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 |
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High Grade Glioma Brain Cancer | Drug: Nivolumab | Phase 2 |
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 |
Arm | Intervention/treatment |
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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.
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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
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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 |
Inclusion Criteria:
The following laboratory values obtained ≤ 7 days prior to inclusion:
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
Exclusion Criteria:
France | |
Groupe Hospitalier Pitié-Salpêtrière | |
Paris, France |
Principal Investigator: | DEHAIS Caroline, MD | Assistance Publique - Hôpitaux de Paris |
Tracking Information | |||||
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First Submitted Date ICMJE | March 14, 2019 | ||||
First Posted Date ICMJE | April 24, 2019 | ||||
Last Update Posted Date | July 2, 2020 | ||||
Actual Study Start Date ICMJE | July 30, 2019 | ||||
Estimated Primary Completion Date | December 2020 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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.
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Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas | ||||
Official Title ICMJE | A Phase II Study From the POLA National Network of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas | ||||
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. |
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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.
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Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 2 | ||||
Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE | 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
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Study Arms ICMJE | 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.
Intervention: Drug: Nivolumab
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Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Active, not recruiting | ||||
Actual Enrollment ICMJE |
43 | ||||
Original Estimated Enrollment ICMJE |
39 | ||||
Estimated Study Completion Date ICMJE | June 2021 | ||||
Estimated Primary Completion Date | December 2020 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 85 Years (Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
Listed Location Countries ICMJE | France | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT03925246 | ||||
Other Study ID Numbers ICMJE | P160923J 2017-004140-38 ( EudraCT Number ) |
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Has Data Monitoring Committee | Yes | ||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Assistance Publique - Hôpitaux de Paris | ||||
Study Sponsor ICMJE | Assistance Publique - Hôpitaux de Paris | ||||
Collaborators ICMJE | Bristol-Myers Squibb | ||||
Investigators ICMJE |
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PRS Account | Assistance Publique - Hôpitaux de Paris | ||||
Verification Date | July 2020 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |