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Trial record 1 of 1 for:    revolumab
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Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas (REVOLUMAB)

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ClinicalTrials.gov Identifier: NCT03925246
Recruitment Status : Active, not recruiting
First Posted : April 24, 2019
Last Update Posted : July 2, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.


Condition or disease Intervention/treatment Phase
High Grade Glioma Brain Cancer Drug: Nivolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study From the POLA National Network of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas
Actual Study Start Date : July 30, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab
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

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 Name: Opdivo




Primary Outcome Measures :
  1. 24 weeks progression-free survival (PFS24w) rate, documented by RANO criteria [ Time Frame: At 24 weeks (+/- 2 weeks) after treatment initiation ]
    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.


Secondary Outcome Measures :
  1. Progression-Free survival at 24 weeks (PFS24w) rate estimated by iRANO criteria [ Time Frame: 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.

  2. Median progression-free survival (median-PFS) assessed by RANO criteria [ Time Frame: 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-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

  3. Median progression-free survival (median-PFS) assessed by iRANO criteria [ Time Frame: 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-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

  4. Overall survival (OS) [ Time Frame: From the date of the treatment initiation until the date of death due to any cause, assessed up to 30 months ]
    Overall survival is defined as the time from treatment initiation to death due to any cause

  5. Overall response rate (ORR) assessed by RANO criteria [ Time Frame: From the date of the treatment initiation to the date of the end of treatment, assessed up to 30 months ]
    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

  6. Overall response rate (ORR) assessed by iRANO criteria [ Time Frame: From the date of the treatment initiation to the date of the end of treatment, assessed up to 30 months ]
    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

  7. Duration of response assessed by RANO criteria [ Time Frame: From the date of the treatment initiation until the date of tumor progression, assessed up to 30 months ]
    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

  8. Duration of response assessed by iRANO criteria [ Time Frame: From the date of the treatment initiation until the date of tumor progression, assessed up to 30 months ]
    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

  9. Longitudinal changes in quality of life (EORTC QLQ-C30 and BN20) [ Time Frame: Before day 1 (t0) then every 4 cycles during 8 first cycles, then every 2 cycles until cycle 16 (1 cycle = 28 days) ]
    Data at each time point will be compared to t0 (before first infusion of Nivolumab)

  10. Safety: Type, frequency and severity of adverse events and serious adverse events [ Time Frame: Up to 30 months after the date of the treatment initiation ]
    The adverse events will be described and graded according to the revised NCI Common Terminology Criteria V4.03 for Adverse Events (CTCAE V4.03)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histological confirmation of grade III or IV high-grade glioma
  2. Tumor is mutated for IDH1 or IDH2 gene (detected by R132HIDH immunochemistry or IDH1/IDH2 sequencing)
  3. Age between 18 and 85 years old
  4. Recurrence after radiotherapy and at least one line of alkylating chemotherapy (Temozolomide or PCV (Procarbazine, CCNU, Vincristine) (Surgery at recurrence is allowed before trial inclusion)
  5. Recurrence occurring more than 12 weeks from the end of the radiotherapy or occurring outside the irradiated volume
  6. Karnofsky performance status > 50
  7. 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
  8. Patients must be able to taper steroids (preferably discontinued). Dose at inclusion must be ≤ 10 mg prednisone (or equivalent*). The decrease in dose will be evaluated by clinical examination, the ability to decrease the corticosteroids being related to the absence of increased headaches and the absence of increased of neurological disability (impaired alertness)
  9. 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)
  10. The following laboratory values obtained ≤ 7 days prior to inclusion:

    • 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)
    • Negative serum pregnancy test for women of childbearing potential
  11. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 5 months after the last dose of study treatment (ie, 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo approximately five half-lives)
  12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo approximately five half-lives.}
  13. Written informed consent dated and signed, prior to any study specific procedures (sampling, treatment and analyses).
  14. Affiliation to a French social security system (recipient or assign) excluding AME.

Exclusion Criteria:

  1. Pregnant or breastfeeding women
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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).
  7. 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.
  8. Any chemotherapy, anticancer immunotherapy or anticancer agents within 4 weeks (6 weeks for nitrosourea) before the first dose of study treatment,
  9. 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).
  10. 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.
  11. History of allergy or Hypersensitivity to Nivolumab or to any of the excipients
  12. Any unresolved toxicities (excepted alopecia), from prior therapy greater than CTCAE grade 1 at the time of inclusion.
  13. 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.
  14. Surgical procedure < 7 days prior to first study treatment administration, vascular access device no restriction;
  15. Subjects unable (e.g., due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head;
  16. Known allergy or contraindication to Gadolinium;
  17. Patients under guardianship

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03925246


Locations
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France
Groupe Hospitalier Pitié-Salpêtrière
Paris, France
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Bristol-Myers Squibb
Investigators
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Principal Investigator: DEHAIS Caroline, MD Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03925246    
Other Study ID Numbers: P160923J
2017-004140-38 ( EudraCT Number )
First Posted: April 24, 2019    Key Record Dates
Last Update Posted: July 2, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Recurrent high grade gliomas
IDH mutation
Immune Checkpoint inhibitor
Nivolumab
Additional relevant MeSH terms:
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Glioma
Brain Neoplasms
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
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents