Clinical Trials /

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

NCT02977156

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Gastric Carcinoma
  • Head and Neck Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ET14-035 (ISI-JX)
  • NCT ID: NCT02977156

Conditions

  • Metastatic Tumor
  • Advanced Tumor

Interventions

DrugSynonymsArms
Pexa-VecJX-594, TG6006, VAC GM-CSFCombination PexaVec + Ipilimumab
IpilimumabYervoy®Combination PexaVec + Ipilimumab

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Combination PexaVec + IpilimumabExperimentalPEXA-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.
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patients aged ≥ 18 years at time of inform consent signature

          -  Histologically confirmed, advanced/metastatic solid tumor refractory or relapsing
             to/after standard therapy or the patient has refused or does not tolerate standard
             therapy. Any tumor types can be considered in Part A except hepatocellular carcinoma
             (HCC). In part B, tumor types may include melanoma, MSI-High colorectal carcinoma
             (CRC), head and neck tumors, gastric cancers, triple negative breast cancers and
             mesothelioma.

          -  Tumor status (as determined by radiology evaluation): At least one injectable site
             ≥2cm and ≤8 cm in diameter and one distant non-injected measurable site (target site).

          -  PS ECOG 0 or 1

          -  Minimal wash-out period for prior anti-cancer regimens (i.e. chemotherapy,
             immunotherapy, or radiation therapy) > 3 weeks before Week 1 day 1.

          -  Resolution (i.e. ≤ Grade 1) of all toxicity related to prior anti-cancer treatment
             with exceptions of alopecia Grade 2, neuropathy Grade 2 and according to biological
             values presented in Criteria I8.

          -  No major surgery within 4 weeks prior Week 1 day 1

          -  Laboratory requirements:

               1. Absolute neutrophil count (ANC) ≥ 1 x 109/L

               2. Lymphocytes ≥1 x 109/L

               3. Platelets ≥ 100 x 109/L;

               4. Hemoglobin ≥ 90 g/L

               5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x ULN (if
                  patient exhibits liver metastasis, up to 5 x ULN acceptable) and total bilirubin
                  ≤ 3mg/dL

               6. Serum creatinine ≤1.5 x ULN or creatinine clearance is ≥60 mL/min according to
                  Cockcroft-Gault formula

               7. International normalized ratio (INR) ≤1.7

               8. Serum chemistries within normal limits (high or low) or Grade 1 (with exception
                  of sodium, potassium, glucose, calcium, upon Investigator discretion)

          -  Life expectancy > 3 months

          -  Negative pregnancy test for women of child-bearing potential within 72 hours before
             Week 1 Day 1

          -  Men and women of reproductive potential must be willing to double barrier methods of
             contraception during the treatment period and for up to 6 weeks after last Pexa Vec
             administration.

          -  Patient should understand, sign, and date the written voluntary informed consent form
             prior to any protocol-specific procedures performed. Patient should be able and
             willing to comply with study visits and procedures as per protocol.

          -  Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or
             immune-suppressive medication including systemic corticosteroids and/or blood CD4+
             T-cells < 200/µL.

          -  History of auto-immunity or untreated wounds from infection or inflammatory skin
             conditions. Ancient auto-immunity with stable endocrine oral substitution and vitiligo
             could be considered eligible by investigators.

          -  Experience of a severe systemic reaction or side-effect as a result of a previous
             smallpox vaccination

          -  Ongoing severe inflammatory skin condition (as determined by the investigator)
             requiring medical treatment

          -  History of severe eczema (as determined by the investigator) requiring medical
             treatment

          -  Severe or unstable cardiac disease, including significant coronary artery disease
             requiring angioplasty or stenting within the preceding 12 months, unless
             well-controlled and on stable medical therapy for at least 3 months

          -  Medical conditions, per the investigator's judgment, that predispose the patient to
             untoward medical risk of tachycardia, or hypotension during or following treatment
             with Pexa-Vec

          -  Previous treatment with Pexa-Vec or other vaccinia vector based treatment

          -  Tumor tissue sample not available for biological studies (from the initial diagnosis
             and/or relapse) at time of inclusion

          -  History of allergic reactions attributed to one of the compound of ipilimumab or
             compound of similar composition (as per Yervoy SPC® - see Appendix 5)

          -  Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin or by
             extension any other hepatitis C virus therapy that cannot be discontinued within 14
             days prior to any Pexa Vec injection. Sponsor should be consulted if the patient is
             taking any other antiviral medications to determine eligibility and/or to determine
             wash-out duration.

          -  Significant bleeding event within the last 12 months that places the patient at risk
             for IT injection procedure based on Investigator assessment

          -  Anticoagulant or anti-platelet medication that cannot be interrupted prior to IT
             injections (as listed in the protocol).

          -  Inability to suspend treatment with anti-hypertensive medication (including but not
             limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors,
             aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after each Pexa Vec
             injection.

          -  Prior malignancy except for the following: basal or squamous cell skin cancer, in situ
             cervical cancer, or other cancer adequately treated from which the patient has been
             disease-free for at least 3 years

          -  Active brain metastasis (treated and stable brain metastasis accepted).

          -  Any prior or planned organ transplant (e.g., liver transplant) or allogeneic
             hematopoietic stem cell transplantation.

          -  Pregnant or breastfeeding women

          -  Household contact exclusions for patients enrolled: Women who are pregnant or nursing
             an infant, Children < 1 year old, People with skin disease (e.g. eczema, atopic
             dermatitis and related diseases…), Immunocompromised hosts (severe deficiencies in
             cell-mediated immunity, including AIDS, organ transplant recipients, hematologic
             malignancies).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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)
Safety Issue:
Description:DLT is defined as the occurrence of any of the following events evaluated as related to study drugs and occurring during the first 5 weeks (Part A) of investigative treatment(s): any Grade ≥ 4 treatment related toxicity, any Grade≥ 3 treatment related toxicity lasting more than 7 days (except for flu-like symptoms that respond to standard therapies.), any Grade ≥ 3 treatment related acute immune related AE involving major end organs, Grade ≥ 3 injection site reaction, Any other study drug related toxicity considered significant enough to be qualified as DLT in the opinion of the investigators after discussion with the sponsor. Indeed, as a principle in this Phase I study, any toxicity that the investigator or the sponsor determines to be dose-limiting, regardless of the grade, may be considered as a DLT.

Secondary Outcome Measures

Measure:3-month objective response rate (ORR)
Time Frame:3 months of treatment
Safety Issue:
Description:defined by the percentage of patients having complete response (CR) or partial response (PR) according to irRC (immune related Response Criteria) and to RECIST 1.1 criteria.
Measure:Best objective response rate
Time Frame:from the date of inclusion up to 12 months
Safety Issue:
Description:defined by the percentage of patients having complete response (CR) or partial response (PR) as best response at any time point according to irRC and to RECIST 1.1 criteria.
Measure:Disease Control Rate
Time Frame:from the date of inclusion up to 12 months
Safety Issue:
Description:defined by the rate of patients having complete response (CR), partial response (PR) or stable disease (SD) according to irRC and to RECIST 1.1 criteria.
Measure:Duration of response
Time Frame:from the time of first documented objective response (PR or CR according to irRC and to RECIST 1.1 criteria) until the first documented disease progression or death due to underlying cancer, assessed up to 12 months
Safety Issue:
Description:
Measure:ORR of injected and non injected lesions
Time Frame:from the date of inclusion up to 12 months
Safety Issue:
Description:OR defined as at least 50% decrease of tumor size
Measure:Progression Free Survival (PFS)
Time Frame:from the date of inclusion until the date of first documented event (progression, according to irRC and to RECIST 1.1 criteria, or death due to any cause),up to 12 months
Safety Issue:
Description:PFS will be estimated using Kaplan Meier method.
Measure:Time To progression (TTP)
Time Frame:from the date of inclusion until the date of first documented radiographic tumor progression, according to irRC and to RECIST 1.1 criteria, up to 12 months
Safety Issue:
Description:TTP does not include deaths
Measure:Overall Survival (OS)
Time Frame:from the time of inclusion, until the date of death due to any cause, up to 12 months
Safety Issue:
Description:
Measure:Adverse Events reporting
Time Frame:from the treatment start (Week1 Day 1), up to 12 months
Safety Issue:
Description:All AEs will be graded according to NCI-CTCAE, Version 4

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Injectable lesion
  • Intra-tumoral injection

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