Low-dose Pembrolizumab Plus Chemotherapy for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer.

This is a phase II single-arm study of low-dose pembrolizumab plus chemotherapy in women aged 18 years or older with histologically confirmed persistent, recurrent, or metastatic cervical cancer who are ineligible for curative-intent treatment (surgery and/or radiation therapy) and who have not been previously treated with systemic chemotherapy, with the exception of chemotherapeutic agents used as radiosensitizers (cisplatin or carboplatin concurrent with radiation therapy).

Participants must have measurable disease as defined by RECIST 1.1, as assessed by the local investigator/radiologist, and must provide a tumor tissue sample no older than 4 years for PD-L1 expression status determination. PD-L1 expression will be analyzed using the 22C3 antibody (Dako®) and classified according to the Composite Positive Score (CPS).

Treatment will consist of pembrolizumab 100mg administered by intravenous infusion plus chemotherapy every 3 weeks. Chemotherapy may be paclitaxel 175 mg/m2 plus carboplatin AUC 5 or paclitaxel 175 mg/m2 plus cisplatin 50 mg/m2 for patients not previously exposed to cisplatin. Both carboplatin and cisplatin should be administered immediately after paclitaxel. All study treatments should be administered on Day 1 (D1) of each 3-week treatment cycle. All participants should receive premedication to prevent severe hypersensitivity reactions according to local practice. Premedication should be administered after the pembrolizumab infusion and before chemotherapy.

During the treatment period, participants will have routine clinical visits for treatment administration, safety and well-being monitoring, and assessment of disease status changes.

Primary safety assessments will include physical examinations, vital signs, electrocardiography (ECG), hematology and biochemistry tests, thyroid function tests, and urinalysis. At each visit, adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 1 5.0. Study treatment doses may be interrupted or reduced (applicable only to chemotherapy) or discontinued in case of severe adverse events.

Imaging assessments will include computed tomography (CT) of the chest and magnetic resonance imaging (MRI) of the abdomen and pelvis. The first study imaging assessment will be performed at 9 weeks (63 days ± 7 days) from the date of Cycle 1 (C1) Day 1 infusion. Subsequent imaging should be performed every 9 weeks (63 days ± 7 days) until Week 54 and every 12 weeks (84 days ± 7 days) thereafter. Other imaging exams such as bone scintigraphy or brain imaging should be performed as clinically indicated.

Participants may interrupt or discontinue pembrolizumab and continue in the study. Similarly, participants may interrupt or discontinue chemotherapy and continue treatment with pembrolizumab.

Participants will receive study treatments until disease progression as defined by RECIST 1.1, unacceptable toxicities, intercurrent illness that precludes continued treatment, investigator's decision to withdraw the participant from treatment, withdrawal of consent, or administrative reasons requiring treatment discontinuation.

Participants may receive up to 6 cycles of paclitaxel-platinum (carboplatin or cisplatin). Participants may receive a maximum of 35 administrations of pembrolizumab (approximately 2 years). In the case of complete response (CR), study treatment may be discontinued at the investigator's discretion after the CR has been confirmed by radiographic imaging and the participant has received at least 2 cycles of pembrolizumab and to have completed a minimum of 8 total treatment cycles (approximately 24 weeks).

Participants who discontinue study treatment for reasons other than radiographic disease progression will be followed until documented disease progression by RECIST 1.1 criteria, initiation of new anticancer therapy, withdrawal of consent, loss to follow-up, or death.

After discontinuation of study treatment, participants may initiate subsequent anticancer treatments at the discretion of the treating physician and in accordance with local standard of care.

After verification of disease progression by RECIST 1.1 and/or initiation of subsequent oncological treatment, all participants will be followed up for overall survival (by telephone contact or in-person visits to the center) until withdrawal of consent, loss to follow-up, death, or until the study is completed or terminated early, whichever occurs first.

Symptomatic improvement is a recognized clinical benefit. Participants will complete the EuroQol EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CX24 to assess quality of life.

The study will begin when the first participant signs the Informed Consent Form and will end when the last participant completes the final study-related call or visit, withdraws from the study, or is lost to follow-up (i.e., the participant cannot be contacted by the investigator).

Inclusion criteria

• ) Female participants aged 18 years and older
• ) Patients with persistent, recurrent, or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer, with PD-L1 CPS ≥ 1 expression, who have not received prior chemotherapy and are ineligible for curative surgery and/ or radiotherapy. Prior chemotherapy used as a radiosensitizer and completed at least 2 weeks before the scheduled date for C1D1 with resolution of all treatment-related toxicities is allowed. Adverse events due to prior treatments must be resolved to ≤ grade 1 or the participant's baseline. Neuropathy ≤ grade 2 or alopecia of grade ≤ 2 are eligible.
• ) Not pregnant or breastfeeding a ) Fertile-age women with the potential to become pregnant must agree to follow contraceptive guidance during treatment and for at least 120 days after the last dose of pembrolizumab and 210 days after the last dose of chemotherapy. Abstinence is acceptable if it is the participant's usual lifestyle and preferred contraception.
• ) The participant (or legal representative, if applicable) must provide written informed consent for the study. The participant may also provide consent for future biomarker research. However, the participant may participate in the main study without participating in future biomarker research.
• ) Have measurable disease according to RECIST 1.1 criteria, as assessed by the local investigator/radiologist. Lesions located in a previously irradiated area are considered measurable only if progression has been demonstrated.
• ) Have an archived tumor tissue sample (recurrent or metastatic cervical cancer) no older than 4 years or provide a biopsy of a previously unirradiated tumor lesion for prospective PD-L1 status determination, since only participants with PD-L1 expression CPS ≥ 1 will be included in the study.
• ) Performance Status/Eastern Cooperative Oncology Group (ECOG) of 0 to 1 within 7 days prior to C1D1
• ) Have adequate organ function, as indicated by the following laboratory values within 7 days prior to C1D1: a ) Absolute neutrophil count (ANC) ≥ 1,500/mcL; b ) Platelets ≥ 100,000/mcL; c ) Hemoglobin ≥ 9.0 g/dL - The criterion must be met without erythropoietin dependence and without transfusion in the last 2 weeks prior to Cycle 1 Day 1; d ) Creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60 mL/min for participants with creatinine levels > 1.5 x upper limit of normal - creatinine clearance (CrCl) should be calculated according to institutional standard using the Cockcroft-Gault formula; d ) Total serum bilirubin ≤ 1.5 x upper limit of normal; e ) AST and ALT ≤ 2.5 x upper limit of normal or ≤ 5 x upper limit of normal for participants with hepatic metastases; f ) International Normalized Ratio (INR) or Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5 x upper limit of normal, unless the participant is receiving anticoagulant, provided that PT or aPTT is within the therapeutic range for the intended use of anticoagulants.

Exclusion criteria

• ) Positive urine pregnancy test within 72 hours prior to C1D1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
• ) Presence of known active central nervous system metastases and/or carcinomatous meningitis. Participants with known brain metastases may be included provided that the brain metastases have been previously treated (except with chemotherapy) and are radiographically stable. To demonstrate radiographic stability of previously treated brain metastases, a minimum of two post-treatment brain imaging evaluations are required: 1) The first brain image should be acquired after completion of the treatment of brain metastases. 2) The second image should be obtained during screening (i.e., within 28 days prior to the scheduled C1D1 date) and >4 weeks after the prior post-treatment brain image.Known brain metastases are considered active if any of the following criteria apply: a ) The brain image obtained during screening shows progression of existing metastases or the appearance of new lesions compared to brain images taken at least 4 weeks earlier b ) The neurological symptoms attributed to brain metastases have not returned to baseline; c) Steroid doses exceeding 10 mg of prednisone daily (or equivalent) were used to treat symptoms related to brain metastases within 28 days prior to the scheduled C1D1 date.
• ) Presence of other known malignancies within the past 3 years. Participants with basal cell carcinoma or squamous cell carcinoma of the skin who have undergone potentially curative therapy are not excluded.
• ) Having a diagnosis of immunodeficiency or being on chronic systemic steroid therapy (at doses greater than 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the scheduled C1D1 date.
• ) Having an active autoimmune disease that has required systemic treatment within the past 2 years (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is permitted.
• ) History of non-infectious pneumonitis requiring steroid use.
• ) Having an active infection requiring systemic therapy.
• ) Having a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required.
• ) Having a known history of hepatitis B (defined as positive hepatitis B surface antigen [HBsAg]) or known active hepatitis C virus (defined as detectable HCV RNA [qualitative]). No testing for hepatitis B and hepatitis C is required .
• ) Having a known history of active tuberculosis.
• ) Having received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or any other immune checkpoint inhibitor (CTLA-4, OX40, LAG3, etc.).
• ) Having received prior systemic chemotherapy for the treatment of advanced cervical cancer (chemotherapy used as a radiosensitizer and completed at least 2 weeks prior to the scheduled start date of cycle 1, day 1).
• ) Not having recovered adequately from toxicities and/or complications of major surgery prior to the scheduled start date of cycle 1, day 1.
• ) Having received radiotherapy within 2 weeks prior to the scheduled start date of cycle 1, day 1.
• ) Having received a live vaccine within 30 days prior to the scheduled start date of cycle 1, day 1 (measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid fever vaccine, etc.). Seasonal influenza vaccines are permitted.
• ) Having a contraindication or hypersensitivity to any component of carboplatin, paclitaxel, or cisplatin
• ) Currently participating or has participated in a study of an investigational agent or used an experimental device within 4 weeks prior to the scheduled start date of cycle 1, day 1.
• ) History of allogeneic solid organ/tissue transplantation.
• ) Having a known psychiatric disorder or substance abuse that may interfere with the study requirements.
• ) To have a history or current evidence of any condition, therapy, or laboratory abnormality that could confound the study results, interfere with participation, in the opinion of the treating investigator.