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

• 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: European Organisation for Research and Treatment of Cancer - EORTC
• 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

Tracking Information

• First Submitted Date: February 28, 2008
• First Posted Date: February 29, 2008
• Results First Submitted Date: February 14, 2023
• Results First Posted Date: September 11, 2023
• Last Update Posted Date: September 11, 2023
• Actual Study Start Date: December 2007
• Actual Primary Completion Date: September 5, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 30, 2023)

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.

• Original Primary Outcome Measures (submitted: February 28, 2008): Overall survival as measured from the day of randomization

Current Secondary Outcome Measures (submitted: August 30, 2023)

• 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.
• 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
• 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

Original Secondary Outcome Measures (submitted: February 28, 2008)

• Progression-free survival
• Neurological deterioration-free survival
• Quality of life as assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20
• Toxicity as measured by CTCAE version 3.0
• Development of cognitive deterioration as measured by the Mini Mental Status Exam

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase III Trial of Anaplastic Glioma Without 1p/19q Loss of Heterozygosity (LOH)
• Official Title: Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma. The CATNON Intergroup Trial.

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Brain and Central Nervous System Tumors

Intervention

• 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

Study Arms

• Active Comparator: Radiotherapy (RT) alone
  radiation therapy alone
  Interventions:

  • Genetic: DNA methylation analysis
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
  • Radiation: radiation therapy
• Active Comparator: RT & Concurrent CT
  Radiotherapy and concurrent temozolomide chemotherapy
  Interventions:

  • Drug: temozolomide
  • Genetic: DNA methylation analysis
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
  • Radiation: radiation therapy
• Active Comparator: RT + Adjuvant CT
  Radiotherapy plus adjuvant temozolomide chemotherapy
  Interventions:

  • Drug: temozolomide
  • Genetic: DNA methylation analysis
  • Other: laboratory biomarker analysis
  • Procedure: adjuvant therapy
  • Procedure: quality-of-life assessment
  • Radiation: radiation therapy
• Active Comparator: RT & Concurrent CT + adjuvant CT
  Radiotherapy and concurrent chemotherapy plus adjuvant temozolomide chemotherapy
  Interventions:

  • Drug: temozolomide
  • Genetic: DNA methylation analysis
  • Other: laboratory biomarker analysis
  • Procedure: adjuvant therapy
  • Procedure: quality-of-life assessment
  • Radiation: radiation therapy

Publications *

• Tesileanu CMS, Sanson M, Wick W, Brandes AA, Clement PM, Erridge SC, Vogelbaum MA, Nowak AK, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Rogers L, Taal W, Ruda R, Weller M, McBain C, van Linde ME, Aldape K, Jenkins RB, Kros JM, Wesseling P, von Deimling A, Hoogstrate Y, de Heer I, Atmodimedjo PN, Dubbink HJ, Brouwer RWW, van IJcken WFJ, Cheung KJ, Golfinopoulos V, Baumert BG, Gorlia T, French PJ, van den Bent MJ. Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial. Clin Cancer Res. 2022 Jun 13;28(12):2527-2535. doi: 10.1158/1078-0432.CCR-21-4283.
• van den Bent MJ, Tesileanu CMS, Wick W, Sanson M, Brandes AA, Clement PM, Erridge S, Vogelbaum MA, Nowak AK, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Rogers L, Taal W, Ruda R, Weller M, McBain C, Reijneveld J, Enting RH, Caparrotti F, Lesimple T, Clenton S, Gijtenbeek A, Lim E, Herrlinger U, Hau P, Dhermain F, de Heer I, Aldape K, Jenkins RB, Dubbink HJ, Kros JM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, French P, Baumert BG. Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2021 Jun;22(6):813-823. doi: 10.1016/S1470-2045(21)00090-5. Epub 2021 May 14.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 9, 2016): 751
• Original Enrollment (submitted: February 28, 2008): 748
• Estimated Study Completion Date: December 2029
• Actual Primary Completion Date: September 5, 2018 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
• Original Responsible Party: Not Provided
• Current Study Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Original Study Sponsor: Same as current

Collaborators

• NCIC Clinical Trials Group
• Radiation Therapy Oncology Group
• Medical Research Council
• Merck Sharp & Dohme LLC

Investigators

• 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

• PRS Account: European Organisation for Research and Treatment of Cancer - EORTC
• Verification Date: August 2023