Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer

Randomized Phase II Study to Evaluate Induction Nivolumab-Ipilimumab, Followed by Nivolumab With Chemoradiotherapy Versus Chemoradiotherapy for Advanced Cervical Cancer

A total of 112 patients with locally advanced cervical cancer will be randomized 1:1 to standard therapy with cisplatin-based chemoradiation or nivolumab-ipilimumab induction followed by cisplatin-based chemoradiation. The primary outcome will be 3-year disease-free survival.

Patients with adenocarcinoma or squamous cell carcinoma of the cervix, FIGO Stage IB2-IB3 node positive or Stage IIB-IVA will be randomized to conventional cisplatin-based chemo-radiation or to 4 cycles of induction immunotherapy with nivolumab 1mg/kg and ipilimumab 3mg/kg every 3 weeks, followed by cisplatin chemo-radiation with concurrent nivolumab 240mg every 2 weeks. Primary outcome will be 3-year progression-free survival.

Inclusion Criteria:

• Female participants older than 18 years
• Documented evidence of cervical adenocarcinoma or squamous carcinoma FIGO Stage IB2-IB3 node positive or Stage IIB-IVA
• No prior chemotherapy, immune checkpoint inhibitors or radiotherapy for cervical cancer
• WHO/ECOG performance status of 0-1
• At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 Target Lesion at baseline.

Exclusion Criteria:

• Diagnosis of small cell (neuroendocrine) histology cervical cancer
• Intent to administer a fertility-sparing treatment regimen
• Undergone a previous hysterectomy
• Evidence of metastatic disease per RECIST 1.1 including lymph nodes ≥15 mm (short axis) above the L1 cephalad body or outside the planned radiation field.
• History of allogeneic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders
• Uncontrolled intercurrent illness
• History of another primary malignancy and active primary immunodeficiency
• Patients with active infection

Laboratory values that fall into:

1. WBC count (WBC) < 2000/μL ;

2. Neutrophil count < 1500/μL;

3. Platelet count < 100 x 103/μL;

4. Hemoglobin level < 9.0 g/dL;

5. Serum creatinine > 1.5 x upper limit of normal (ULN) unless creatinine clearance is

   ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula);

6. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): > 3.0 x ULN;

7. Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN);

8. Any positive test result for hepatitis B virus or hepatitis C virus that indicates the presence of the virus, for example, positive Hepatitis B surface antigen (HBsAg, Australia antigen) or Hepatitis C antibodies (anti- HCV) positive (unless the HCV-RNA is negative).

   • Participants with a condition requiring systemic treatment or with corticosteroids (>10 mg daily of a prednisone equivalent) or other immunosuppressive drugs within 14 days of initiating study treatment.
   • Pregnant or breastfeeding woman