UAMS - Translational Research Institute

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

Purpose

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.

Conditions

Locally Advanced Cervical Adenocarcinoma
Locally Advanced Cervical Adenosquamous Carcinoma
Locally Advanced Cervical Squamous Cell Carcinoma
Stage IIIA Cervical Cancer FIGO 2018
Stage IIIB Cervical Cancer FIGO 2018
Stage IIIC1 Cervical Cancer FIGO 2018
Stage IIIC2 Cervical Cancer FIGO 2018
Stage IVA Cervical Cancer FIGO 2018

Eligibility

Eligible Ages: Over 18 Years
Eligible Sex: Female
Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- 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)

Study Design

Phase: Phase 3
Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Active Comparator Arm 1 (Standard care)	CHEMORADIATION: Patients receive cisplatin IV QW for 5 weeks and pembrolizumab IV over 30 minutes Q3W for 5 doses. Patients also undergo radiation therapy with EBRT or IMRT 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 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.	Procedure: Biospecimen Collection Undergo blood sample collection Other names: Biological Sample Collection Biospecimen Collected Specimen Collection Radiation: Brachytherapy Undergo brachytherapy Other names: Brachytherapy, NOS Internal Radiation Internal Radiation Brachytherapy Internal Radiation Therapy Radiation Brachytherapy Radiation, Internal Procedure: Chest Radiography Undergo chest x-ray Other names: Chest X-ray Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Procedure: Computed Tomography Undergo CT scan Other names: CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan Diagnostic CAT Scan Diagnostic CAT Scan Service Type tomography Radiation: External Beam Radiation Therapy Undergo EBRT Other names: Definitive Radiation Therapy EBRT External Beam Radiation External Beam Radiotherapy External Beam Radiotherapy (conventional) External Beam RT external radiation External Radiation Therapy external-beam radiation Radiation, External Beam Teleradiotherapy Teletherapy Teletherapy Radiation Radiation: Intensity-Modulated Radiation Therapy Undergo IMRT Other names: IMRT Intensity modulated radiation therapy (procedure) Intensity Modulated RT Intensity-Modulated Radiotherapy Radiation, Intensity-Modulated Radiotherapy Procedure: Magnetic Resonance Imaging Undergo MRI Other names: Magnetic Resonance Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (procedure) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance MR MR Imaging MRI MRI Scan MRIs NMR Imaging NMRI Nuclear Magnetic Resonance Imaging sMRI Structural MRI Biological: Pembrolizumab Given IV Other names: BCD-201 GME 751 GME751 Keytruda Lambrolizumab MK 3475 MK-3475 MK3475 Pembrolizumab Biosimilar BCD-201 Pembrolizumab Biosimilar GME751 Pembrolizumab Biosimilar QL2107 Pembrolizumab Biosimilar RPH-075 Pembrolizumab Biosimilar SB27 QL2107 RPH 075 RPH-075 RPH075 SB 27 SB-27 SB27 SCH 900475 SCH-900475 SCH900475 Procedure: Positron Emission Tomography Undergo PET scan Other names: Medical Imaging, Positron Emission Tomography PET PET Scan Positron emission tomography (procedure) Positron Emission Tomography Scan Positron-Emission Tomography PT
Experimental Arm 2 (induction and standard care)	INDUCTION: Patients receive carboplatin IV and paclitaxel IV QW on weeks 1-3 and pembrolizumab IV over 30 minutes Q3W on week 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 with EBRT or IMRT 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.	Procedure: Biospecimen Collection Undergo blood sample collection Other names: Biological Sample Collection Biospecimen Collected Specimen Collection Radiation: Brachytherapy Undergo brachytherapy Other names: Brachytherapy, NOS Internal Radiation Internal Radiation Brachytherapy Internal Radiation Therapy Radiation Brachytherapy Radiation, Internal Drug: Carboplatin Given IV Other names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 JM8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo Procedure: Chest Radiography Undergo chest x-ray Other names: Chest X-ray Drug: Cisplatin Given IV Other names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Procedure: Computed Tomography Undergo CT scan Other names: CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan Diagnostic CAT Scan Diagnostic CAT Scan Service Type tomography Radiation: External Beam Radiation Therapy Undergo EBRT Other names: Definitive Radiation Therapy EBRT External Beam Radiation External Beam Radiotherapy External Beam Radiotherapy (conventional) External Beam RT external radiation External Radiation Therapy external-beam radiation Radiation, External Beam Teleradiotherapy Teletherapy Teletherapy Radiation Radiation: Intensity-Modulated Radiation Therapy Undergo IMRT Other names: IMRT Intensity modulated radiation therapy (procedure) Intensity Modulated RT Intensity-Modulated Radiotherapy Radiation, Intensity-Modulated Radiotherapy Procedure: Magnetic Resonance Imaging Undergo MRI Other names: Magnetic Resonance Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (procedure) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance MR MR Imaging MRI MRI Scan MRIs NMR Imaging NMRI Nuclear Magnetic Resonance Imaging sMRI Structural MRI Drug: Paclitaxel Given IV Other names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat Biological: Pembrolizumab Given IV Other names: BCD-201 GME 751 GME751 Keytruda Lambrolizumab MK 3475 MK-3475 MK3475 Pembrolizumab Biosimilar BCD-201 Pembrolizumab Biosimilar GME751 Pembrolizumab Biosimilar QL2107 Pembrolizumab Biosimilar RPH-075 Pembrolizumab Biosimilar SB27 QL2107 RPH 075 RPH-075 RPH075 SB 27 SB-27 SB27 SCH 900475 SCH-900475 SCH900475 Procedure: Positron Emission Tomography Undergo PET scan Other names: Medical Imaging, Positron Emission Tomography PET PET Scan Positron emission tomography (procedure) Positron Emission Tomography Scan Positron-Emission Tomography PT