We aim to determine feasibility, safety and efficacy of TDLN-targeted immune checkpoint inhibition in different doses (nivolumab) in patients with cervical cancer.

Objective: We aim to determine feasibility, safety and efficacy of TDLN-targeted immune checkpoint inhibition in different doses (nivolumab) in patients with cervical cancer.

Trial design: This is a single-arm, single-center phase 1 study to evaluate the feasibility and dose-finding of neoadjuvant nivolumab in newly diagnosed cervical cancer patients. Two 3-weekly subcutaneous administrations of nivolumab (5, 10, 15, or 30 mg) will be given in the inner-upper thigh, targeting the tumor-draining lymph nodes. Treatment will occur between diagnosis and standard-of-care surgery, followed by adjuvant therapy. The dose levels are based on the established bioavailability and previous reports of biological activity. Subjects participate in the study for 11 weeks with late follow-up visits after 3 and 6 months.

Trial population: The study will include female patients aged 18 and older with newly diagnosed cervical cancer (FIGO stage < IB3) who are eligible for standard-of-care surgery. Participants must not be pregnant or breastfeeding and must provide informed consent. Key exclusion criteria include prior systemic immunotherapy, recent systemic anti-cancer therapy, live vaccines, active infections, autoimmune diseases requiring treatment, known CNS metastases, and other malignancies within the last three years. Patients with hypersensitivity to nivolumab or severe comorbidities, including active pneumonitis or immunodeficiency, will be excluded.

Intervention: Nivolumab (5, 10, 15, or 30 mg), subcutaneous Q3W for a total of 2 administrations per patient, integrated into standard-of-care protocol prior to surgery. Based on the well-established timelines, the interval between diagnosis and standard-of-care (SoC) surgery is sufficient to treat patients with two administrations of nivolumab without interfering with standard treatment.

Inclusion Criteria:

• Female participants with uterus and cervix in situ who are at least 18 years of age on the day of signing informed consent with histologically confirmed primary diagnosis of cervical cancer and are intended to be treated with standard-of-care surgery (< FIGO IB3). Only female participants with reproductive organs still in situ are eligible because this ensures the highest chance of the correct lymph(node) anatomy needed for the administration of the IMP;
• The participant is not pregnant, not breastfeeding, is not a woman of childbearing potential (WOCBP) or agrees to follow contraceptive guidance as described in 9.2.1. during the treatment period and at least until SoC surgery;
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

Exclusion Criteria:

• WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• 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).
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• 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 vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• 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.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (defined as >10 mg prednisone equivalent per day) or other systemic immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of systemic corticosteroids and other immunosuppressants prior to initiation of study treatment should be avoided due to potential interference with the pharmacodynamic activity of nivolumab. Use of immunosuppressive agents after initiation of treatment is allowed when clinically indicated for the management of immune-related adverse events.
• 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, squamous 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.
• Has known active CNS metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity (≥Grade 3) to nivolumab and/or any of its excipients.
• 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.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Any contraindication to MRI, including but not limited to the presence of non-MRI-compatible implants (e.g., pacemakers, cochlear implants, neurostimulators), ferromagnetic metal fragments, or severe claustrophobia unmanageable with standard precautions.
• Prior surgical intervention in the inguinal region with potential disruption of lymphatic drainage.
• Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Any condition, as assessed by the research physician and/or medical oncologist, that in their clinical judgment makes the patient unsuitable for participation in the study. This may include, but is not limited to, poor physical condition, abnormal laboratory values, or other medical or psychosocial factors that could compromise patient safety or study integrity. Patients that are excluded based on this criterium will always be reported to the DSMB.