NCT03233152

A Phase I/II Clinical Trial on the Per-operative Intratumoral Administration of Myeloid Dendritic Cells Plus Ipilimumab and Nivolumab, Followed by Repeated Intracavitary Plus Intravenous Administration of Nivolumab in Patients With Recurrent Glioblastoma.

A Phase I/II Clinical Trial on the Per-operative Intratumoral Administration of Myeloid Dendritic Cells Plus Ipilimumab and Nivolumab, Followed by Repeated Intracavitary Plus Intravenous Administration of Nivolumab in Patients With Recurrent Glioblastoma

• Status: Active Not Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 110 (actual)
• Sponsor: Universitair Ziekenhuis Brussel · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Phase I/II clinical trial on the per-operative intra-tumoral administration of myeloid dendritic cells plus ipilimumab and nivolumab, followed by repeated intracavitary administration of ipilimumab and nivolumab plus intravenous administration of nivolumab in patients with recurrent glioblastoma. The aim of this clinical trial is to exploit the potential synergy of combined intra-tumoral CTLA-4 and autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC 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.

Detailed description

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). \[15\] 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. Recent insight into the interplay of myeloid and lymphoid cells in the tumor microenvironment (TME) has indicated a pivotal role for myeloid dendritic cells (myDC) as key-mediators in mediating an adaptive anti-tumor immune response and also in "re-licensing" antitumoral CTL within the TME. Even when present in very low numbers, these cells play an essential role in "re-licensing" of antitumoral CTL within the TME. (Broz, Binnewies et al. 2014) CD1c (BDCA-1)+ myDC and CD141 (BDCA-3)+ myDC are able to capture tumor antigens in vivo. Through the cross presentation of tumor antigens CD1c (BDCA-1)+ myDC and CD141 (BDCA-3)+ myDC can coordinate an effective antitumoral T-cell response.

Conditions

• Glioblastoma

Interventions

Type	Name	Description
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.
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).
BIOLOGICAL	Autologous CD1c(BDCA-1)+ /CD141(BDCA-3)+ myDC	Autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC will be isolated from PBMC obtained from the leukapheresis. These are injected in the neighbouring brain tissue post tumor resection.

Timeline

• Start date: 2016-11-17
• Primary completion: 2026-11-17
• Completion: 2026-11-17
• First posted: 2017-07-28
• Last updated: 2025-11-21

Locations

1 site across 1 country: Belgium