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

Sponsor
Centre Leon Berard
Study ID
NCT02977156
Phase
PHASE1
Status
Completed

Conditions

  • Advanced Tumor
  • Metastatic Tumor

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Pexa-Vec — BIOLOGICAL
    IT Injections will be performed by a radiologist using imaging-guidance, ultrasound or computed tomography (CT). The dose to be injected could be divided between 1 to 5 tumor lesions.
  • Ipilimumab — DRUG
    IT Injections will be performed by a radiologist using imaging-guidance, ultrasound or computed tomography (CT). The dose to be injected could be divided between 1 to 5 tumor lesions.

Study Details

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.

Key Dates

Start date
Jan 3, 2017
Status verified
Jul 2022
Primary completion
Apr 13, 2022
Completion
Jun 6, 2022

Study Design

Enrollment
22 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Combination PexaVec + Ipilimumab
    * PEXA-VEC (Pexastimogene devacirepvec): Oncolytic live replicating virus, Recombinant vaccinia virus GM-GCF of Classe 1, administered by Intra-tumoral injection with fixed-dosage regimen of 1x109 pfu (9.0 Log pfu)/ injection. Up to 5 IT injections, at Week 1 Day 1, Week 3 Day 1, Week 5 Day 1 and Week 9 Day 1, and one additional IT treatment allowed in case of disease progression following a documented objective response at W12. Provided by Transgene. * IPILIMUMAB: Anti-CTLA-4 monoclonal antibody (IgG1k) produced in CHO cells by recombinant DNA technology, administered by Intra-tumoral injection. Up to 4 IT injections at Week 3 Day 1, Week 5 Day 1 and Week 9 Day 1, and one additional IT treatment allowed In case of disease progression following a documented objective response at W12. Four dose levels of ipilimumab will be tested in dose escalation step: 2.5mg, 5mg, 7.5mg, 10mg, 20mg or 40 mg.

Primary Outcome Measure

Part A (dose selection part): Dose Limiting Toxicities (DLTs) [ Time Frame: during the DLT assessment window (i.e. during the first 5 weeks of treatment) ]

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