Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05331521




Registration number
NCT05331521
Ethics application status
Date submitted
15/03/2022
Date registered
15/04/2022
Date last updated
23/09/2022

Titles & IDs
Public title
A Clinical Study to Improve Brain Function and Quality of Life of Patients With Newly Diagnosed Brain Tumors (Gliomas).
Scientific title
Improvement of Functional Outcome for Patients With Newly Diagnosed Grade II or III Glioma With Co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 Trial
Secondary ID [1] 0 0
2018-005027-16
Secondary ID [2] 0 0
NOA-18
Universal Trial Number (UTN)
Trial acronym
ImproveCodel
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Oligodendroglioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - CETEG
Treatment: Drugs - PCV
Treatment: Other - RT

Active Comparator: RT PCV - Radiotherapy (RT) for over approximately 5-6 weeks:
at 50.4/54 Gy in 1.8 Gy fractions for grade II and
at 59.4 Gy in 1.8 Gy fractions for grade III gliomas
PCV cycles are 6 weeks long and given as:
Day 1: Lomustine (CCNU) at 110 mg/m2 body surface orally,
Days 8/29: Vincristine 1.4 mg/m2 i.v. (capped at 2 mg),
Days 8-21: Procarbazine 60 mg/m2 orally (capped at 100 mg).

Experimental: CETEG - Six 42-day cycles of lomustine plus temozolomide according to the commonly used regimen:
Day 1: Lomustine (CCNU) at 100 mg/m2
Days 2-6: Temozolomide at 100 mg/m2 (cycles 1) and in 50 mg/m2 steps to 200 mg/m2 from cycle 2 on dependent on hematological toxicity


Treatment: Drugs: CETEG
At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.

Treatment: Drugs: PCV
In the comparator arm there is the option for second radiotherapy or even reuse of the full radiochemotherapy regimen as it had been given at diagnosis (BIC).

Treatment: Other: RT
Radiotherapy at 50.4/54 Gy in 1.8 Gy fractions for grade II and 59.4 Gy in 1.8 Gy fractions for grade III gliomas
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Qualified overall survival (qOS)
Timepoint [1] 0 0
From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
Primary outcome [2] 0 0
Short-term qOS deterioration in NeuroCogFX®
Timepoint [2] 0 0
Every 12 months, after a decline within 1 week and after 90 days
Primary outcome [3] 0 0
Short-term qOS deterioration in KPI
Timepoint [3] 0 0
From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
Primary outcome [4] 0 0
Short-term qOS deterioration in HrQoL
Timepoint [4] 0 0
From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
Primary outcome [5] 0 0
Short-term qOS deterioration in NANO scale
Timepoint [5] 0 0
From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
Primary outcome [6] 0 0
Short-term qOS deterioration due to death
Timepoint [6] 0 0
From start of randomization until death from any cause
Secondary outcome [1] 0 0
Short-term qOS
Timepoint [1] 0 0
From 3 months after start of treatment until maximum of 10 years or date of death from any cause, whichever came first.
Secondary outcome [2] 0 0
Overall survival (OS)
Timepoint [2] 0 0
From start of randomization until death from any cause
Secondary outcome [3] 0 0
Progression-free survival (PFS)
Timepoint [3] 0 0
From randomization until the day of first documentation of clinical or radiographic tumor progression or death of any cause, whichever occurs first

Eligibility
Key inclusion criteria
- Histologically confirmed, newly diagnosed WHO grade II or III glioma.

- Tumor carries an isocitrate dehydrogenase (IDH) mutation (determined by
immunohistochemistry (IHC) and/or deoxyribonucleic acid (DNA) sequencing).

- Tumor is co-deleted for 1p/19q (determined by copy number variations, fluorescence in
situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) or
other appropriate methods).

- Open biopsy or resection.

- Age =18 years.

- Karnofsky Performance Index (KPI) =60%.

- Life expectancy > 6 months.

- Availability of formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tissue and
ethylenediamine tetraacetic acid (EDTA) blood for biomarker research.

- Standard magnetic resonance imaging (MRI) = 72 post-surgery according to the present
national and international guidelines.

- Craniotomy or intracranial biopsy site must be adequately healed.

- = 2 weeks and = 3 months from surgery without any interim radio- or chemotherapy or
experimental intervention.

- Willing and able to comply with regular neurocognitive and health-related quality of
life tests/questionnaires.

- Indication for postsurgical cytostatic/-toxic therapy.

- Written Informed consent.

- Female patients with reproductive potential have a negative pregnancy test (serum or
urine) within 6 days prior to start of therapy. Female patients are surgically sterile
or agree to use adequate contraception during the period of therapy and 6 months after
the end of study treatment, or women have been postmenopausal for at least 2 years.

- Male patients are willing to use contraception.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participation in other ongoing interventional clinical trials.

- Insufficient tumor material for molecular diagnostics.

- Inability to undergo MRI.

- Abnormal (= Grade 2 CTCAE v5.0) laboratory values for hematology (Hb, WBC (White Blood
Cell), neutrophils, or platelets), liver (serum bilirubin, ALT (Alanine Amino
Transferase), or AST (Aspartate Amino Transferase)) or renal function (serum
creatinine).

- Active tuberculosis; known HIV infection or active Hepatitis B (HBV) or Hepatitis C
(HCV infection, or active infections requiring oral or intravenous antibiotics or that
can cause a severe disease and pose a severe danger to lab personnel working on
patients' blood or tissue (e.g. rabies).

- Any prior anti-cancer therapy or co-administration of anti-cancer therapies other than
those administered/allowed in this study. History of low-grade glioma that did not
require prior treatment with chemotherapy or radiotherapy is not an exclusion
criterion.

- Immunosuppression not related to prior treatment for malignancy.

- History of other malignancies (except for adequately treated basal or squamous cell
carcinoma or carcinoma in situ) within the last 5 years unless the patient has been
disease-free for 5 years.

- Any clinically significant concomitant disease (including hereditary fructose
intolerance) or condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or the absorption of oral medications or that
would, in the opinion of the Principal Investigator, pose an unacceptable risk to the
patient in this study.

- Any psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol requirements and/or follow-up procedures;
those conditions should be discussed with the patient before trial entry.

- Pregnancy or breastfeeding.

- History of hypersensitivity to the investigational medicinal product or to any drug
with similar chemical structure or to any excipient present in the pharmaceutical form
of the investigational medicinal product.

- QTc (corrected QT interval) time prolongation > 500 ms.

- Patients under restricted medication for procarbazine, lomustine, vincristine and
temozolomide.

- Liver disease characterized by:

- ALT or AST (= Grade 2 CTCAE v5.0) confirmed on two consecutive measurements OR

- Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or
other conditions of decompensated liver disease such as coagulopathy, hepatic
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices (=
Grade 2 CTCAE v5.0) OR

- Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis

- Known uncorrected coagulopathy, platelet disorder, or history of non-drug induced
thrombocytopenia.

- History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis; autoimmune-related
hypothyroidism (patients on a stable dose of thyroid replacement hormone are eligible
for this study) and type I diabetes mellitus (patients on a stable dose of insulin
regimen are eligible for this study).

- Vaccination with life vaccines during treatment and 4 weeks before start of treatment.

- Existing neuromuscular diseases, especially neural muscular atrophy with segmental
demyelination (demyelinising form of Charcot-Marie-Tooth syndrome)

- Chronic constipation and subileus

- Combination treatment with mitomycin (risk of a pronounced bronchospasm and acute
shortness of breath)

- Hypersensitivity to dacarbazine (DTIC)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/04/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/03/2029
Actual
Sample size
Target
406
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Baden-Württemberg
Country [2] 0 0
Germany
State/province [2] 0 0
Berlin
Country [3] 0 0
Germany
State/province [3] 0 0
Bochum
Country [4] 0 0
Germany
State/province [4] 0 0
Bonn
Country [5] 0 0
Germany
State/province [5] 0 0
Chemnitz
Country [6] 0 0
Germany
State/province [6] 0 0
Cologne
Country [7] 0 0
Germany
State/province [7] 0 0
Duesseldorf
Country [8] 0 0
Germany
State/province [8] 0 0
Frankfurt
Country [9] 0 0
Germany
State/province [9] 0 0
Göttingen
Country [10] 0 0
Germany
State/province [10] 0 0
Homburg
Country [11] 0 0
Germany
State/province [11] 0 0
Jena
Country [12] 0 0
Germany
State/province [12] 0 0
Leipzig
Country [13] 0 0
Germany
State/province [13] 0 0
Mannheim
Country [14] 0 0
Germany
State/province [14] 0 0
Minden
Country [15] 0 0
Germany
State/province [15] 0 0
Munich
Country [16] 0 0
Germany
State/province [16] 0 0
Regensburg
Country [17] 0 0
Germany
State/province [17] 0 0
Schwerin
Country [18] 0 0
Germany
State/province [18] 0 0
Tuebingen
Country [19] 0 0
Germany
State/province [19] 0 0
Würzburg

Funding & Sponsors
Primary sponsor type
Other
Name
University Hospital Heidelberg
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Universitätsmedizin Mannheim
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Ruhr University of Bochum
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Oligodendrogliomas in the novel edition of the Central Nervous System (CNS) World Health
Organization (WHO) classification are now molecularly defined by isocitrate dehydrogenase
(IDH)1 or IDH2 mutations and 1p/19q co-deletion. The prognosis of these molecularly defined
tumors is to be determined in new series since survival data from older histology-based
studies and population-based registries are confounded by the inclusion of 20-70% not
molecularly matching subsets. Also, the optimal treatment is a matter of ongoing
investigations. An extensive, but safe surgery is associated with improved outcome as is the
addition of chemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) to the
partial brain radiotherapy (RT). However, the exact timing of postsurgical therapy especially
for tumors of the WHO grade II and acknowledging some variability in grading as well as the
choice of chemotherapy, temozolomide instead of PCV (CODEL: NCT00887146 randomizing CNS WHO
grade 2 and 3 oligodendrogliomas to chemoradiation(CHRT)therapy with PCV or with
temozolomide) or the need for primary radiotherapy RT are subjects of clinical studies
(POLCA: NCT02444000 randomizing patients with newly diagnosed CNS WHO grade 3
oligodendrogliomas to standard CHRT with PCV or PCV alone). Given the young age of patients
with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive,
functional and quality-of-life impairment with the current aggressive standard of care
treatment, chemoradiation with PCV, of the tumor located in the brain optimizing care is the
major challenge.

NOA-18/IMPROVE CODEL aims at improving qualified overall survival (qOS) for adult patients
with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation
with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and
temozolomide (CETEG), thereby delaying radiotherapy (RT) and adding the chemoradiotherapy
(CHRT) concept at progression after initial radiation-free chemotherapy, allowing for an
effective salvage treatment and delaying potentially deleterious side effects. QOS represents
a new concept and is defined as OS without functional and/or cognitive and/or quality of life
(QOL) deterioration regardless whether tumor progression or toxicity is the main cause.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05331521
Trial related presentations / publications
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106.
Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8. Erratum In: Nat Rev Clin Oncol. 2022 May;19(5):357-358.
Fliessbach K, Rogowski S, Hoppe C, Sabel M, Goeppert M, Helmstaedter C, Calabrese P, Schackert G, Tonn JC, Simon M, Schlegel U. Computer-based assessment of cognitive functions in brain tumor patients. J Neurooncol. 2010 Dec;100(3):427-37. doi: 10.1007/s11060-010-0194-9. Epub 2010 May 7.
Hoffermann M, Bruckmann L, Mahdy Ali K, Zaar K, Avian A, von Campe G. Pre- and postoperative neurocognitive deficits in brain tumor patients assessed by a computer based screening test. J Clin Neurosci. 2017 Feb;36:31-36. doi: 10.1016/j.jocn.2016.10.030. Epub 2016 Nov 9.
Taphoorn MJ, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, Saran F, Nishikawa R, Hilton M, Theodore-Oklota C, Ravelo A, Chinot OL. Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma. J Clin Oncol. 2015 Jul 1;33(19):2166-75. doi: 10.1200/JCO.2014.60.3217. Epub 2015 May 26.
Nayak L, DeAngelis LM, Brandes AA, Peereboom DM, Galanis E, Lin NU, Soffietti R, Macdonald DR, Chamberlain M, Perry J, Jaeckle K, Mehta M, Stupp R, Muzikansky A, Pentsova E, Cloughesy T, Iwamoto FM, Tonn JC, Vogelbaum MA, Wen PY, van den Bent MJ, Reardon DA. The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria. Neuro Oncol. 2017 May 1;19(5):625-635. doi: 10.1093/neuonc/nox029.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.
Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. doi: 10.1093/neuonc/now133. Epub 2016 Jul 1. Erratum In: Neuro Oncol. 2016 Nov;18(11):e1.
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Wolfgang Wick, Prof. Dr.
Address 0 0
University Hospital Heidelberg
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Wolfgang Wick, Prof. Dr.
Address 0 0
Country 0 0
Phone 0 0
+49 6221 56
Fax 0 0
Email 0 0
wolfgang.wick@med.uni-heidelberg.de
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05331521