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Immune Checkpoint Inhibitors

Nivolumab

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Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 weeks for 8 doses (4 months), followed by a 60 minutes intravenous infusion at dose of 480 mg every 4 weeks for 8 doses (8 months) or until progression, death , unacceptable toxicity or end of the research.

Nivolumab (Opdivo) is a potent human monoclonal antibody (mAb) of the IgG4 isotype designed to directly block the interaction between Programmed Cell Death 1 (PD-1) and its ligands, Programmed Death Ligand 1 (PD-L1) and PD-L2.

Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 (+/- 2 days) weeks for 8 cycles (4 months), followed by a dose of 480 mg administered by a 60 minutes intravenous infusion every 4 weeks (+/-3 days) (beginning at cycle 9) for a total therapy duration of 1 year (maximum 16 cycles of treatment) or until progression, death, unacceptable toxicity.

DEHAIS Caroline, MD

Immune checkpoint blockade therapies targeting the immunomodulatory effect of cytotoxic T-lymphocyte antigen (CTLA-4) and programmed cell death-1/ Programmed death-ligand 1 (PD-1/PD-L1) have recently demonstrated survival benefit and durable response in phase III trials in several human cancers, especially in tumors that bear high mutation load and/or tumor-associated neoantigen signatures. The aim of these treatments is to restore effector T-cell function and antitumor activity, which could be enhanced in the context of high mutational/neoantigen load. In Isocitrate DeHydrogenase mutated High Grade Gliomas (IDHm HGGs), acquired resistance to alkylating chemotherapy frequently results from the inactivation of mismatch-repair (MMR) proteins which in turn leads to the acquisition of a hypermutator phenotype. These findings suggest that at least in a subset of recurrent IDHm HGGs immune checkpoint blockade therapies may be particularly effective. IDHm HGGs most frequently occur in young adults. The first line treatment consists of maximal safe surgical resection followed by radiotherapy and adjuvant alkylating chemotherapy (Temozolomide or Procarbazine-CCNU-Vincristine regimen (PCV)). Despite these treatments, most IDHm HGGs recurred in few years. There is no standard of care at recurrence and the median overall survival after it is less than 3 years.

The investigators make the hypothesis that treatment with the anti-PD-1 monoclonal antibody Nivolumab will improve 24 weeks progression-free survival in IDHm HGGs that have recurred after initial treatment with radiotherapy and alkylating chemotherapy.

IDHm HGGs (High-Grade (grade III or IV) Gliomas that harbor mutations in Isocitrate Dehydrogenase 1 (IDH1) or Isocitrate Dehydrogenase 2 (IDH2)) most frequently occur in young adults. Favorable prognostic factors include high Karnofsky performance score, young age, 1p/19q codeletion and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Despite primary management, which consists of maximal safe surgical resection followed by radiotherapy and adjuvant alkylating chemotherapy with temozolomide (TMZ) or Procarbazine, CCNU, Vincristine (PCV), most IDHm HGGs recur, resulting in death with a median overall survival of 5 years. At recurrence, there is currently no standard of care. Because of the lack of clinical trials specifically designed for patients with relapsed IDHm HGGs, most patients receive alkylating chemotherapy (nitrosourea- or TMZ-containing regimens). However, these treatments have modest efficacy, as shown in several phase II trials that have reported response rates of 17-44% and 6-month progression-free survival (PFS6) of 29-51%. The efficacy of alkylating agents as DNA damaging agents is dependent on a functional MMR pathway. In IDHm HGGs, acquired resistance to alkylating chemotherapy can arise after the inactivation of MMR proteins, which in turn leads to the acquisition of a hypermutator phenotype. Paired analyses of newly diagnosed and recurrent tumors (after treatment with alkylating agents), have demonstrated that IDHm HGGs that recur after treatment with alkylating chemotherapy often harbor hypermutator phenotype associated with defects in the MMR pathway. While such MMR defects are extremely rare in newly diagnosed IDHm HGGs, MMR mutations were reported in 20-50% of patients with recurrent IDHm HGGs giving support that there is selective pressure to decreased MMR in glial tumors treated with alkylating chemotherapy. These findings suggest that, at least in a subset of recurrent IDHm HGGs, Nivolumab may be effective. Nivolumab has demonstrated overall survival (OS) benefit in multiple tumor types and has demonstrated a manageable safety profile in \> 12300 subjects across all clinical trials. For monotherapy, the safety profile is similar across tumor types. Preliminary data from phase I and phase III trials in patient with gliomas have indicated that Nivolumab is well tolerated in patients with primary brain tumors. Yet, these tumors may represent particularly good candidates for immune checkpoint blockade therapies since they frequently develop a hypermutated phenotype after alkylating chemotherapy.

This is a phase II, open label, non-randomized multicentric trial evaluating the efficacy of Nivolumab in adults' patients with recurrent IDHm HGGs. The main objective is to evaluate the efficacy of Nivolumab, based on 24 weeks progression-free survival (PFS24w) rate as assessed by RANO criteria.

Nivolumab is administered by a 30 minutes intravenous infusion at dose of 240 mg every 2 (+/- 2 days) weeks for 8 cycles (4 months), followed by a dose of 480 mg administered by a 60 minutes intravenous infusion every 4 weeks (+/-3 days) (beginning at cycle 9) for a total therapy duration of 1 year (maximum 16 cycles of treatment) or until progression, death, unacceptable toxicity.

Patients will undergo efficacy assessments using magnetic resonance imaging (MRI) every 8 weeks (every 4 cycles during 8 first cycles, then every 2 cycles). Patient outcomes measures will be completed at the time of each imaging study. Toxicity assessments will occur before the initiation of each cycle. Health related Quality of life (EORTC QLQ-C30 and QLQ-BN20) will be assessed before day 1, every 4 cycles during 8 first cycles, then every 2 cycles.

* In case of discontinuation from study treatment for toxicity or severe adverse events, subject request or investigator decision :

  * PFS-24w assessment should be done at W24 +/- 2weeks if applicable
  * date of tumor progression according to RANO and iRANO criteria and date of death if applicable
* In case of end of treatment duration :

  * A brain MRI will be performed 4 weeks after the C16
  * After the end of the research, patient will be followed every 3 months as usual care, by phone, to record date of tumor progression according to RANO criteria and date of death, if applicable.
* Adverse events must be notified and documented by investigator for a minimum of 100 days after last dose of treatment. Drug-related toxicities should continue be followed until they resolve, return to baseline or are deemed irreversible.

Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

A Phase II Study From the POLA National Network of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

Data are available upon reasonable request. The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Efficacy of Nivolumab will be based on PFS24w. PFS24w was defined by the percentage of patients alive without progression according to RANO criteria at 24 weeks +/- 2 weeks after treatment initiation.

PFS24w was defined by the percentage of patients alive without progression according to iRANO criteria at 24 weeks +/- 2 weeks after treatment initiation.

Median-PFS is defined by the time in which fifty percent (50%) of patients have experienced tumor progression or death due to any cause. It will be documented using RANO criteria

Median-PFS is defined by the time in which fifty percent (50%) of patients have experienced tumor progression or death due to any cause. It will be documented using iRANO criteria

Overall survival is defined as the time from treatment initiation to death due to any cause

Overall response rate is defined by the percentage of patients with at least a complete response and partial response using RANO criteria documented during treatment

Overall response rate is defined by the percentage of patients with at least a complete response and partial response using iRANO criteria documented during treatment

Duration of response is defined by the time from confirmation of stable, partial and complete response using RANO criteria until the tumor progression has been shown

Duration of response is defined by the time from confirmation of stable, partial and complete response using iRANO criteria until the tumor progression has been shown

Data at each time point will be compared to t0 (before first infusion of Nivolumab)

The adverse events will be described and graded according to the revised NCI Common Terminology Criteria V4.03 for Adverse Events (CTCAE V4.03)

Spots Global Cancer Trial Database for recurrent high grade gliomas