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

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ClinicalTrials.gov Identifier: NCT00626990
Recruitment Status : Active, not recruiting
First Posted : February 29, 2008
Results First Posted : September 11, 2023
Last Update Posted : September 11, 2023
Sponsor:
Collaborators:
NCIC Clinical Trials Group
Radiation Therapy Oncology Group
Medical Research Council
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Study Description
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Brief 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.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: temozolomide Genetic: DNA methylation analysis Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: quality-of-life assessment Radiation: radiation therapy Phase 3

Detailed 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 751 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma. The CATNON Intergroup Trial.
Actual Study Start Date : December 2007
Actual Primary Completion Date : September 5, 2018
Estimated Study Completion Date : December 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Radiotherapy (RT) alone
radiation therapy alone
 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: 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
Active Comparator: RT & Concurrent CT
Radiotherapy and concurrent temozolomide chemotherapy
 Drug: temozolomide
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
Other Names:
  • Temodar
  • Temodal

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: 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
Active Comparator: RT + Adjuvant CT
Radiotherapy plus adjuvant temozolomide chemotherapy
 Drug: temozolomide
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
Other Names:
  • Temodar
  • Temodal

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.

Procedure: 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
Active Comparator: RT & Concurrent CT + adjuvant CT
Radiotherapy and concurrent chemotherapy plus adjuvant temozolomide chemotherapy
 Drug: temozolomide
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
Other Names:
  • Temodar
  • Temodal

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.

Procedure: 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


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival as Measured From the Day of Randomization [ Time Frame: from date from enrollment till the date of death (time till death is up to 10.9 years after patient enrollment in the study) ]
    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.


Secondary Outcome Measures :
  1. Progression-free Survival [ Time Frame: 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) ]
    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.

  2. Quality of Life of the Patient [ Time Frame: 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) ]
    Quality of life was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20

  3. Neurological Deterioration Free Survival [ Time Frame: 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. ]

    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



Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00626990


Locations
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Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
NCIC Clinical Trials Group
Radiation Therapy Oncology Group
Medical Research Council
Merck Sharp & Dohme LLC
Investigators
Layout table for investigator information
Study Chair: Wolfgang Wick Universitatsklinikum Heidelberg
Study Chair: Warren P. Mason, MD Princess Margaret Hospital, Canada
Study Chair: Michael A. Vogelbaum, MD, PhD The Cleveland Clinic
Study Chair: S. Erridge Medical Research Council
Study Chair: Anna Nowak, MD Sir Charles Gairdner Hospital - Nedlands
  Study Documents (Full-Text)

Documents provided by European Organisation for Research and Treatment of Cancer - EORTC:
Study Protocol and Statistical Analysis Plan  [PDF] September 7, 2020

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Ruda R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Oct 7;390(10103):1645-1653. doi: 10.1016/S0140-6736(17)31442-3. Epub 2017 Aug 8. Erratum In: Lancet. 2017 Oct 7;390(10103):1644.

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT00626990    
Other Study ID Numbers: EORTC-26053-22054
NCIC CTG CEC.1 ( Other Identifier: NCI-C )
RTOG-0834 ( Other Identifier: RTOG )
2006-001533-17 ( EudraCT Number )
P04839 ( Other Grant/Funding Number: Merck )
MRC BR14 ( Other Identifier: MRC CTU )
First Posted: February 29, 2008    Key Record Dates
Results First Posted: September 11, 2023
Last Update Posted: September 11, 2023
Last Verified: August 2023
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
adult anaplastic oligodendroglioma
adult anaplastic astrocytoma
Additional relevant MeSH terms:
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Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms
Neoplasms by Site
Nervous System Diseases
 Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents