
United States	Dixie Medical Center Regional Cancer Center	Saint George	Utah
United States	St John's Mercy Medical Center	Saint Louis	Missouri
United States	Cancer Care Center, Incorporated	Salem	Ohio
United States	LDS Hospital	Salt Lake City	Utah
United States	University Of Utah - Huntsman Cancer Institute	Salt Lake City	Utah
United States	UCSF University of California San Francisco Medical Center-Mount Zion	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Medical Center	Scarborough	Maine
United States	Swedish Cancer Institute	Seattle	Washington
United States	Virginia Mason CCOP	Seattle	Washington
United States	Cancer Centers of the Carolinas - Seneca	Seneca	South Carolina
United States	June E. Nylen Cancer Center	Sioux City	Iowa
United States	Spartanburg Regional Medical Center	Spartanburg	South Carolina
United States	Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Reading Hospital and Medical Center	West Reading	Pennsylvania
United States	UHHS - Westlake Medical Center	Westlake	Ohio
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Cancer Treatment Center	Wooster	Ohio

Sponsors (5)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Medical Research Council, Merck Sharp & Dohme LLC, NCIC Clinical Trials Group, Radiation Therapy Oncology Group

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival as Measured From the Day of Randomization	The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination.	from date from enrollment till the date of death (time till death is up to 10.9 years after patient enrollment in the study)
Secondary	Progression-free Survival	Disease progression is defined as radiological or neurological/clinical progression (whichever occurs first); progression free survival (PFS) is the time interval between the date of randomization and the date of disease progression or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination. Radiological progression was defined as increase of contrast enhancing area on MRI or CT scans of more than 25% as measured by two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique. The appearance of new lesions with or without contrast enhancement Neurological/clinical progression was defined as:decrease in WHO performance status,deterioration of neurological functions,appearance of signs/symptoms of increased intracranial pressure,and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological symptoms.	from randomization till the date of disease progression or death (time till death is up to 10.9 years after patient enrollment in the study)
Secondary	Quality of Life of the Patient	Quality of life was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20	from 14 days prior to randomization till five years or death (time till death is up to 10.9 years after patient enrollment in the study)
Secondary	Neurological Deterioration Free Survival	Neurological deterioration is defined as a decrease in WHO performance status as follows: decrease in WHO performance status; for patients with baseline WHO performance status 0: deterioration to WHO performance status 2 or worse for which no other explanation is present, and which is maintained for at least three months; for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance status 3 or worse for which no other explanation is present and which is maintained for at least three months; The date of neurological deterioration will be the first date the persistent decrease in performance status was diagnosed. Neurological deterioration free progression is the time interval between the date of randomization and the date of neurological deterioration or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination	within 2 weeks of randomization; during radiotherapy at week 4 and 6; 4 weeks after the end of radiotherapy; Six monthly after the end of radiotherapy; Prior to each cycle of adjuvant therapy; Every six months after the documentation of first progression.

External Links

•   Clinical trial summary from the EORTC database