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

• ClinicalTrials.gov Identifier: NCT00626990
• Recruitment Status: Active, not recruiting
• First Posted: February 29, 2008
• Last Update Posted: February 3, 2021
• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: NCIC Clinical Trials Group; Radiation Therapy Oncology Group; Medical Research Council; Cooperative Trials Group for Neuro-Oncology; Merck Sharp & Dohme Corp.
• 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
• Last Update Posted Date: February 3, 2021
• Actual Study Start Date: December 2007
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 9, 2016): Overall survival as measured from the day of randomization [ Time Frame: from randomisation till the date of death (assessed up to estimated 15 years from FPI) ]
• Original Primary Outcome Measures (submitted: February 28, 2008): Overall survival as measured from the day of randomization

Current Secondary Outcome Measures (submitted: February 9, 2016)

• Progression-free survival [ Time Frame: from randomization till the date of disease progression or death (assessed up to estimated 15 years from FPI) ]
• Neurological deterioration-free survival [ Time Frame: from randomization till the date of neurological deterioration or death (assessed up to estimated 15 years from FPI) ]
• Quality of life as assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20 [ Time Frame: from 14 days prior to randomization till five years or death (assessed up to estimated 15 years from FPI) ]
• Toxicity as measured by CTEP Active Version of CTCAE [ Time Frame: from randomization till disease progression or death (assessed up to estimated 15 years from FPI) ]
• Development of cognitive deterioration as measured by the Mini Mental Status Exam [ Time Frame: from start RT till death (assessed up to estimated 15 years from FPI) ]

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 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, 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.

NOTE: *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 QLQ-C30 version 3, 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
  • Temcad
• Genetic: DNA methylation analysis
  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: 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 *: 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, Rudà 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: January 2024
• Estimated Primary Completion Date: January 2022 (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
• 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
• AST and 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
• Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
• Study Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Collaborators

• NCIC Clinical Trials Group
• Radiation Therapy Oncology Group
• Medical Research Council
• Cooperative Trials Group for Neuro-Oncology
• Merck Sharp & Dohme Corp.

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: February 2021