Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial

Abstract

Background: 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 tumour located in the brain optimizing care is the major challenge.

Methods: NOA-18 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) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for 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 deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany.

Discussion: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification.

Trial registration: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Keywords: CCNU and Temozolomide for Glioma (CETEG); Health-related quality of life (HRQoL); Neurocognition; Oligodendroglioma; Procarbazine, CCNU, vincristine (PCV); Qualified overall survival (qOS).

Fig. 1

Trial summary of IMPROVE CODEL/NOA-18. RT: For CNS WHO grade 3 oligodendroglioma: Radiotherapy is performed as 33 fractions of 1.8 Gy for a total dose of 59.4 Gy. One fraction is given daily five days per week for about 6 to 7 weeks. For CNS WHO grade 2 oligodendroglioma, radiotherapy is performed as 28 fractions of 1.8 Gy for a total dose of 50.4/54 Gy for over approximately 5–6 weeks. Tx Break: Rest period is 4 weeks long (± 2 weeks) total. PCV: PCV chemotherapy, cycles are about 6 weeks long each. Day 1: CCNU 110 mg/m² orally (capped at 200 mg); Days 8 and 29: vincristine 1.4 mg/m² i.v. (capped at 2 mg); Days 8 to 21: procarbazine 60 mg/m² orally (capped at 100 mg). CETEG: CCNU/temozolomide chemotherapy cycles are 6 weeks long. Day 1: CCNU 100 mg/m² orally (capped at 200 mg); Days 2–6: Temozolomide 100 mg/m² (cycle 1) with dose escalation in 50 mg/m² steps according to toxicity in subsequent cycles. ⁺Therapy at progression is as suggested at the time of the protocol preparation. It is reasonable that patients without prior radiotherapy will undergo radiotherapy; it is also very likely that PCV will be used as adjunct chemotherapy if bone marrow reserve allows and if there are no safety concerns from the initial CETEG treatment. The treatment at progression in the standard arm is less predictable; there may be an option for second radiotherapy or even reuse of the full radiochemotherapy regimen as it had been given at diagnosis. The trial will therefore continue to assess any endpoint-relevant scans and scales and also list the secondary treatments, but not attempt a full registration of the treatment, which is considered standard and not driven by trial requirements

Fig. 2

RT-PCV administration and dosing. ¹Follow these procedures for pseudoprogression: a) if pseudoprogression is felt to be present, treatment should continue and functional imaging (i.e., MRI perfusion, spectroscopy) or pathological confirmation should be considered; b) if pseudoprogression is known to be present, continue treatment per study protocol; c) if tumor progression is present, the patient should be discontinued from the study; d) if equivocal, contact the study PI. ²For CNS WHO grade 3 oligodendroglioma phase 1 RT is about 6 to 7 weeks long total. For CNS WHO grade 2 oligodendroglioma phase 1 RT is about 6 weeks. ³Phase 2 Rest Period is 4 weeks long (± 2 weeks) total. ⁴Phase 3 (chemotherapy cycles) are about 6 to 7 weeks long each. ⁵The maximum dose of CCNU (dose cap) is 200 mg. CCNU is administered at a dose of 110 mg/m² body surface area calculated according to Du Bois once every six weeks. It is recommended to be taken at least 3 h after the last meal in the morning or the evening. An antiemesis using a 5HT3 antagonist or a comparable medication should be used one hour before CCNU. The capsules should be swallowed whole and not opened or dissolved. If the dose is missed it can be taken within 48 hours of the usual starting day, but the interval to the first dose of procarbazine needs to be maintained. ⁶The maximum dose (dose cap) of vincristine is 2 mg. ⁷Procarbazine is usually taken fasting in the morning or 3 hours after the last meal at any time at 2 capsules. There is no specific concomitant medication. Some patients may benefit from an antiemesis at the discretion of the investigator

Fig. 3

CETEG administration and dosing. ¹ CCNU is administered at a dose of 100 mg/m² body surface area calculated according to Du Bois once every six weeks. It is recommended to be taken at least 3 h after the last meal in the morning or the evening. An antiemesis using a 5HT3 antagonist or a comparable medication should be used one hour before CCNU. The capsules should be swallowed whole and not opened or dissolved. If the dose is missed it can be taken within 48 hours of the usual starting day, but the interval to the first dose of TMZ needs to be maintained. ² The first cycle of temozolomide is administered at the dose of 100 mg/m². It will be taken once daily (QD) at 100 mg per m² body surface area calculated according to Du Bois on days 2–6 of a 42 days cycle, fasting in the morning. An antiemesis using a 5HT3 antagonist or a comparable medication should be used one hour before temozolomide. The capsule should be swallowed whole and not opened or dissolved. If a dose is missed it can be taken within 6 hours of the usual morning dose. If the time is greater than 6 hours than the regular time or the patient vomits the dose, the patient should wait and take the next dose. The dose is escalated to 150 mg/m² and 200 mg/m² as of subsequent cycles in the absence of toxicity. ³ Follow these procedures for pseudoprogression: a) if pseudoprogression is felt to be present, treatment should continue and functional imaging (i.e., MRI perfusion, spectroscopy) or pathological confirmation should be considered; b) if pseudoprogression is known to be present, continue treatment per study protocol; c) if tumor progression is present, the patient should be discontinued from the study; d) if equivocal, contact the study PI. ⁴Treatment cycles are about 6 weeks long each

Fig. 4

Definition of the primary endpoint (including handling of missing values/visits). Green means that there is no decline, and red means that there is a decline that is relevant in terms of the primary endpoint