Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

NCT03925246 | Completed Phase 2 DMC

• 2 other identifiers: P160923J2017-004140-38
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

High Grade Glioma; Brain Cancer

Keywords

Recurrent high grade gliomas; IDH mutation; Immune Checkpoint inhibitor; Nivolumab

Outcome Measures

Primary Outcomes (1)

• 24 weeks progression-free survival (PFS24w) rate, documented by RANO criteria

  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.

  At 24 weeks (+/- 2 weeks) after treatment initiation

Secondary Outcomes (10)

• Progression-Free survival at 24 weeks (PFS24w) rate estimated by iRANO criteria

  24 weeks (+/- 2 weeks) after treatment initiation

• Median progression-free survival (median-PFS) assessed by RANO criteria

  From the date of treatment initiation until the date of first documented tumor progression or until the date of death due to any cause assessed up to 30 months

• Median progression-free survival (median-PFS) assessed by iRANO criteria

  From the date of treatment initiation until the date of first documented tumor progression or until the date of death due to any cause assessed up to 30 months

• Overall survival (OS)

  From the date of the treatment initiation until the date of death due to any cause, assessed up to 30 months

• Overall response rate (ORR) assessed by RANO criteria

  From the date of the treatment initiation to the date of the end of treatment, assessed up to 30 months

Study Arms (1)

Nivolumab

EXPERIMENTAL

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.

Drug: Nivolumab

Interventions

Nivolumab DRUG

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.

Also known as: Opdivo

Nivolumab

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological confirmation of grade III or IV high-grade glioma
• Tumor is mutated for IDH1 or IDH2 gene (detected by R132HIDH immunochemistry or IDH1/IDH2 sequencing)
• Age between 18 and 85 years old
• Recurrence occurring more than 12 weeks from the end of the radiotherapy or occurring outside the irradiated volume
• Karnofsky performance status \> 50
• Radiologically measurable disease based on RANO criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Available archived tissue for molecular (MGMT methylation, mutational load estimation) and immunohistochemical analysis (PD1, PD-L1, CD3, CD4, FoxP3, CD8, CD68, CD163, GFAP, olig2, ATRX, CIC, Ki67, P53)
• WBC ≥ 2000/μL
• Neutrophils ≥ 1500/μL
• Platelets ≥ 100 x103/μL
• Hemoglobin \> 9.0 g/dL
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
• Female CrCl = \[(140 - age in years) x weight in kg x 1.04\] / serum creatinine in µmol/l Male CrCl = (\[140 - age in years) x weight in kg x 1.23\] / serum creatinine in µmol/l
• AST/ALT ≤ 3 x ULN
• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)

You may not qualify if:

• Pregnant or breastfeeding women
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity or congestive cardiac insufficiency
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus and a known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or \> 1,5 mg dexamethasone or equivalent\*) or other immunosuppressive medications within 14 days of first study treatment administration. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone or \> 1,5 mg dexamethasone or equivalent, are permitted in the absence of active autoimmune disease.
• Any chemotherapy, anticancer immunotherapy or anticancer agents within 4 weeks (6 weeks for nitrosourea) before the first dose of study treatment,
• Receiving any other investigational agent or study drugs from a previous clinical study within 4 weeks before the first dose of study treatment (6 weeks for nitrosoureas).
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• History of allergy or Hypersensitivity to Nivolumab or to any of the excipients
• Subjects with history of life-threatening toxicity, including hypersensitivity reaction, related to prior immunoglobulin treatment for another condition (except those considered unlikely to re-occur) or any other study drug component.
• Surgical procedure \< 7 days prior to first study treatment administration, vascular access device no restriction;
• Subjects unable (e.g., due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head;
• Known allergy or contraindication to Gadolinium;

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Bristol-Myers Squibb: collaborator

Study Sites (7)

Groupe Hospitalier Saint-André

Bordeaux, 33000, France

Location

Hospices Civils de Lyon, Hôpital Pierre Wertheimer

Bron, 60900, France

Location

AP-HM, La Timone, Hôpital Universitaire

Marseille, 13000, France

Location

Institut de Cancérologie de l'Ouest (ICO) - site CLCC René Gauducheau

Nantes, 44000, France

Location

AP-HP - Groupe Hospitalier Pitié-Salpêtrière

Paris, France

Location

AP-HP - Hôpital Saint-Louis

Paris, France

Location

IUCT Oncopole - CLCC Institut Claudius Regaud

Toulouse, 31000, France

Location

Related Publications (1)

• Picca A, Touat M, Belin L, Gourmelon C, Harlay V, Cuzzubbo S, Cohen-Jonathan Moyal E, Bronnimann C, Di Stefano AL, Laurent I, Lerond J, Carpentier C, Bielle F, Ducray F, Dehais C; POLA Network. REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas. Eur J Cancer. 2024 May;202:114034. doi: 10.1016/j.ejca.2024.114034. Epub 2024 Mar 22.

  PMID: 38537315 RESULT

MeSH Terms

Conditions

Glioma; Brain Neoplasms

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• DEHAIS Caroline, MD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2019
• First Posted: April 24, 2019
• Study Start: July 30, 2019
• Primary Completion: December 2, 2020
• Study Completion: August 18, 2021
• Last Updated: April 2, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (7)