Intra-tumoral Ipilimumab Plus Intravenous Nivolumab Following the Resection of Recurrent Glioblastoma (GlitIpNi)
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|ClinicalTrials.gov Identifier: NCT03233152|
Recruitment Status : Recruiting
First Posted : July 28, 2017
Last Update Posted : July 28, 2017
Phase I clinical trial on intra-tumoral ipilimumab plus intravenous nivolumab following the resection of recurrent glioblastoma.
The aim of this clinical trial is to exploit the potential synergy of combined intra-tumoral CTLA-4 and systemic PD-1 blockade while minimizing the risk for increased immune-related toxicity by intratumoral administration of the CTLA-blocking mAb ipilimumab following the resection of the recurrent glioblastoma.
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma||Drug: Ipilimumab (YervoyTM, 50 mg/10 mL solution) Drug: Nivolumab (OpdivoTM, 40 mg/4mL solution)||Phase 1|
Nivolumab (OpdivoTM, BMS), a human IgG-4 mAb that blocks the Programmed cell death protein 1 (PD-1, CD279) has demonstrated anti-tumor activity in patients with various solid- and hematological neoplasms. Nivolumab has been registered by EMA and/or FDA for the treatment of patients with advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and Hodgkin lymphoma. In a phase I dose escalation clinical trial, receptor blockade of PD-1 by nivolumab on circulating lymphocytes was maximal at a dose of 0,3 mg/kg. In patients with advanced melanoma nivolumab had a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks. Nivolumab was further developed at a dose of 3 mg/kg q2wks and improved the overall survival of patients with advanced melanoma, NSCL, RCC and HNSCC.
Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the overall survival of patients with advanced melanoma; and the relapse-free survival after complete resection of high-risk stage III melanoma. Animal models have established the safety and efficacy of intra-tumoral administration of ipilimumab. An intratumoral dose of CTLA-4 blocking mAb administered at a ratio of [1:100] compared to intravenous dosing was found to result in equivalent anti-tumor effect and was associated with less systemic toxicity.
Combined treatment with ipilimumab (3 mg/kg q3wks x4) plus nivolumab (1 mg/kg q3 wks x4 followed by 3 mg/kg q2 wks) further increases the tumor response rate and progression-free survival of patients with advanced melanoma and has been registered by EMA and FDA; this combination therapy is associated with a higher incidence of immune related adverse events. Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (CHECKMATE-143) were presented at the 2015 and 2016 ASCO Annual meetings (20 pts were treated, 10 in each arm).  All nivolumab related AEs were grade 1 or 2. Eight (80%) nivolumab plus ipilimumab treated patients experienced grade 3/4 AEs. Drug-related AEs leading to discontinuation occurred only in nivolumab plus ipilimumab patients (n = 5; 50%), including colitis, cholecystitis, diabetic ketoacidosis, confusion, and increased lipase. There were no drug-related deaths. Based on these experiences, the sponsor (BMS) decided to further investigate nivolumab as a mono-therapy in patients with recurrent- and newly diagnosed glioblastoma (CA209-143; CA209-498 and CA209-548). Antitumor activity of nivolumab has recently been established in children with recurrent glioblastoma that is characterized by biallelic mismatch repair deficiency.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||6 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Clinical Trial on Intra-tumoral Ipilimumab Plus Intravenous Nivolumab Following the Resection of Recurrent Glioblastoma|
|Actual Study Start Date :||November 17, 2016|
|Estimated Primary Completion Date :||November 17, 2018|
|Estimated Study Completion Date :||November 17, 2019|
Experimental: ipilimumab + nivolumab
Only one study cohort will be predefined in this phase I clinical trial; a classical phase I "3+3 patient" recruitment design will be used to guide patient recruitment.
Ipilimumab (YervoyTM, 50 mg/10 mL) will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (2 ml of YervoyTM, 50 mg/10mL vial).
First administration of 10 mg Nivolumab (OpdivoTM, 40 mg/4mL solution) by the intravenous route will be administered within 24 hours prior to the planned neurosurgical resection. The following administrations of 10 mg nivolumab will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).
Drug: Ipilimumab (YervoyTM, 50 mg/10 mL solution)
Ipilimumab will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (: 2 ml of YervoyTM, 50 mg/10mL vial).
Injections will be performed manually using a 100 μ-liter dispensing syringe. Twenty needle tracks will dispense the ipilimumab solution within the brain tissue lining the resection cavity. The region suspect on preoperative MRI of the brain to be invaded by glioblastoma cells but not amenable to safe resection will be targeted by adjacent needle tracks through which up to 2 cm of depth a volume of 100 μl per needle track will be injected (: in total 20 needle tracks will be performed). This methodology has been applied previously within the context of phase III clinical trials with sitimagene ceradenovec.
Other Name: Nivolumab (OpdivoTM, 40 mg/4 mL solution)
Drug: Nivolumab (OpdivoTM, 40 mg/4mL solution)
First administration of 10 mg of nivolumab by the intravenous route should be administered within 24 hours prior to the planned neurosurgical resection. Administrations of 10 mg nivolumab (OpdivoTM, 40 mg/4mL solution) will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).
- Progression-free survival (PFS) [ Time Frame: up to 30 weeks ]Estimate the survival of patients who are free from confirmed tumor.
- Overall Survival (OS) [ Time Frame: an average of 1 year ]Estimate the survival of patients who are alive.
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): NCT03233152
|Contact: Prof. Dr. Bart Neyns, MD, PhD||+3224775447||Bart.Neyns@uzbrussel.be|
|Contact: Dr. Johnny Deurinck, MD, PhD||+3224775514||Johnny.Duerinck@uzbrussel.be|
|Universitair Ziekenhuis Brussel||Recruiting|
|Brussels, Belgium, 1090|
|Principal Investigator: Prof. Dr. Bart Neyns, MD, PhD|
|Sub-Investigator: Dr. Johnny Deurinck, MD, PhD|