Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA Cervical Cancer

Phase 1

Completed

• Conditions: Stage IB2 Cervical Cancer AJCC v6 and v7; Cervical Adenosquamous Carcinoma; Stage II Cervical Cancer AJCC v7; Stage IIB Cervical Cancer AJCC v6 and v7; Stage IVA Cervical Cancer AJCC v6 and v7; Cervical Adenocarcinoma; Stage IIA Cervical Cancer AJCC v7; Stage IIIB Cervical Cancer AJCC v6 and v7; Cervical Squamous Cell Carcinoma, Not Otherwise Specified
• Interventions: Drug: Cisplatin; Radiation: External Beam Radiation Therapy; Radiation: Internal Radiation Therapy; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis

• Registration Number: NCT01711515
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I trial studies the side effects and best dose of ipilimumab when given after chemoradiation therapy in treating patients with stages IB2-IIB or IIIB-IVA cervical cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as ipilimumab, may find tumor cells and help carry tumor-killing substances to them. Giving ipilimumab together with chemoradiation therapy may be a better way treat cervical cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of adjuvant ipilimumab following concurrent weekly cisplatin and extended field radiation in women with newly diagnosed locally advanced cervical cancer stage IB2/ IIA with-positive para-aortic lymph nodes only and stage IIB/IIIB/IVA with positive lymph nodes.

II. To determine the feasibility of the treatment regimen over the four cycles of adjuvant ipilimumab once the MTD is estimated.

III. To assess the toxicities of the treatment regimen per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

SECONDARY OBJECTIVES:

I. To examine progression free survival for 1 year after study completion. II. To determine site of recurrence, loco-regional versus distant, for one year after completion of therapy.

III. To estimate the frequency of chronic toxicities experienced within one year after completion of therapy.

TERTIARY OBJECTIVES:

I. To enumerate the human papillomavirus (HPV)-subtype-specific T-cells and characterize the kinetics of HPV-subtype-specific T-cell expansion associated with chemoradiation and ipilimumab treatment.

II. To characterize the association between differential expression of immune markers on leukocytes from human leukocyte antigen (HLA)-A\*0201 patients and response to chemoradiation and ipilimumab treatment.

III. To assess qualitative changes in maximum standardized uptake value (SUVmax) from positron emission tomography (PET)/computed tomography (CT) after treatment with chemoradiation and ipilimumab.

IV. To bank residual plasma (obtained from leukocyte processing) for future research.

OUTLINE: This is a dose-escalation study of ipilimumab.

Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo external beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 1 year.

Study Timeline

• Study Start: 2012-10-01
• Study First Submitted: 2012-10-18
• Study First Submitted QC: 2012-10-18
• Study First Posted: 2012-10-22
• Primary Completion: 2017-02-09
• Study Completion: 2020-07-17
• Status Verified: 2020-08
• Last Update Submitted: 2020-09-01
• Last Update Posted: 2020-09-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 34

Inclusion Criteria

• Patients with histologically confirmed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): International Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive para-aortic lymph nodes or FIGO clinical stages IIB/IIIB/IVA with positive pelvic and/or para-aortic lymph nodes; nodal status will be confirmed by PET/CT scan, fine needle biopsy, extra peritoneal biopsy, laparoscopic biopsy or lymphadenectomy
• Patients must have a Gynecologic Oncology Group (GOG) performance status of 0-1
• Absolute neutrophil count (ANC) >= 1,500/mcl
• Platelets >= 100,000/mcl
• Creatinine =< institutional upper limit normal (ULN); note: if creatinine > ULN, creatinine clearance must be > 50 mL/min
• Bilirubin =< 1.5 x ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Alkaline phosphatase =< 2.5 x ULN
• Neuropathy (sensory and motor) =< grade 1
• Patients with ureteral obstruction (i.e., hydronephrosis identified on CT imaging) must undergo stent or nephrostomy tube placement prior to study entry
• Patients must meet the pre-entry requirements specified
• Patients must have signed an approved informed consent and authorization permitting the release of personal health information
• Patients of child-bearing potential must have a negative serum pregnancy test prior to study entry (within 72 hours prior to initiation of study treatment) and be practicing an effective form of contraception; women should not breast-feed while on this study
• Patients must not be receiving any other investigational agent
• Patients should have an audiogram at baseline, and patients with pre-existing hearing loss or hearing loss during treatment should be assessed frequently during cisplatin therapy

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Exclusion Criteria

• Patients who have received previous pelvic or abdominal radiation, cytotoxic chemotherapy, or previous therapy of any kind for this malignancy or any pelvic or abdominal radiation for any prior malignancy
• Patients with active infection
• Patients who have circumstances that will not permit completion of this study or the required follow-up
• Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal transplantation, that would require modification of radiation fields
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment prevents full delivery of this protocol therapy
• Patients who have undergone major surgery, excluding diagnostic biopsy, within 30 days (to allow for full recovery) prior to registration
• Patients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, congestive heart failure, or uncontrolled arrhythmias within 6 months of registration
• Patients with a history of prior treatment with ipilimumab, anti-programmed cell death (PD) 1 antibody, cluster of differentiation (CD)137 agonist or other immune activating therapy such as anti-CD 40 antibody
• Patients who are receiving any other investigational agents
• Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis)
• Patients with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) antibody
• History of allergic reactions attributed to compounds of similar chemical or biologic composition ipilimumab or other agents used in study
• Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections should be excluded

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cisplatin, radiation therapy, and ipilimumab)	Ipilimumab	Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.
Treatment (cisplatin, radiation therapy, and ipilimumab)	Internal Radiation Therapy	Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.
Treatment (cisplatin, radiation therapy, and ipilimumab)	External Beam Radiation Therapy	Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.
Treatment (cisplatin, radiation therapy, and ipilimumab)	Laboratory Biomarker Analysis	Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.
Treatment (cisplatin, radiation therapy, and ipilimumab)	Cisplatin	Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.

Primary Outcome Measures

Name	Time	Method
DLTs occurring during adjuvant ipilimumab in the dose escalation phase	During first 2 courses of treatment
Toxicities as assessed by CTCAE version 4	Up to 2 years post-treatment
DLTs occurring in the feasibility phase	Over 4 courses of treatment

Secondary Outcome Measures

Name	Time	Method
Response rate in patients enrolled with measurable disease assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	Up to 2 years post-treatment	Relationships of translational research endpoints to response will be explored if practical.
Overall survival	From time of study entry to time of death or the date the patient was last confirmed to be alive, assessed up to 1 year post-treatment	Will be summarized using Kaplan-Meier plots.
Chronic toxicities experienced within one year of completion of therapy	Up to 1 year post-treatment
Location of recurrence (loco-regional versus distant)	Up to 1 year post-treatment
Progression-free survival (PFS)	From time of study entry to time of progression or death, whichever occurs first, assessed up to 1 year post-treatment	Will be summarized using Kaplan-Meier plots. Relationships of translational research endpoints to PFS will be explored if practical.

Trial Locations

Locations (16)

UC Irvine Health/Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

University of New Mexico Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

Montefiore Medical Center-Einstein Campus; 🇺🇸 Bronx, New York, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Women and Infants Hospital; 🇺🇸 Providence, Rhode Island, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

Los Angeles County-USC Medical Center; 🇺🇸 Los Angeles, California, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Hartford Hospital; 🇺🇸 Hartford, Connecticut, United States

Augusta University Medical Center; 🇺🇸 Augusta, Georgia, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

The Hospital of Central Connecticut; 🇺🇸 New Britain, Connecticut, United States