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Study of Immunotherapy in Combination With Chemotherapy in HER2-negative Inflammatory Breast Cancer (PELICAN)

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.
 
ClinicalTrials.gov Identifier: NCT03515798
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
MSD France
Oncodistinct
Information provided by (Responsible Party):
Institut Paoli-Calmettes

Brief Summary:
This phase II multicentre randomized open-label study will assess the safety and efficacy of Pembrolizumab in combination with standard chemotherapy in inflammatory breast cancer. Pembrolizumab will be administered every 3 weeks during the neoadjuvant chemotherapy. Tissue and blood samples will be collected pre- and post-treatment for translational research.

Condition or disease Intervention/treatment Phase
Inflammatory Breast Cancer Drug: Pembrolizumab Injection Drug: neoadjuvant (F)EC-paclitaxel chemotherapy Phase 2

Detailed Description:

Inflammatory breast cancer (IBC) is a rare and highly aggressive subtype of locally advanced breast cancer representing approximately 5% of all breast cancers that requires immediate aggressive treatment. Significant progress has been made in recent years using a combination of treatments, including neoadjuvant chemotherapy, surgery and radiation therapy.

Accumulating data indicate a prognostic and/or predictive impact for immune-response variables in BC. Recent data, suggest that PD-L1 is overexpressed in a significant number of BC, notably in IBC and may have significant prognostic or predictive value. Furthermore it may be targeted to restore or boost functional antitumor immunity. Pembrolizumab, a PD-1-directed monoclonal antibody is already registered and has an out-standing activity in advanced melanoma and NSCLC patients, with promising results in several other tumor types, including triple-negative BC, and a favorable profile of tolerance.

Thus, potential benefits of pembrolizumab in combination with a conventional cytotoxic backbone may be considered as high in HER2-negative IBC.

The aim of the study is to assess the pathological complete response rate following neoadjuvant (F)EC-paclitaxel chemotherapy plus pembrolizumab and to assess if neoadjuvant chemotherapy with anthracycline-based induction in combination with pembrolizumab exposes IBC patients to significant toxicity. rates.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Multicenter Open-label, Randomized Phase II Study of Pembrolizumab in Combination With Neoadjuvant (F)EC-Paclitaxel Regimen in HER2-negative Inflammatory Breast Cancer.
Actual Study Start Date : July 24, 2018
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : April 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab
(F)EC Paclitaxel + Pembrolizumab Injection
Drug: Pembrolizumab Injection
Patients will receive intravenously 1 dose of Pembrolizumab every 3 weeks
Other Name: MK3475

Drug: neoadjuvant (F)EC-paclitaxel chemotherapy
The cytotoxic regimen is a combination of FEC (if hormone receptor-positive IBC), followed by weekly paclitaxel or combination of dose-dense EC (if hormone receptor negative i.e. triple-negative IBC), followed by weekly paclitaxel
Other Name: (5-Fluorouracil), Epirubicine, Cyclophosphamide, Paclitaxel

Active Comparator: Standard neoadjuvant chemotherapy
(F)EC Paclitaxel alone
Drug: neoadjuvant (F)EC-paclitaxel chemotherapy
The cytotoxic regimen is a combination of FEC (if hormone receptor-positive IBC), followed by weekly paclitaxel or combination of dose-dense EC (if hormone receptor negative i.e. triple-negative IBC), followed by weekly paclitaxel
Other Name: (5-Fluorouracil), Epirubicine, Cyclophosphamide, Paclitaxel




Primary Outcome Measures :
  1. Central evaluation of pathological complete response rate [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)

  2. Dose Limiting Toxicity (DLT) rates [ Time Frame: during 21 days following the first administration of pembrolizumab ]
    incidence of DLT during the 21 days following the first administration of pembrolizumab in combination with FEC/EC, will be assessed separately in the first 6 patients of each stratum (HR+ and HR-). DLTs will be defined according to CTCAE.


Secondary Outcome Measures :
  1. occurrence of serious adverse events and adverse events starting grade 2 or grade 1 (run-in period) [ Time Frame: during 21 days following the first administration of pembrolizumab ]
    according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03

  2. Local evaluation of pathological complete response rate [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)

  3. Invasive disease-free survival (IDFS) [ Time Frame: 3 years ]
    time from surgery to the first documented occurrence of an event, defined as: Ipsilateral invasive breast tumor recurrence, Ipsilateral local-regional invasive breast cancer recurrence, Distant recurrence, Contralateral invasive breast cancer, Death from any cause

  4. Invasive disease-free survival (IDFS) [ Time Frame: 5 years ]
    time from surgery to the first documented occurrence of an event, defined as: Ipsilateral invasive breast tumor recurrence, Ipsilateral local-regional invasive breast cancer recurrence, Distant recurrence, Contralateral invasive breast cancer, Death from any cause

  5. Event free survival (EFS) [ Time Frame: 3 years ]
    time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non invasive]), or death from any cause)

  6. Event free survival (EFS) [ Time Frame: 5 years ]
    time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non invasive]), or death from any cause)

  7. Overall survival (OS) [ Time Frame: 3 years ]
    time from randomization to death from any cause

  8. Overall survival (OS) [ Time Frame: 5 years ]
    time from randomization to death from any cause


Other Outcome Measures:
  1. Evaluation of PD-L1 expression in pre, per and post-treatment tissue [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    by IHC and mass spectrometry-based proteomics; and in plasma samples using quantitative proteomics,

  2. Measurement of baseline Circulating tumor cells for prospective validation of their prognostic value in IBC [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    Measurement of baseline CTC for prospective validation of their prognostic value in IBC

  3. Disease monitoring [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    Purification of ctDNA and specific sequencing for disease monitoring.

  4. Identification of mechanisms of treatment resistance [ Time Frame: Following completion of neoadjuvant systemic treatment, an average of 24 weeks ]
    Immune profiling, NGS and mouse xenografing for ex-vivo phenotypic approaches on post-treatment residual disease in order to identify mechanisms of resistance.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male/female participants who are at least 18 years of age on the day of signing informed consent
  2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Evaluation of ECOG is to be performed within 7 days prior to the date of randomization. Note: may consider ECOG PS 2 if good rationale provided and discussed with Sponsor team.
  3. Able to comply with the protocol,
  4. Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen, or any other regimen of social security
  5. Patient (or legally acceptable representative if applicable) has provided written informed consent for the trial,
  6. Previously untreated, histologically confirmed diagnosis of breast cancer and confirmed inflammatory breast cancer defined as follows:

    - T4d any N following American Joint Committee on Cancer (AJCC)-8th ver-sion classification: breast erythema, edema and/or peau d'orange, occupying at least 1/3 of the breast, with or without underlying palpable mass, duration of history of no more than 6 months.

  7. HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluores-cent/chromogenic in situ hybridization (FISH- or CISH-)
  8. Hormone receptors status known,
  9. No metastases,
  10. Have adequate organ function. Specimens must be collected within 10 days prior to the start of study treatment.
  11. Adequate hematologic function: absolute neutrophil count ≥ 1.5 x 109/L AND platelets ≥ 100 x 109 AND Hb ≥ 9.0 g/dL or ≥5.6 mmol/L, Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
  12. Adequate liver function: total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AND - ASAT ≤ 2.5 ULN AND ALAT ≤ 2.5 ULN,
  13. Adequate kidney function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 30 mL/min for participant with creatinine levels >1.5 × institutional ULN, Creatinine clear-ance (CrCl) should be calculated per institutional standard.
  14. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 ULN unless subject is receiving anticoagulant therapy, as long as PT or TCA is within therapeutic range of intended use of the anticoagulants,
  15. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ul-trasound methods),
  16. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
    2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 12 months after the last dose of cyclophosphamide and 4 months after the last dose of pembrolizumab, whichever come last.

    Note: Abstinence is acceptable if this is the established and preferred contraception for the subject

  17. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period (corresponding to time needed to eliminate any study treatments plus an additional 120 days (a spermatogenesis cycle) for study treatments with risk of genotoxicity at any dose).

Exclusion Criteria:

  1. Has metastatic breast cancer,
  2. Has HER2-positive breast cancer,
  3. Has bilateral breast cancer
  4. If subject should receive 5-Fluorouracile (HR-positive patients), then no dihydropyrimi-dine deshydrogenase enzyme deficit as identified by plasma uracil dosage
  5. Prior allogeneic stem cell or solid organ transplantation
  6. A WOCBP who has a positive serum pregnancy test within 72 hours prior to randomiza-tion
  7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment, Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
  8. Has known active CNS disease or carcinomatous meningitis.
  9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppres-sive therapy within 7 days prior to the first dose of study drug,
  10. Has a known history of active TB (Bacillus Tuberculosis),
  11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients,
  12. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,
  13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squa-mous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment,
  15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneu-monitis,
  16. Has an active infection requiring systemic therapy.
  17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator,
  18. Has known psychiatric or substance abuse disorders that would interfere with coopera-tion with the requirements of the trial,
  19. Is pregnant or breastfeeding, or expecting to conceive or father children within the pro-jected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment,
  20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).,
  21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
  22. Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected)
  23. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vac-cines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

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 ClinicalTrials.gov identifier (NCT number): NCT03515798


Contacts
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Contact: Dominique GENRE, MD 33 4 91 22 37 78 drci.up@ipc.unicancer.fr
Contact: Margot Berline 33 4 91 22 37 78 drci.up@ipc.unicancer.fr

Locations
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Belgium
Sint-Augustinus Hospital Not yet recruiting
Antwerp, Belgium
Contact: Luc Dirix         
Principal Investigator: Dirix         
Jules Bordet Not yet recruiting
Bruxelles, Belgium
Contact: Ahmad Awada, Dr         
Principal Investigator: Ahmad Awada, Dr         
Grand Hôpital de Charleroi Not yet recruiting
Charleroi, Belgium
Contact: Jean-Luc Canon         
Principal Investigator: Canon         
UZ Gand Not yet recruiting
Gand, Belgium
Contact: Hannelore Denys         
Principal Investigator: Denys         
UCL Not yet recruiting
Louvain, Belgium
Contact: François Duhoux         
Principal Investigator: Duhoux         
CHU Ambroise Pare Not yet recruiting
Mons, Belgium
Contact: Stephane Holbrechts         
Principal Investigator: Holbrechts         
Saint Elisabeth Not yet recruiting
Namur, Belgium
Contact: Peter Vuysteke         
Principal Investigator: Vuysteke         
France
Clinique de L'Europe Not yet recruiting
Amiens, France
Contact: GOZY         
Principal Investigator: GOZY, Dr         
Institut de Cancerologie de L'Ouest Not yet recruiting
Angers, France
Contact: Augereau, Dr         
Principal Investigator: Augereau, Dr         
Institut Sainte Catherine Recruiting
Avignon, France
Contact: Julien GRENIER, Dr         
Principal Investigator: Julien GRENIER, Dr         
Institut BERGONIE Not yet recruiting
Bordeaux, France
Contact: Camille CHAKIBA-BRUGERE, Dr         
Principal Investigator: Camille CHAKIBA-BRUGERE, Dr         
CENTRE Francois Baclesse Recruiting
Caen, France
Contact: Christelle LEVY, Dr         
Principal Investigator: Christelle LEVY         
Centre Leon Berard Not yet recruiting
Lyon, France
Contact: Thomas BACHELOT, Dr         
Principal Investigator: Thomas BACHELOT, Dr         
Institut Curie Recruiting
Paris, France
Contact: Florence LEREBOURS, Dr         
Principal Investigator: Florence Lerebours, Dr         
Centre Henri Becquerel Recruiting
Rouen, France
Contact: Marianne LEHEURTEUR, Dr         
Principal Investigator: Marianne LEHEURTEUR, Dr         
Institut Curie hopital rene huguenin Recruiting
Saint-Cloud, France
Contact: Florence Lerebours, Dr         
Principal Investigator: Florence Lerebours         
Institut De Cancérologie de l'Ouest Not yet recruiting
Saint-Herblain, France
Contact: FRENEL, Dr         
Principal Investigator: FRENEL, Dr         
Institut de cancérologie de la loire Not yet recruiting
Saint-Priest-en-Jarez, France
Contact: Jean-Philippe JACQUIN, Pr         
Principal Investigator: Jean-Philippe JACQUIN, Pr         
Centre Paul Strauss Recruiting
Strasbourg, France
Contact: Thierry PETIT, Pr         
Principal Investigator: Thierry PETIT, Pr         
IUCT-Oncopole Institut Claudius Rigaud Recruiting
Toulouse, France
Contact: Florence DALENC, Dr         
Principal Investigator: Florence DALENC, Dr         
Institut Gustave Roussy Not yet recruiting
Villejuif, France
Contact: Arnedos, Dr         
Principal Investigator: Arnedos, Dr         
Sponsors and Collaborators
Institut Paoli-Calmettes
MSD France
Oncodistinct
Investigators
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Principal Investigator: Anthony Goncalves, Pr Institut Paoli-Calmettes

Additional Information:
Publications:
Binder-Foucard F, Rasamimanana Cerf N, Belot A, Bossard N. Estimation nationale de l'incidence et de la mortalité par cancer en France entre 1980 et 2012. Étude à partir des registres des cancers du réseau Francim. Partie 1 - Tumeurs solides-Synthèse. In: http://www.invs.sante.fr. 2013.

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Responsible Party: Institut Paoli-Calmettes
ClinicalTrials.gov Identifier: NCT03515798     History of Changes
Other Study ID Numbers: PELICAN-IPC 2015-016
2016-001868-11 ( EudraCT Number )
First Posted: May 4, 2018    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Breast Neoplasms
Inflammatory Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological