Induction Pembrolizumab and Chemotherapy Followed by Pembrolizumab Before Chemoradiation and Pembrolizumab Maintenance Compared to Standard Chemoradiation With Pembrolizumab Followed by Pembrolizumab Maintenance in High-Risk Cervical Cancer

Официальное название

NRG-GY037: A Phase III Study of Induction Pembrolizumab and Chemotherapy Followed by Chemoradiation and Pembrolizumab Versus Chemoradiation and Pembrolizumab Both Followed by Pembrolizumab for High Risk Locally Advanced Cervical Cancer

Обзор

This phase III trial compares the addition of induction chemotherapy, with carboplatin, paclitaxel and pembrolizumab, to chemotherapy and radiation, with cisplatin and pembrolizumab followed by pembrolizumab maintenance for the treatment of patients with cervical cancer that has spread to nearby tissue or lymph nodes (locally advanced). Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Adding induction chemotherapy to the usual treatment of chemotherapy and radiation followed by maintenance may be more effective in treating patients with high risk, locally advanced cervical cancer.

Подробное описание

PRIMARY OBJECTIVE:

I. To determine whether induction immunotherapy (IO) and chemotherapy prior to concurrent chemoradiation therapy (CCRT) + IO improves progression-free survival (PFS) compared to CCRT+IO alone.

SECONDARY OBJECTIVES:

I. To assess whether induction IO and chemotherapy prior to CCRT+IO improves the overall survival (OS) compared to CCRT+IO alone.

II. To determine the nature and degree of toxicity of induction IO and chemotherapy prior to CCRT + IO as compared to concurrent CCRT+IO as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

III. To determine the impact on CCRT start, CCRT completion time, and number of cycles of cisplatin administered; with induction IO and chemotherapy prior to CCRT+IO arm as compared to CCRT+IO.

IV. To assess the association between allostatic load and PFS/OS. V. To assess the predictive value of the integrated biomarker: PD-L1 expression at baseline for progression free survival.

VI. To assess the prognostic and predictive value of the integrated biomarker: circulating tumor deoxyribonucleic acid (ctDNA) at baseline and at 3 months post radiation therapy (RT) for progression free survival.

VII. To explore radiotherapy quality pretreatment scores conducted by expert review with assistance from artificial intelligence (AI) models and correlation with outcomes.

EXPLORATORY OBJECTIVES:

I. To assess the evolution of T cell receptor (TCR) repertoire on treatment and its correlation with clinical outcomes.

II. To identify pre-treatment tumor microenvironment biomarkers predictive of outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1:

CHEMORADIATION: Patients receive cisplatin intravenously (IV) once weekly (QW) for 5 weeks and pembrolizumab IV over 30 minutes every 3 weeks (Q3W) for 5 doses. Patients also undergo radiation therapy once daily 5 days per week for 25-29 treatments in weeks 1-5 followed by brachytherapy up to twice per week for 4-5 treatments in weeks 5-7. Treatment is given in the absence of disease progression or unacceptable toxicity

MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes every 6 weeks (Q6W) for 15 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo positron emission tomography (PET) scan, computed tomography (CT) scan, chest x-ray and/or magnetic resonance imaging (MRI) and blood sample collection throughout the study.

ARM 2:

INDUCTION: Patients receive carboplatin IV and paclitaxel IV QW on weeks 1-3 and pembrolizumab IV over 30 minutes Q3W on weeks 1 for each cycle. Cycles repeat every 3 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity.

CHEMORADIATION: Patients receive cisplatin IV QW for 5 weeks and pembrolizumab IV over 30 minutes every Q3W for 5 doses. Patients also undergo radiation therapy once daily 5 days per week for 25-29 treatments in weeks 7-11 followed by brachytherapy up to twice per week for 4-5 treatments in weeks 11-13. Treatment is given in the absence of disease progression or unacceptable toxicity

MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes Q6W for 14 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo PET scan, CT scan, chest x-ray and/or MRI and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months for 3 years.

Вмешательства

• Процедура Biospecimen Collection
  Undergo blood sample collection
• Лучевая терапия Brachytherapy
  Undergo brachytherapy
• Препарат Carboplatin
  Given IV
• Процедура Chest Radiography
  Undergo chest x-ray
• Препарат Cisplatin
  Given IV
• Процедура Computed Tomography
  Undergo CT scan
• Лучевая терапия External Beam Radiation Therapy
  Undergo EBRT
• Лучевая терапия Intensity-Modulated Radiation Therapy
  Undergo IMRT
• Процедура Magnetic Resonance Imaging
  Undergo MRI
• Препарат Paclitaxel
  Given IV

Первичные конечные точки

• Progression free survival (PFS) [Срок оценки: From randomization to time of progression or death from any cause, whichever occurs first, or date of last contact if neither progression nor death has occurred, up to 7 years]

Вторичные конечные точки (8)

• Overall survival (OS) [Срок оценки: From randomization to death from any cause, up to 7 years]
• Incidence of adverse events (AEs) [Срок оценки: Up to 7 years]
• Duration of concurrent chemoradiation therapy (CCRT) completion [Срок оценки: From CCRT start date to CCRT end date]
• Number of cycles of cisplatin [Срок оценки: From 7 days after the last dose of induction chemotherapy to the CCRT start date for Arm 2, the planned CCRT start date to actual CCRT start date for Arm 1]
• Allostatic load [Срок оценки: Up to 2 years]
• Tumor PD-L1 expression [Срок оценки: At baseline]
• Circulating tumor deoxyribonucleic acid expression [Срок оценки: At baseline and at 3 months post radiation therapy]
• Radiation quality pre-treatment score [Срок оценки: At time of radiation]

Критерии участия

Критерии включения

• Patients must have pathologically confirmed newly diagnosed cervical cancer. Eligible pathologic types: squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma
• Patients must have locally advanced cervical cancer (LACC) with T3 or T4 disease with or without lymph node involvement:

• IIIA (T3aN0M0)
• IIIB (T3bN0M0)
• IIIC1(T3aN1M0, T3bN1M0)
• IIIC2 (T3aN2M0, T3bN2M0)
• IVA (T4aN0M0, T4aN1M0, T4aN2M0) No prior hysterectomy defined as removal of the entire uterus.
• NOTE: prior partial/subtotal hysterectomy for reasons other than cervical cancer are eligible to participate in the study. No plan to perform a hysterectomy as part of initial cervical cancer therapy.

No paraaortic lymph node (PALN) metastases above the T12/L1 interspace.

• Note: Nodal status can be confirmed by imaging (CT, MRI, or PET/CT), fine needle aspirate/core biopsy, extra peritoneal biopsy, laparoscopic biopsy, or lymphadenectomy.

Radiologic definition of lymph node staging:

• N1:

• One or more pelvic lymph nodes with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or
• One or more pelvic lymph nodes with short axis diameter of ≥ 10 mm and standardized uptake value maximum (SUVmax) ≥ 2.5 by fludeoxyglucose (FDG)-PET
• N2:

• One or more para-aortic lymph node with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or
• One or more para-aortic lymph node with short axis diameter of ≥ 10 mm and SUVmax ≥ 2.5 by FDG-PET

• No prior definitive surgical, radiation, or systemic therapy for cervical cancer
• No prior immunotherapy
• No prior pelvic radiation therapy for any disease
• Age ≥ 18
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Not pregnant and not nursing
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm\^3
• Platelets ≥ 100,000 cells/mm\^3
• Hemoglobin ≥ 8 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobulin \[Hgb\] ≥ 8 g/dl is acceptable)
• Creatinine clearance (CrCL) of ≥ 50 mL/min by the Cockcroft-Gault formula
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• No active infection requiring parenteral antibiotics
• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille Calmette Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
• No diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior registration
• No active autoimmune disease that has required systemic treatment in 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) is not considered a form of systemic treatment and is allowed
• No history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
• No history of allergic reaction to the study agent(s) or compounds of similar chemical or biologic composition to the study agent(s) (or any of its excipients)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 311 центров

• University of Alabama at Birmingham Cancer Center — Birmingham
• Highlands Oncology Group - Fayetteville — Fayetteville
• University of Arkansas for Medical Sciences — Little Rock
• Highlands Oncology Group - Rogers — Rogers
• Highlands Oncology Group — Springdale
• Kaiser Permanente-Bellflower — Bellflower
• City of Hope Corona — Corona
• City of Hope Comprehensive Cancer Center — Duarte
• … и ещё 303 центра

Идентификаторы

NCT: NCT07061977 · NCI-2025-04695 · NCI-2025-04695 · NRG-GY037 · NRG-GY037 · U10CA180868

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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