Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas
Condition: High Grade Glioma; Brain Cancer
MeSH terms: Glioma; Brain Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Nivolumab
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Opdivo
Intervention MeSH terms: Nivolumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Recurrent high grade gliomas; IDH mutation; Immune Checkpoint inhibitor; Nivolumab