Clinical trial NCT03298893: Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cervical Cancer
Locally Advanced Cervical Cancer
Keywords: cervical cancer
nivolumab
cisplatin
radiotherapy
Lead sponsor: Institut Curie
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-10-02
Enrollment: 21
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: rate of occurrence of dose-limiting toxicity (DLT)
timeFrame: within 11 weeks after the initiation of treatment.
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: after the end of RT and before brachytherapy and again up to 2 months after brachytherapy
measure: Progression Free Survival (PFS)
timeFrame: 2 years
measure: Disease Free Survival (DFS)
timeFrame: 2 years
measure: Incidence of Serious Adverse Events (SAEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy
timeFrame: from the first intake of the IMP until 100 days after the last intake of the IMP
measure: Incidence of Adverse Events (AEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy
timeFrame: from the first intake of the IMP until 100 days after the last intake of the IMP
measure: validation of molecular alterations detected by molecular analyses
timeFrame: 2 years
measure: ctDNA heterogeneity
timeFrame: baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104
measure: tumor microenvironment description
timeFrame: 2 years
measure: tumor PD-L1 immunohistochemistry
timeFrame: 2 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hopital Européen Georges Pompidou
city: Saint Cloud
country: France
facility: Institut Curie Hopital René Huguenin
Study officials:
affiliation: Institut Curie
name: Emanuela Romano, MD
role: STUDY_DIRECTOR
References: