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

Summary

This is a phase II single-arm study of low-dose pembrolizumab (100mg, fixed-dose) 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).

Eligibility

Inclusion Criteria:

1. ) Female participants aged 18 years and older
2. ) 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.
3. ) 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.
4. ) 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.
5. ) 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.
6. ) 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.
7. ) Performance Status/Eastern Cooperative Oncology Group (ECOG) of 0 to 1 within 7 days prior to C1D1
8. ) 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:

1. ) 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;
2. ) 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.
3. ) 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.
4. ) 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.
5. ) 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.
6. ) History of non-infectious pneumonitis requiring steroid use.
7. ) Having an active infection requiring systemic therapy.
8. ) Having a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required.
9. ) 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 .
10. ) Having a known history of active tuberculosis.
11. ) 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.).
12. ) 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).
13. ) Not having recovered adequately from toxicities and/or complications of major surgery prior to the scheduled start date of cycle 1, day 1.
14. ) Having received radiotherapy within 2 weeks prior to the scheduled start date of cycle 1, day 1.
15. ) 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.
16. ) Having a contraindication or hypersensitivity to any component of carboplatin, paclitaxel, or cisplatin
17. ) 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.
18. ) History of allogeneic solid organ/tissue transplantation.
19. ) Having a known psychiatric disorder or substance abuse that may interfere with the study requirements.
20. ) 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.

Conditions2

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