SENTICOL III International validation study of sentinel node biopsy in early cervical cancer

 
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
SENTICOL III
International validation study of sentinel node biopsy
               in early cervical cancer

            INVESTIGATORS MEETING_FRANCE
                    17th MAY 2019
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
SENTICOL III
                                           ID-RCB: 2017-A00945-48
                  Sponsor: Centre Hospitalier Universitaire de Besançon
                               2 place Saint-Jacques 25030 Besançon Cedex
                                                FRANCE
                                       Pr Fabrice LECURU
                                       Hôpital Européen Georges Pompidou
COORDINATING INVESTIGATOR
                                       Phone: +33 (0)1 56 09 35 84
                                       Email: fabrice.lecuru@aphp.fr
                                       Dr Amélie ANOTA
STUDY BIOSTATISTICIANS                 CHU de Besançon
                                       Phone: +33 (0)3 70 63 21 72
                                       Email: aanota@chu-besancon.fr
                                       Marie-Aude LE FRERE BELDA
PATHOLOGIST                            Hôpital Européen Georges Pompidou
                                       Phone: +33 (0)1 56 09 35 84
                                       Email: marie-aude.le-frere-belda@aphp.fr
                                       Rachida MAMA ABDOU (international project manager)

                                       Sandra MABALUKIDI (CTA)
TRIAL MANAGEMENT COORDINATING CENTER
                                       ARCAGY-GINECO
AND PHARMACOVIGILANCE
                                       Phone: +33 (0)1 84 85 20 20
                                       E-mail: senticol3-study@arcagy.org
                                       Pharmacovigilance: pharmacovigilance@arcagy.org
                                       Kristina MOUYABI (project manager)
                                       Aude Le Breton(CRA) / Caroline CARETTE (CRA)
MONITORING                             CHU de Besançon
AND CONTRACTS FEES                     Phone: + 33 (0)3 81 21 83 56
                                       E-mail: kmouyabi@chu-besancon.fr
                                       a1lebreton@chu-besancon.fr/ ccarette@chu-besancon.fr

                                                                                              2
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
AGENDA
ITEMS                                  WHO
Standard of care and rationale         Pr Lecuru

SLN and nSLN (mapping and biopy)       Pr Lecuru
Protocol overview                      Pr Lecuru and Rachida

Translational research                 Pr Lecuru

Communication and Timelines            Rachida
Study tools and monitoring             Rachida and Kristina

                                   3               ARCAGY - GINECO
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
STANDARD OF CARE AND RATIONALE

               4      ARCAGY - GINECO
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
STUDY RATIONALE (1/2)

❖   Cervical cancer: 2nd cause of cancer death in women worldwide. Incidence:
    527600/year, mortality: 265700/year.

❖   Prognosis of early stage cervical cancers relatively good, especially in patients
    without risk-factors and in the absence of nodal disease. FIGO 2009 meeting: 5
    years OS > 97 % for stage Ia2 and > 91% for stage Ib1.

❖   Standard of care to assess nodal involvement in early stage cervical cancer is
    lymphadenectomy. However:
    ➢   A minority of patient presents with nodal metastasis at this stage,
    ➢   The number of involved nodes is small in case of nodal spread,
    ➢   Tumor deposits’ size small
    ➢   Per and post operative complications of nodal dissection reported in 0 to 58 % of cases:
        bleeding and injuries during surgery, lymphocysts, lymphedema….

                                                                                               5
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
STUDY RATIONALE                   (2/2)

❖   Sentinel lymph node (SLN) mapping: technique introduced in the management of
    gynaecologic malignancies for nearly 20 years. It aims to maintain survival and
    improve quality of life in good prognosis patients by surgery de-escalation

❖   SLN biopsy also provides additional information compared with routine pelvic
    dissection:
    ➢ Diagnosis of low volume metastasis,
    ➢ SLN can be found in « unexpected » areas, outside of the classical lymphadenectomy
      territories.

❖   Despite these data, SLN biopsy is not a standard of care in most guidelines.

❖   Missing data: Survival! No study demonstrated that patients assessed with SLN
    biopsy have the same prognosis than after a classical pelvic dissection.

         Outcomes of patients after SLN biopsy vs SLN biopsy
         + pelvic dissection must be compared!

                                                                                           6
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
SENTICOL IIII STUDY DESIGN

An international, prospective, randomized, multicenter, single blind trial to
compare sentinel lymph node (SLN) biopsy versus SLN biopsy + pelvic
lymphadenectomy in term of DFS and HR-QoL.

                                                                         7
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
STUDY DESIGN
                                           •Squamous or adenocarcinoma of the cervix,
                                   •Stage Ia1 with lympho vascular emboli , Ia2, Ib1, Ib2, IIa1 (FIGO
                                   2018)
                                           •Maximum diameter ≤ 40mm.

                                                            Randomization

            Patients with bilateral detection without
         macroscopic suspicious node and negative frozen                           Patients with nodal involvement
                         section on SLN                                                         (pN1)
                              (pN0)

                            Randomisation

                                  1 : 1

     Arm A (experimental) :                  Arm B (reference) :
         SLN biopsy only                          SLN biopsy
+ hysterectomy or trachelectomy           + Pelvic Lymphadenectomy
                                              + hysterectomy or
                                                trachelectomy

                      DFS, RFS, QOL, OS                                          Followed in a separate cohort to
                                                                                 record treatment and outcomes

                                                                                                                     8
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
SENTINEL LYMPH NODE (SLN) and
NON SENTINEL LYMPH NODE (nSLN)

                 9       ARCAGY - GINECO
SENTICOL III International validation study of sentinel node biopsy in early cervical cancer
1) Pre-randomization assessment (SLN mapping and biopsy):
➢   SLN Mapping

Planar lympho-scintigraphy
 or SPECT/CT -> number                                                 General anesthesia,
                                  Pelvic examination -> clinical
   and location of SLN                                             laparotomy or laparoscopic
                                        stage verification
 according to the Marnitz                                               or robotic access
       classification

                                      SLN biopsy -> pathological
                                             examination                Collection of a paraffin
Intracervical injection of blue                                           embedded sample
          dye or ICG                    nSLN sample (only for
                                          patients in arm B)->
                                        translationnal research

                                                                                         10
1) Pre-randomization assessment (SLN mapping and biopsy):

➢   Techniques of SLN detection:
❖   In case of isotope alone
    ➢ The surgical access will be obtained by laparoscopy, laparotomy or robotically assisted laparoscopy
    ➢ Correlation performed with the result of the lympho-scintigraphy
             Number, location according to Marnitz classification, and intensity are noted on a schema
    ➢ The “hot” nodes are biopsied.
       Pelvic nodes: no more than 5 SLN/side should be harvested. If numerous per-operative SLN, the lymphoscintigram
      could help to limit the harvest to first echelon SLN only.
    ➢ SLN given to the pathologist for frozen section

❖   In case of blue dye (associated with isotope) or in case of ICG (alone or in association with
    isotope)
    ➢ Dye injected into the cervix under anaesthesia at the beginning of the operation or after set-up of the endoscopic
      access
    ➢ The progression of the dye under the peritoneum is followed to localize the first labelled nodes
             Number, location according to Marnitz classification, and intensity are noted on a schema
    ➢ The “hot” and/or “colored nodes” are biopsied by a specific incision. Only the first echelon nodes should be harvested
      (and no more than 5 SLN/pelvic side)
    ➢ SLN given to the pathologist for frozen section

                                                                                                                   11
1) Pre-randomization assessment (SLN mapping and biopsy):

 ➢   Techniques of surgical SLN biopsy:

 ❖   MSKCC algorithm
     ➢ All the mapped nodes must be harvested,
     ➢ All suspicious node must be removed,
     ➢ In case of unilateral pelvic detection, perform a lymphadenectomy. These patients will not be
       randomized.
     ➢ Inspection of the nodal areas during the radical hysterectomy (especially parametria).

                                                                                               12
TUTORIAL

      13
2) Pathology of SLN and nSLN (non-sentinel lymphnode):

                                     One part examined in FS in
.                                    one level after staining with
                                                  HES
SLNs cut in half along
   their long axis                                                              Histological examination
                                                                                performed after staining
                                       One part immediately fixed                       with HES
                                      for definitive examination on
                                         sections of 200 microns                Negative SLNs with HES
                                                                                    -> IHC with anti-
                                                                                 cytokeratine AE1-AE3

    ❖ nSLN sectioned once and examined after staining with HES. Histological analyses carried out
    systematically in the same center by the same pathologist referent for SLN biopsy.

    ❖ The isolated tumour cells are defined as  2 mm

                                                                                             14
AMENDEMENT AU PROTOCOLE

Definitive examination and ultrastaging

Each SLN (if nonmetastatic with frozen section) tissue blocks should be further examined by an ultrastaging
protocol consisting of five step sections spaced at 200-250 µm intervals with four sections stained with HES
and one section used for immunohistochemistry with pancytokeratin antibodies (e.g. AE1/AE3).

                                      AE1/
  HES               HES               AE3                   HES             HES

         200-250           200-250           200-250              200-250
         microns           microns           microns              microns

Non-sentinel lymph nodes will be sectioned once and examined after staining with HES.

                                                       15
AMENDEMENT AU PROTOCOLE

Protocol for collection of SLN and nSLN for translational research:

 Before cutting specimens of each new patient, the blade must be
cleaned with an alcoholic solution and moved in order to avoid any
potential contamination
Then, proceed as follows:
- Cut 5 sections of 10 µm thick on each sentinel lymph node and store
  it in a tube at room temperature
- Cut 10 sections of 10 µm thick of the cervix tumour biopsy and store it
  in a tube at room temperature with one HES stained slide

                                    16
PROTOCOL OVERVIEW

        17
STUDY OBJECTIVES (1/2)

1) Co-Primary Objectives and associated endpoints:

              Objective                                Outcome measure
  To assess that Disease Free Survival    Disease free survival (DFS) is defined as the time
  (DFS) is similar between pN0 patients   interval between randomization and physical or
  after SLN biopsy versus SLN biopsy +    radiographic evidence of recurrence (local/
  PLN                                     distant) or second cancer or death (all causes)
                                          whichever occur first
  To assess a superiority of SLN biopsy   HR-QoL of patients assessed with EORTC QLQC 30
  for quality of life (HR-QoL)            and QLQ-CX24 with 3 targeted dimensions: pain,
                                          global health score and physical functioning
                                          scores at 3 years.

                                                                                               18
STUDY OBJECTIVES (2/2)

2) Secondary Objectives:

❖   Outcome of pN1 patients according to the size of metastasis and treatment
    (isolated tumor cells and micrometastasis)
❖   Evaluation of mapping with indocyanine green (ICG)
❖   Surgical morbidity and mortality
❖   Other dimensions of HR-QoL (QLQ-C30 and QLQ-CX24) at three years and
    longitudinal analysis of all HR-QoL dimensions
❖   Positive and negative predictive values of SLN biopsies
❖   Overall survival (OS)
❖   Recurrence free survival (RFS)
❖   A cost analysis will be performed in France
❖   Lymphatic and lower limb complications, LEL screening questionnaire

                                                                                19
STUDY POPULATION (1/2)

1) Inclusion criteria:
Patient must meet ALL of the following criteria to be eligible for inclusion in
this study
❖   I 1. Patient must be ≥ 18 years old,
❖   I 2. With squamous or adenocarcinoma of the cervix (proven by biopsy or cone biopsy),
❖   I 3. Stage Ia1 with lymphovascular emboli, Ia2, Ib1, IIa1 and Ib2 (clinical stage) of
    the 2018 FIGO classification
❖   I 4. Maximum diameter ≤ 40 mm by clinical examination and/or magnetic resonance
    imaging (MRI),
❖   I 5. No suspicious node on pelvic MRI with an exploration up to the left renal vein
    (according to RECIST 1.1),
❖   I 6. ECOG performance status 0-2
❖   I 7. Signed informed consent and ability to comply with follow-up,
❖   I 8. French subjects: In France, a subject will be eligible for inclusion in this study
    only if either affiliated to, or a beneficiary of, a social security category.

                                                                                     20
STUDY POPULATION (2/2)

2) Exclusion criteria:

Patient must meet NONE of the following criteria to be eligible for inclusion in this
study

❖   E 1. Pregnancy,
❖   E 2. Previous pelvic or abdominal cancer,
❖   E 3. Previous chemo and/or radiation therapy for the cervical cancer (previous brachytherapy
    is accepted),
❖   E 4. Proven allergy to blue dye, isotope or indocyanine green (ICG).
!   E.5. Other malignancy within the last 5 years except for treated cancer free of disease and
    treatment,
!   E.6. Patients with synchronous cancer

                                                                                        21
STUDY CONDUCT
Pre-randomization assessment:
➢   Must be realized within the 30 days prior to randomization:
    ❖ Informed consent (before performing any specific study procedures)
    ❖ Eligibility criteria verification, which includes:
       ▪   Medical history (and particularly lymphatic risk factors),
       ▪   Childbirth history,
       ▪   Demographic data,
       ▪   Results of a punch biopsy or a cone biopsy (preferred option) available
       ▪   Tumor assessment with a pelvic MRI with an exploration up to the left renal vein.
            A CT-scan can be performed in case of contra-indication or refusal of the MRI.
       ▪   Collection of an archival paraffin embedded tumor tissue sample (mandatory).
    ❖ Baseline conditions (ongoing pathologies, symptoms and concomitant medications)
    ❖ Physical examination (BMI, nodal areas, abdominal-lumbar-gynecological examination, specific
      assessment for lymphatic and lower limb complications, PS, laboratory analysis, serum or urine
      pregnancy test for women of childbearing potential, Quality of Life Questionnaires).
    ❖ LEL screening questionnaire for French sites only
    ❖ Blood sample and archived tumor sample (block) for translational research

                                                                                                       22
STUDY CONDUCT
 Randomization:

 The randomization will be processed the day of the surgery, after SLN biopsy results
 available.

 ❖   Only patients with bilateral detection and fulfilling the “safety algorithm” without macroscopic
     suspicious node and with negative frozen section on SLN will be randomized.

 ❖   Patient will be randomized using an Interactive Web Response System (IWRS) in a 1:1 ratio to one of the
     2 study arms:

     ➢ Arm A (experimental arm): SLN dissection only. A full lymphadenectomy will not be performed. The radical
       hysterectomy or trachelectomy will be done.

     ➢ Arm B (reference arm): SLN + PLN dissection. A full lymphadenectomy will be performed. The radical
       hysterectomy or trachelectomy will be done.

REMINDER:
For translational research, collect nSLN for patient randomized in arm B !

                                                                                                23
•Squamous or adenocarcinoma of the cervix,
                                       •Stage Ia1 with lympho vascular emboli , Ia, Ib1, Ib2, IIa1 (FIGO
                                       2018)
                                               •Maximum diameter ≤ 40mm.

                                                    At the time of surgery

                 Patients with bilateral detection without
              macroscopic suspicious node and negative frozen                     Patients with nodal involvement including
                              section on SLN                                          unilateral and bilateral detection
                                   (pN0)                                                        (pN1 cohorte)

                                  Randomisation

                                      1 : 1

     Arm A (experimental) :                          Arm B (reference) :
         SLN biopsy only                                  SLN biopsy
+ hysterectomy or trachelectomy                   + Pelvic Lymphadenectomy
                                                      + hysterectomy or
                                                        trachelectomy

                                                                24
STUDY CONDUCT

Randomization:
❖   Be careful:

      ❖ Single blind study.
      To ensure the blinding, we recommande to indicate in the surgical report that, in
      the context of SENTICOL III study, the SLN procedure was performed and that a
      complementary lymphadenectomy may be performed according to the allocated
      arm.

         The screening section of the CRF must be completed JUST before the
    surgery!

Stratification:
Patients randomized will be stratified according to:

❖   Center,
❖   Stage of the disease (FIGO stage).
❖   Laparotomy vs laparoscopy or robotics ?

                                           25             ARCAGY - GINECO 2014
QUESTIONS

- Avez-vous des difficultés à conserver le simple insu?

- Que pensez-vous de la stratification sur le type de chirurgie?

                               26
STUDY CONDUCT

    pN1 cohorte

❖   Patients pN1: Are not randomized in the study.

     ➢ If the nodal involvement (bilateral or unilateral) is diagnosed
     during surgery, the radical hysterectomy (or trachelectomy) should
     be aborted and only lymphadenectomy should be performed.

     ➢ These patients will be followed up as a separate cohort to
     record treatment and survival outcomes on the eCRF.

                                     27          ARCAGY - GINECO
STUDY CONDUCT

Screening/ baseline failure:

A subject is considered to be a screen/baseline failure if she signs the
informed consent but could not be randomized.

All subjects screened for enrolment, including screening/baseline
failures, will be entered in the eCRF and listed on the Subject Screening
Log/Identification List.

Reasons for exclusion will be recorded in the CRF for subjects who do not
enter the study.

                                   28
AMENDEMENT AU PROTOCOLE

Autres modifications du protocole : Ajout des traitements autorisés:

- La curiethérapie avant l’hystérectomie selon les habitudes des centres : SLN
  puis curieT - HT OU curieT puis SLN-HT

- La chimiothérapie néoadjuvante avant la trachélectomie

              Amendement à déposer dans les prochaines semaines

                                      29
STUDY CONDUCT

Post-operative visit :
❖   Post-operative follow-up performed 30 days (+/- 7 days) after surgery

❖   Pathological results and proposal of management given and explained to the patient.

❖   Assessments to be done:
    ➢ Physical examination,
    ➢ Body weight,
    ➢ ECOG PS,
    ➢ Laboratory analysis (according to symptoms or examination findings evocating recurrence),
    ➢ Adverse events and particularly: surgical morbidity, complications (infection,
      necrotizing fasciitis, mycoses…), specific assessment of lymphatic and lower limb
      complications (anesthesia, paresthesia, dysesthesia)
    ➢ Patient education regarding sexual health will be performed,
    ➢ Health Related Quality of Life questionnaires (EORTC QLQ-C30 and QLQ-CX24)
    ➢ LEL questionnaire

                                                                                       30
STUDY CONDUCT

Post-operative treatment recommendations:
❖   Post-operative treatment is not imposed in this protocol

❖   Recommendations are described in paragraph 5.7 according to the NCCN
    guidelines.

Follow-up visits:
❖   To be done:
    ➢ Every 3 months +/- 1 week during the first year,
    ➢ Every 4 months +/- 1 week during the second year,
    ➢ Every 6 months +/- 2 weeks during the third-fifth year.

❖   Assessments: same as post operative visit assessments

                                                                           31
SAFETY (1/4)
 1) Definitions (1/2):
❖ A serious adverse event (SAE) is an AE occurring during the study that fulfils one or more of the
  following criteria:
     ➢   Results in death,
     ➢   Is immediately life-threatening,
     ➢   Requires in-patient hospitalization or prolongation of existing hospitalization,
     ➢   Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct
         normal life functions,
     ➢   Is a congenital abnormality or birth defect,
     ➢   Is an important medical event that may jeopardize the patient or may require medical intervention to
         prevent one of the outcomes listed above.

❖ should not be considered as SAEs in the context of this trial:
     ➢   Disease progression or death as a result of disease progression,
     ➢   Elective hospitalization and surgery for treatment of cervix cancer or its complications,
     ➢   Elective hospitalization to simplify treatment or procedures,
     ➢   Elective hospitalization in palliative care or respite care unit,
     ➢   Elective hospitalization for pre-existing conditions that have not been exacerbated by acts performed or
         methods used in the study and also hospitalization
SAFETY (2/4)
 1) Definitions (2/2):
❖ An expected serious adverse event is an event that is mentioned in the information described in the
  SENTICOL study or information relative to the acts and methods used during the research.
❖ An unexpected adverse event (SUSAR) is an event that is not mentioned in the information relative to the
  acts and methods used during the research, or for which the nature, the intensity or the outcome is not
  consistent with the information relating to the practised acts and to the methods used during the research.
❖ An adverse event of special interest (AESI) is one of scientific and medical interest specific to
  understanding of the acts and methods used and may require close monitoring and rapid communication by
  the investigator to the sponsor. An AESI may be serious or non-serious.
   The following adverse events have been identified as AESI and require that they should be followed
  longer than regular AEs and should be declared as SAE even if occurred after the 30 day post -
  operative period:
    ➢ Lymphatic and lower limb complications and particularly lymphedema, neurological symptoms
       (anaesthesia, paraesthesia, dysesthesia) and venous insufficiency.
❖ A new fact is any new data which may lead to:
    ➢ A reassessment of the risk-benefits balance of the research or acts and methods used on the research,
    ➢ Changes in the acts or methods used, the conduct or documents related to the research,
    ➢ Suspend or interrupt or modify the protocol of the search or similar searches.

                                                                                                  33
SAFETY (3/4)

 2) Recording of adverse events:
❖ AEs will be collected from time of informed consent throughout the 30-days following the surgery where
  acts or methods are used.
❖ All ongoing and any new AEs/SAEs identified during the 30 calendar days post-operative period after surgery
  or methods used in the study must be followed to resolution.
❖ The severity should be graded according to CTC-AE V4.03 and to:
    • Clavien-Dindo classification for surgical complications
    • Stage in case of lymphodema
❖ Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs should be reported
  as AEs only if they fulfil any of the SAE criteria.

❖ Deterioration of a laboratory value, which is unequivocally due to disease progression, should not be reported
  as an AE/SAE.

                                                       34
SAFETY (4/4)
 3) Reporting of Serious Adverse Events:
❖ From the day when the informed consent form is signed to the surgery where acts will be performed, only
  SAEs related to study procedures must be reported.
❖ from the surgery and until 30 days after surgery where acts and methods are used, or until the initiation of
  alternative cancer therapy, all SAEs, whether or not considered causally related to the acts and methods
  used or to the study procedures must be reported.
❖ All SAEs will be recorded in the CRF.
❖ If any reportable SAE occurs in the course of the study, then investigators or other site personnel inform
  ARCAGY-GINECO for safety immediately after he or she becomes aware of it.

❖ The notification shall be made using an SAE form, documented as accurately as possible, by fax or e-mail
  to the ARCAGY-GINECO pharmacovigilance department:

                                Pharmacovigilance ARCAGY-GINECO
                                    Fax: +33 (0)1 84 25 40 68
                                  pharmacovigilance@arcagy.org

                                                                                                  35
TRANSLATIONAL RESEARCH

          36     ARCAGY - GINECO 2014   Date
TRANSLATIONAL RESEARCH (1/5)
❖ Each site participating to the SENTICOL III study will participate to a tumor bank. The
  translational research program will be performed in a second step.

❖ Collection of tumor and blood samples will be used for exploratory work to search for
  biological predictors of relapse in “low risk” early cervical cancer.

Samples for translational research

         Time of the study                     Type of sample                         Optional/mandatory

                             •   Archival tumor sample from cervix biopsy or part
             Inclusion           of the conisation,                                        Mandatory
                             •   Blood sample (20 mL)
                             •   1 SLN sample from the surgery
              Surgery        •   nSLN sample from the surgery (for patient in arm          Mandatory
                                 B only)
                            •    Tumor samples
        Disease progression •                                                       Optional and if available
                                 Blood sample (20mL)

                                                                                                                37
TRANSLATIONAL RESEARCH (2/5)
Provided material:
❖ The CHU of Besançon, as sponsor, provides the material to constitute and ship bood samples
  with the exception of EDTA tubes.

                Use a kit dedicated to SENTICOL III and 1 bag/patient.

❖ Each site will receive one kit at its activation

❖ Additional kit will be sent at each randomization

                                                                                         38
TRANSLATIONAL RESEARCH (3/5)
Blood samples process at inclusion and progression:

                                                      39
TRANSLATIONAL RESEARCH (4/5)
Biological samples traceability:
❖ Samples collected for translational research must be identified with patient ID in real time
  by filling a specific form in the eCRF.

                                                                                            40
TRANSLATIONAL RESEARCH (5/5)

Biological Samples shipment:
❖ Samples collected will be centralized to the biological resources center (CRB) of the Institut
  Curie (Paris, France) until analysis.

❖ Tumor samples collection will be organized by the sponsor. Sites will be informed as soon as a
  collection is planned.

                                                                                             41
COMMUNICATION AND TIMELINES

            42
STUDY CALENDAR

❖   Sites number: 300, including 50 in France
❖   Patients number : 950, including 200 in France
❖   Study start: 1st patient enrolled on the 3rd May 2018 in France
❖   Accrual period: 36 months
❖   End of accrual period: Q2 2021
❖   Follow-up period: 5 years
❖   Total study duration: 8 years
❖   Last follow-up: Q2 2026

                                                                      43
STATUT EN FRANCE
39 centres déclarés
31 centres ouverts (en noir)
19 centres recruteurs (en bleu)
  Etablissement                                  Ville                PI
  CHU Amiens - Picardie                          AMIENS               Fabrice SERGENT
  Hôpital Jean Minjoz                            BESANCON             Rajeev RAMANAH
  Clinique Tivoli                                BORDEAUX             Sophie RICHARD
  Institut Bergonié                              BORDEAUX             Frédéric GUYON
  Centre Hospitalier Universitaire Caen          CAEN                 Raffaèle FAUVET
  Centre François Baclesse                       CAEN                 Sandrine MARTIN-FRANCOISE
  Hôpital Antoine Béclère                        CLAMART              Xavier DEFFIEUX
  CHU Estaing                                    CLERMONTFERRAND      Nicolas BOURDEL
  Centre Hospitalier Intercommunal de Créteil    CRETEIL              Cyril TOUBOUL
  CHU de Dijon                                   DIJON                Serge DOUVIER
  Centre Hospitalier de Marne-la-Vallée          JOSSIGNY             Estelle WAFO
  Centre Hospitalier Universitaire Kremlin-      Le Kremlin-Bicêtre   Hervé FERNANDEZ
  Centre Hospitalier Régional Universitaire de
  Lille - Hôpital Jeanne de Flandre              LILLE                Pierre COLLINET

                                                 44
STATUT EN FRANCE

Etablissement                                 Ville             PI
Institut Paoli Calmettes                      MARSEILLE         Eric LAMBAUDIE
Hôpital Saint-Joseph                          MARSEILLE         Elisabeth CHEREAU-EWALD
ICM Val d'Aurelle                             MONTPELLIER       Pierre-Emmanuel COLOMBO
Centre Hospitalier de Mulhouse - Hôpital du
Hasenrain                                     MULHOUSE          Ramzi KACEM
Centre Antoine Lacassagne                     NICE              YvesFOUCHE
Centre Hospitalier Bichat - Claude Bernard    PARIS             Martin KOSKAS
Hôpital Européen Georges Pompidou             PARIS             Fabrice LECURU
Groupe Hospitalier Pitié Salpétrière          PARIS             Catherine UZAN
Hôpital Tenon                                 PARIS             Sofiane BENDIFALLAH
Centre Hospitalier Lyon Sud                   PIERRE-BENITE     François GOLFIER
Hôpital de Poissy-Saint-Germain-en-Laye       POISSY            Cyrille HUCHON
Hôpital de la Milétrie - Centre Hospitalier
Universitaire de Poitiers                     POITIERS          Cédric NADEAU
Centre Hospitalier Universitaire_Institut
Mère et Enfant Alix de Champagne              REIMS             Olivier GRAESSLIN
CHU de Rennes - Hôpital Sud                   RENNES            Vincent LAVOUE
Hôpital Félix Guyon                           Saint Denis       Peter VON THEOBALD
Institut Claudius Regaud IUCT-O               TOULOUSE          Gwénaël FERRON
ICL Institut de Cancérologie de Lorraine      VANDOEUVRE-LES-NANCY
                                                                Frédéric MARCHAL
Gustave Roussy                                VILLEJUIF         Sébastien GOUY

                                               45
STATUT EN FRANCE

      11 centres ont inclus             > 1patiente
                                                                              Patientes
                                                            Ptes       Pts    screen
                                                            enregistr randomi failure (sauf Patientes
Etablissement                           PI                  ées        sées   pN1)          PN1
Institut Paoli Calmettes                Eric LAMBAUDIE               7      5             2
Centre Hospitalier Bichat - Claude
Bernard                                  Martin KOSKAS              6        4
Institut Claudius Regaud IUCT-O          Gwénaël FERRON             4        2            1             1
Clinique Tivoli                          Sophie RICHARD             3        2
Hôpital Européen Georges Pompidou        Fabrice LECURU             3        2                          1
Groupe Hospitalier Pitié Salpétrière     Catherine UZAN             3        2            1
CHU Amiens - Picardie                    Fabrice SERGENT            2        1            1
Centre Hospitalier Universitaire Caen    Raffaèle FAUVET            2        1            2
Centre Hospitalier Lyon Sud              François GOLFIER           2        1            1
                                         Sandrine MARTIN-
Centre François Baclesse                 FRANCOISE                  2                     1
ICL Institut de Cancérologie de Lorraine Frédéric MARCHAL           2        2

                                                 46
STATUT EN FRANCE
➢ 8 centres en attente d’ouverture

         Etablissement                       Ville              PI
         Hôpital Henri Duffaut               AVIGNON            Laurene LUGANS

         Groupement Hospitalier Est -
         Hôpital Femme Mère Enfant           BRON               Gautier CHENE

         Hôpital de la Conception            MARSEILLE          Aubert AGOSTINI

         ICO Centre René Gauducheau          SAINT-HERBLAIN     Cécile LOAC
         Centre Jean Perrin                  CLERMONT-FERRAND   Christophe POMEL

         Hôpital des Diaconesses             PARIS              Marcos BALLESTER

         Institut Curie - Hopital Claudius
         Régaud                              PARIS              Virginie FOURCHOTTE

         Centre Hospitalier Universitaire
         Dupuytren                           LIMOGES            Tristan GAUTHIER

                                                     47
COURBE D’INCLUSION
                         44 screening
                         29 randomisées
                         2 pN1
                         10 échec de screening

                     Nous avons besoin de vous!

                                  48
STATUT PAYS ETRANGERS

▪ Soumission aux comités d’éthique faite pour Le japon et la Chine

  Pays                     Statut
  Canada
                              Soumission règlementaire en cours de
  New york
                                           préparation

           Démarrage international Q3/Q4 2019

                                    49
➢ Sélection et préparation des soumissions en cours

          Allemagne            Pays-Bas
           UK                  Pays
          Cuba                 Nordiques

          Thaïlande            Suisse
          Vietnam              Brésil
          Perou
          Colombie             Inde

          Italie
          Texas

                          50
STUDY TOOLS AND MONITORING

              51
eCRF (1/3)

❖ Data Management: EURAXI

❖ eCRF: CLINSIGHT

❖ E CRF Link: https://ecrf.euraxipharma.fr/CSOnline/

❖ Each investigator and CRA will have his access code for randomization and to complete the CRF, they will
  received it by Email:

                                                                                           52
eCRF (2/3)
eCRF home page

                 53
eCRF (3/3)
eCRF Section overview

                        54
IWRS (1/2)
❖ Randomization by IWRS, linked to the eCRF

❖ Be careful: randomization during the surgery
      → dedicated study staff for this procedure
  should be available
      → Mandatory items to be filled for
  randomization: inclusion and exclusion
  criteria, Figo stage
      → All the screening forms should be
  completed before the surgery

                                                         55
IWRS (2/2)
❖   Confirmation of randomization sent to site (CRA + investigator) and sponsor

                                                                                  56
Focus on pN1 cohorte
❖ If nodal involvement at frozen section:

-> record the patient as a screening failure and complete the pN1
forms

❖ If nodal involvement at definitive examination (ie after
  randomization):

-> the patient is no longer followed in the principal study.
Don’t complete the eCRF sections after the “SLN and nSLN definitive
examination” one.
Complete the pN1 forms.

                                                                      57
MONITORING
❖ Monitoring realized by CHU Besançon:
   ▪ CRA: Caroline CARETTE and Aude Le Breton
   ▪ Project Manager for France sites: Kristina MOUYABI : kmouyabi@chu-besancon.fr

❖ Realized according to the Risk-based monitoring

❖ Site Initiation Visit will be conducted by phone

❖ First on-site monitoring visit: One month after the first patient’s surgery

❖ Generally, subsequent monitoring visits will be done. The frequency could be modified according to the
  monitoring plan

❖ High level considerations :
    ▪ Informed Consent Form
    ▪ Inclusion criteria
    ▪ Primary Objectives
    ▪ Secondary Objectives
    ▪ Serious Adverse Event
    ▪ Investigator Site File

❖ Don’t forget data for patient in pN1 cohort!

                                                                                                58
THANK YOU FOR YOUR ATTENTION!

      Any question?

                                59
REGULATORY CONSIDERATIONS (1/2)

❖ Principal Investigator responsibilities:
    ➢ Respect the study confidentiality,
    ➢ Give his curriculum vitae and those of the co-investigators,
    ➢ Give a GCP certificate dated less than 2 years ago (see following slide)
    ➢ Identify the members of the team who participate to the study and define their role and
        responsibilities,
    ➢ Start the patient recruitment after sponsor authorization,
    ➢ Make himself available for the monitoring visit (if any) and for investigator meetings.

❖ Each Investigator responsibilities:
    ➢ Respect the study confidentiality,
    ➢ Collect informed consent that should be signed and personally dated by patients before any study
        procedure,
    ➢ Regularly complete the eCRF of each patient included,
    ➢ Notify as soon as possible any SAE arising in the course of the research,
    ➢ Accept calls or monitoring visits of the CRA and possibly by auditors mandated by the sponsor or by
        the competent authorities,
    ➢ Give direct access to source documents about patients (medical or hospital record, nursing follow-
        up, results of additional tests …) to CRA or auditors.

                                                                                                60
REGULATORY CONSIDERATIONS (2/2)
 GCP certificates:
❖ Good Clinical Practice (GCP) is an international ethical and scientific quality standard
  for designing, conducting, recording and reporting trials that involve the participation of
  human subjects.
❖ Each Principal Investigator must provide a GCP certificate dated less than 2 years ago before its site
  initiation.

❖ If the PI doesn’t have GCP certificate, he can ask the CHU of Besançon for registering him to an
  online training

 Consent withdrawal:
❖ Reminder: If the patient withdraws her consent, sponsor is not allowed to collect any data about
  the patient after the date of withdrawal.

❖    Make the difference between a consent withdrawal and a refusal to participate in one aspect of
    the study (completion of HR-Qol questionnaires at follow-up, for instance).

                                                                                                           61
You can also read