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Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months (NiCOL)

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ClinicalTrials.gov Identifier: NCT03298893
Recruitment Status : Active, not recruiting
First Posted : October 2, 2017
Last Update Posted : October 6, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Institut Curie

Tracking Information
First Submitted Date  ICMJE September 27, 2017
First Posted Date  ICMJE October 2, 2017
Last Update Posted Date October 6, 2020
Actual Study Start Date  ICMJE November 27, 2017
Estimated Primary Completion Date October 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 27, 2017)
rate of occurrence of dose-limiting toxicity (DLT) [ Time Frame: within 11 weeks after the initiation of treatment. ]
DLT is defined as any of the following treatment-related adverse events or laboratory abnormalities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0:
  • non-hematological toxicity ≥ grade 3;
  • immune-related adverse event ≥ grade 3;
  • symptomatic immune-related adverse event ≥ grade 2 resistant to optimal supportive care for > 7 days;
  • dosing delay in RT ≥ 1 week due to toxicity related to nivolumab, chemotherapy or RT;
  • colitis or diarrhea ≥ grade 3.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2017)
  • Objective Response Rate (ORR) [ Time Frame: after the end of RT and before brachytherapy and again up to 2 months after brachytherapy ]
    ORR is defined as the proportion of all subjects whose best response is either a complete response or a partial response.
  • Progression Free Survival (PFS) [ Time Frame: 2 years ]
    PFS is defined as the length of time from the start of treatment to disease progression or death, regardless of the cause of death
  • Disease Free Survival (DFS) [ Time Frame: 2 years ]
    DFS is defined as the length of time from the start of complete response to the time of relapse from complete response. DFS applies only to patients in complete response.
  • Incidence of Serious Adverse Events (SAEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy [ Time Frame: from the first intake of the IMP until 100 days after the last intake of the IMP ]
  • Incidence of Adverse Events (AEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy [ Time Frame: from the first intake of the IMP until 100 days after the last intake of the IMP ]
  • validation of molecular alterations detected by molecular analyses [ Time Frame: 2 years ]
    Retrospective exome, RNA and targeted sequencing analyses will be performed on all patients treated and for whom tumor samples are available.
  • ctDNA heterogeneity [ Time Frame: baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104 ]
    Retrospective exome and targeted sequencing analyses will be performed on all patients treated and for whom tissue samples are available at the different timepoints
  • tumor microenvironment description [ Time Frame: 2 years ]
    phenotypic analysis of the different components of the tumor microenvironment using various technologies
  • tumor PD-L1 immunohistochemistry [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months
Official Title  ICMJE A Phase-I Study of Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months. NiCOL
Brief Summary To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as monotherapy, and the next logical step is to evaluate rational therapeutic associations. The aim of the NiCOL study is to assess the safety of nivolumab in association with chemoradiation therapy and to gain initial insight into its efficacy in association with the current standard of care, including chemoradiation.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cervical Cancer
  • Locally Advanced Cervical Cancer
Intervention  ICMJE
  • Drug: Nivolumab Injection
    2 possible doses : flat dose 240 mg q2 weeks or 1mg/kg q2 weeks
  • Drug: Cisplatin
    40 mg/m2, once a week during radiotherapy
  • Radiation: radiotherapy

    Intensity-modulated radiation therapy (including volumetric-modulated arc therapy and tomography) will be used. A dose of 45 Gy will be delivered to the pelvis in 25 fractions of 1.8 Gy using a 6-MV photon energy.

    An additional dose of 54 Gy in 25 fractions of 2.16 Gy may be delivered to invaded lymph nodes using SIB-IMRT.

    An additional lateral pelvic dose may be delivered if coverage of the target volumes is judged insufficient. The volumes, doses and techniques will be those usually used in each center.

Study Arms  ICMJE Experimental: Nivolumab + radiochemotherapy
5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone
Interventions:
  • Drug: Nivolumab Injection
  • Drug: Cisplatin
  • Radiation: radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 27, 2017)
21
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 15, 2022
Estimated Primary Completion Date October 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Adult patients at least 18 years of age;
  2. Ability to understand and the willingness to sign a written informed consent document.;
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;
  4. Histologically confirmed locally advanced cervical cancer, i.e. FIGO stages IB2 to IVA, squamous-cell carcinoma or adenocarcinoma, with indication for radiotherapy and cisplatin-based chemotherapy with a curative intent as confirmed by a multidisciplinary board including a radiation oncologist. PD-L1 expression on tumor will not be required for inclusion; (staging may include [18F]-fluorodeoxyglucose (FDG) PET-CT and/or para-aortic dissection in accordance with usual practice in each investigational center and at the Investigator's discretion);
  5. Disease amenable to biopsy since three tumor samples are mandatory prior to treatment;
  6. Laboratory values at Screening must meet the following criteria :

    neutrophils ≥ 1.0 x 109/L, lymphocytes ≥ 0.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 8.0 g/dL, creatinine ≤ 2 times the upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 3 ULN, alanine aminotransferase (ALT) ≤ 3 x ULN, total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if genetically documented Gilbert's syndrome).

  7. For women with child-bearing potential, negative blood or urinary pregnancy test within 24 hours of initiation of nivolumab, as well as appropriate method of contraception throughout the study ;
  8. Affiliated to the French Social Security System.

Exclusion Criteria:

  1. Metastases (except pelvic and/or para-aortic nodal metastases) ;
  2. Peritoneal carcinosis;
  3. Sensory or motor neuropathy ≥ grade 2;
  4. Active or recent history of known autoimmune disease or recent history of a syndrome that required systemic corticosteroids or immunosuppressive drugs, except for :

    • hydrocortisone, which is permitted at physiological doses;
    • syndromes that would not be expected to recur in the absence of an external trigger, e.g. glomerulonephritis;
    • vitiligo or autoimmune thyroiditis;
  5. Type-1 or type-2 diabetes;
  6. History of or current immunodeficiency disease, including known history of infection with human immunodeficiency virus;
  7. Prior systemic treatment or radiotherapy for cervical cancer;
  8. Prior allogeneic stem cell transplantation;
  9. Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, anti-PD-1, anti-PD-L1 or similar agents;
  10. Any non-oncologic vaccine for prevention of infectious disease within 28 days prior to inclusion, including but not limited to measles, mumps, rubella, chicken pox, yellow fever, seasonal influenza, H1N1, rabies, BCG, and typhoid vaccine;
  11. Positive serology for hepatitis B surface antigen;
  12. Positive for hepatitis-C ribonucleic acid on polymerase chain reaction;
  13. Active infection requiring therapy;
  14. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on chest CT-scan at Screening;
  15. History of malignancy (excepting non-melanoma skin cancer) unless complete remission was achieved at least 3 years prior to inclusion and no additional therapy is required or planned during the study;
  16. Underlying medical condition that, in the Investigator's opinion, could render the administration of the study treatment hazardous; additional severe and/or uncontrolled concurrent disease;
  17. Concomitant use of other investigational drugs;
  18. Pregnancy or breastfeeding.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03298893
Other Study ID Numbers  ICMJE IC 2016-08
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institut Curie
Study Sponsor  ICMJE Institut Curie
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Study Director: Emanuela Romano, MD Institut Curie
PRS Account Institut Curie
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP