Immunization Strategy With Intra-tumoral Injections of Pexa-Vec With Ipilimumab in Metastatic / Advanced Solid Tumors. — ISI-JX  

Metastatic Tumor Clinical Trial

Official title: A Phase I Dose Escalation Trial Evaluating the Impact of an in Situ Immunization Strategy With Intra-Tumoral Injections of Pexa-Vec in Combination With Ipilimumab in Metastatic / Advanced Solid Tumors With Injectable Lesions.

Status Completed

Clinical Trial Summary

The success of anti-CTLA4 therapy has inaugurated a paradigm shift in oncology where drugs target the immune system rather than cancer cells in order to stimulate the anti-tumor immune response. In situ immunization is a strategy where immunomodulatory products such as pathogens are injected into one tumor site in order to trigger a systemic anti-tumor immune response. Of importance, pre-clinical rationale has demonstrated that combination of anti-CTLA4 therapy together with intra-tumoral (IT) oncolytic virus can overcome primary resistance to systemic anti-CTLA4 therapy. Pexastimogene Devacirepvec (Pexa-Vec) is one of the new vaccinia oncolytic viruses genetically modified to express GM-CSF. This new and innovative oncolytic virotherapy should therefore synergize with anti-CTLA4 therapy via virus-induced tumor cell death & tumor-antigen release, GM-CSF-induced recruitment/maturation/activation of antigen presenting cells, and anti-CTLA4-induced Treg blockade/depletion. Intra-tumoral delivery of immunostimulating agents should, therefore, provide lower toxicity of mAb targeting immune checkpoints. Of note, IT injections of GM-CSF-encoding oncolytic viruses have already been shown to induce immune-mediated tumor responses on local (injected) and distant (not injected) tumor sites. In solid injectable refractory/relapsing metastatic tumors, we make the hypothesis that the addition of Pexa-Vec to IT ipilimumab (anti-CTLA4 Ab) will overcome primary/secondary resistance to standard therapy and/or immunotherapy with a better in situ tumor antigen specific T-cell priming. Our proposal is to conduct a 2-part Phase I clinical trial in order to define the feasibility, the safety and the anti-tumor effects of intra-tumoral injections of ipilimumab in combination with the oncolytic virus Pexa-Vec. Dose escalation step will define the MTD and RP2D of that in situ immunization strategy. Expansion part will assess the anti-tumor effect of the combination.

Clinical Trial Description

The study is a proof of concept, open label, multicentric, 2-parts, Phase I dose escalation trial. In dose selection part (any histological types except HCC), patients will be treated with an IT boost injection with Pexa-Vec (fixed dose of 1x109 pfu / injection ) alone at Week 1 followed by IT injections of Pexa-Vec + ipilimumab (up to 4 dose levels) at Weeks 3, 5 and 9. The dose escalation part will follow a classical 3+3 design. 3 to 6 patients will be enrolled at each DL (Dose Level) depending of the number of Dose Limiting Toxicity (DLT) observed. At the end of each DL cohort, a teleconference (Dose escalation meeting) will be organized with the sponsor, in order to select the dose for the next cohort. In Expansion cohorts ( up to 3 cohorts) patients will be treated with an IT boost injection with Pexa-Vec alone (fixed dose of 1x109 pfu / injection) at Week 1 followed by IT injections of Pexa-Vec + ipilimumab (RP2D) at Weeks 3, 5 and 9. In both parts, the treatment with both IMPs should be continued as per protocol until Withdrawal of consent, Disease progression as per irRC (immune related response criteria), General or specific changes in the patient's condition that render the patient unacceptable for further treatment in the judgment of the investigator, Pregnancy or Unacceptable adverse events(s) including DLTs. ;

Related Conditions & MeSH terms

• Advanced Tumor
• Metastatic Tumor
• Neoplasm Metastasis
• Neoplasms

• NCT number: NCT02977156
• Study type: Interventional
• Source: Centre Leon Berard
• Status: Completed
• Phase: Phase 1
• Start date: January 3, 2017
• Completion date: June 6, 2022