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Definition of an Immune Signature Predictive of Anti-PD1 (Programmed Death-1) Antibody in the Treatment of Advanced Melanoma (PREDIMEL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02938728
Recruitment Status : Not yet recruiting
First Posted : October 19, 2016
Last Update Posted : October 25, 2016
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Melanoma is the most aggressive skin cancer. Major advances in metastatic melanoma treatment emerge from new immunotherapies that target specific immune inhibitory checkpoint receptors, mainly PD1 and CTLA-4, and overcome the exhaustion state of T cells. In this context, checkpoint inhibitors, such as Ipilimumab (anti-CTLA-4 monoclonal antibodies, mAb) and Nivolumab or Pembrolizumab (anti-PD1 mAb), have demonstrated survival benefit in advanced melanoma patients. Anti-PD1 agents and combination of anti-PD1 and anti CTLA-4 have now been approved as first line therapy in melanoma. However, the predictive factors of response to these immunotherapies remain so far elusive. Recent studies provided consistent evidence that the immune infiltration could be tested as a biomarker for such immunotherapies. Moreover, the very recent concept of tumor neoantigens as biomarkers of response to anti-CTLA-4 mAb, and potentially also to anti-PD1 or combination therapies, is promising but needs to be further explored.

In this context, the aim of our program is to identify and validate an immune signature predictive of anti-PD-1 benefit in the treatment of advanced melanoma patients. To this aim, tumor samples from 120 melanoma patients enrolled prospectively, treated with anti-PD1 mAb alone or combined with anti CTLA4, will be collected as well as the corresponding peripheral blood mononuclear cells (PBMC). Tumor infiltration with immune cells will be characterized on paraffin embedded melanoma samples. The investigators will also perform whole-exome sequencing on tumors and matched PBMC samples. Our primary objective is to develop a combined immuno-signature based on an immuno-score (CD3, CD8, CD45RO…) to quantify the in situ immune populations with a dedicated image analysis system combined with the simultaneous detection of CD8-PD-1 and PD-L1 by immunofluorescence in baseline tumor samples. This will permit to predict 1-year survival of patients with advanced melanoma treated with anti-PD1 and transfer in patient's care.

Our secondary objectives are: 1/ To assess the interest of the detection of tissue-resident memory (TRM) T cells (CD8-CD103) as a predictive biomarker of response and survival at 1-year; 2/ To extend the panel of neoantigens published by Snyder et al to other neoantigens using a next-generation sequencing (NGS) approach on tumor samples obtained before therapy; 3/ To establish the prognostic value of this panel of neoantigens to predict tumor response to anti-PD1 and 1-year survival; 4/ To functionally validate the identified tumor neoantigens by stimulating patient PBMC with neoantigen peptides and measuring tumor-specific T-cell reactivity; 5/ To define the best marker and/or the best combination of markers predicting the overall response rate and the survival at 12 and 18 months; 6/ To attempt to establish a correlation between immuno-signature and neoepitopes and 7/ To transfer this immune signature in routine basis if validated.

Thus, our project will integrate two complementary strategies to define a robust and reliable score system for predicting anti-PD1 targeting immunotherapy response. This study will provide a unique opportunity to validate various putative biomarkers in an integrated way that could help in determining the respective value of each isolated parameter and potentially lead to the definition of a composite biomarker. The identified immune signature would be of major interest in the field of cancer immunotherapy in order to select and manage patient treatment, and to consider the benefice or toxicities expected. It will also help to identify new target antigens of effective antitumoral immune responses and to understand the resistance mechanisms established by the tumor and its influence on the response to current immunotherapies.

Condition or disease Intervention/treatment
Malignant Melanoma Other: Biopsies

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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Definition and Validation of an Immune Signature Predictive of Anti-PD1 Antibody Used Alone or an Association With antiCTLA4 in the Treatment of Advanced Melanoma : PREDIMEL
Study Start Date : November 2016
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Group/Cohort Intervention/treatment
Advanced melanoma treated by immunotherapies
Other: Biopsies

Primary Outcome Measures :
  1. Overall survival [ Time Frame: at 1 year ]

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: At 6 months and at 18 months ]
  2. Progression free survival [ Time Frame: At 6, 12 and 18 months ]
  3. Overall response rate [ Time Frame: At 3, 6 and 12 months ]
    Overall response rate given the RECIST criteria

  4. Best overall response rate [ Time Frame: At 12 months ]
    Bets overall response rate given the RECIST criteria

  5. Overall control rate [ Time Frame: at 3, 6 and 12 months ]
  6. Best overall control rate [ Time Frame: At 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patient treated by anti-PD1 either alone or combined to anti CTLA-4for advanced melanoma.

Inclusion Criteria:

  • Unresectable stage III or stage IV melanoma
  • Eligible to anti-PD1 therapy alone or combined to anti CTLA4.
  • Informed consent
  • Age >18 year

Exclusion Criteria:

  • Persistent toxicity > grade 2 (NCIC-CTCAE version 4) related to 1 regimen before switching to the other
  • Ocular melanoma
  • Active, known or suspected autoimmune disease which could be significantly worsened by immunotherapies; patients with vitiligo, type I diabetes mellitus, hypothyroidism, psoriasis non requiring systemic treatment are permitted to enroll.
  • HIV infection
  • Active Interstitial lung disease or pneumonitis
  • Contra-indication for tumor biopsy
  • No health care insurance

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02938728

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Contact: Celeste Lebbe, MD PhD 142499590 ext +33
Contact: Matthieu Resche-Rigon, MD PHD 142499742 ext +33

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris Identifier: NCT02938728    
Other Study ID Numbers: P150960
First Posted: October 19, 2016    Key Record Dates
Last Update Posted: October 25, 2016
Last Verified: October 2016
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas