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Metastatic TumorPhase 1ISI-JXNCT02977156

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

A Phase 1 study testing Pexa-Vec and Ipilimumab in people with Metastatic Tumor and Advanced Tumor, run by Centre Leon Berard at 5 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Tumor, Advanced Tumor
What is being tested?
Pexa-Vec and Ipilimumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
22 participants
Where
5 sitesFrance
Study dates
3 Jan 2017to 6 Jun 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).
  • NotaBene: for the DL5 and DL6, depending of the size of the injectable lesions, patients should present more than 1 injectable lesion (See Appendix 3). Of note, patients with only one injectable lesion with a diameter = 2 cm are not eligible for theses 2 DLs.
  • 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.
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  • 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:
  • Absolute neutrophil count (ANC) ≥ 1 x 109/L
  • Lymphocytes ≥1 x 109/L
  • Platelets ≥ 100 x 109/L;
  • Hemoglobin ≥ 90 g/L
  • 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
  • Serum creatinine ≤1.5 x ULN or creatinine clearance is ≥60 mL/min according to Cockcroft-Gault formula
  • International normalized ratio (INR) ≤1.7
  • 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.

Who cannot join

  • 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
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  • 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).

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

France5 sites

  • Institut Bergonie

    Bordeaux, 33076

  • Centre Léon Bérard

    Lyon, 69008

  • Hopital Saint Louis

    Paris, 75475

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, 69310

  • Institut Gustave Roussy

    Villejuif

Other trials in France

About this study

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.

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.

Read the 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.

Being tested
Pexa-Vec, Ipilimumab
Keywords
Injectable lesion, Intra-tumoral injection
Medical subject headings
Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pexa-VecBiological

    Also called JX-594, TG6006, VAC GM-CSF

    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.

  • IpilimumabDrug

    Also called Yervoy®

    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 groups in NCT02977156
Study groupRoleWhat they receive
Combination PexaVec + IpilimumabExperimental* 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.
Receives: Biological: Pexa-Vec; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Part A (dose selection part): Dose Limiting Toxicities (DLTs)

    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.

    Measured: during the DLT assessment window (i.e. during the first 5 weeks of treatment)

  2. Part B (expansion cohort): The 3-month objective response rate (ORR)

    The 3-month objective response rate is defined by the percentage of patients having complete response (CR) or partial response (PR) according to immune related Response Criteria (irRC).

    Measured: 3 months of treatment

Secondary outcomes (9)

  1. 3-month objective response rate (ORR)

    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.

    Measured: 3 months of treatment

  2. Best objective response rate

    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.

    Measured: from the date of inclusion up to 12 months

  3. Disease Control Rate

    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.

    Measured: from the date of inclusion up to 12 months

  4. Duration of response

    Measured: 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

  5. ORR of injected and non injected lesions

    OR defined as at least 50% decrease of tumor size

    Measured: from the date of inclusion up to 12 months

  6. Progression Free Survival (PFS)

    PFS will be estimated using Kaplan Meier method.

    Measured: 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

  7. Time To progression (TTP)

    TTP does not include deaths

    Measured: 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

  8. Overall Survival (OS)

    Measured: from the time of inclusion, until the date of death due to any cause, up to 12 months

  9. Adverse Events reporting

    All AEs will be graded according to NCI-CTCAE, Version 4

    Measured: from the treatment start (Week1 Day 1), up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Nov 2016 (estimated)
  2. Study start3 Jan 2017
  3. Primary completion13 Apr 2022
  4. Study completion6 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02977156
Sponsor's protocol ID
ET14-035 (ISI-JX)
Acronym
ISI-JX
Status last verified
Jul 2022
First submitted
25 Nov 2016
Last updated
25 Jul 2022
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pexa-Vec and Ipilimumab in people with Metastatic Tumor and Advanced Tumor, run by Centre Leon Berard at 5 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02977156.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jul 2022.

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