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

Cervical Adenocarcinoma Clinical Trial

Official title:

A Phase I Trial of Sequential Ipilimumab After Chemoradiation for the Primary Treatment of Patients With Locally Advanced Cervical Cancer Stages IB2/IIA With Positive Para-Aortic Lymph Nodes Only and Stage IIB/IIIB/IVA With Positive Lymph Nodes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01711515
• Other study ID #: NCI-2012-01733
• Secondary ID: NCI-2012-01733GO
• Status: Completed
• Phase: Phase 1
• Start date: October 1, 2012
• Est. completion date: July 17, 2020

Study information

• Verified date: August 2020
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: July 17, 2020
• Est. primary completion date: February 9, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Carcinoma, Adenosquamous
• Carcinoma, Squamous Cell
• Cervical Adenocarcinoma
• Cervical Adenosquamous Carcinoma
• Cervical Squamous Cell Carcinoma, Not Otherwise Specified
• Stage IB2 Cervical Cancer AJCC v6 and v7
• Stage II Cervical Cancer AJCC v7
• Stage IIA Cervical Cancer AJCC v7
• Stage IIB Cervical Cancer AJCC v6 and v7
• Stage IIIB Cervical Cancer AJCC v6 and v7
• Stage IVA Cervical Cancer AJCC v6 and v7
• Uterine Cervical Neoplasms

Intervention

Drug:
• Cisplatin
Given IV

Radiation:
• External Beam Radiation Therapy
Undergo external beam radiation therapy
• Internal Radiation Therapy
Undergo intracavitary brachytherapy

Biological:
• Ipilimumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Locations

Country	Name	City	State
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Augusta University Medical Center	Augusta	Georgia
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Hartford Hospital	Hartford	Connecticut
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Enumeration of HPV-specific T-cells	Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical.	Up to 2 years
Other	Kinetics of HPV-specific T-cell expansion	Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical.	Up to 2 years
Other	Characterization of differential activated T-cell responses based on HLA-subtype A*0201	Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical.	Up to 2 years
Other	Measurable parameters from the fludeoxyglucose F 18 (FDG)-PET/CT, including SUVmax of the primary tumor, metabolic tumor volume (MTV) if available, the presence of abnormal FDG uptake within lymph nodes	Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical. Within-patient changes in the FDG-PET/CT SUVmax and MTV (if available) will be examined.	Up to 2 years
Primary	DLTs occurring during adjuvant ipilimumab in the dose escalation phase		During first 2 courses of treatment
Primary	DLTs occurring in the feasibility phase		Over 4 courses of treatment
Primary	Toxicities as assessed by CTCAE version 4		Up to 2 years post-treatment
Secondary	Response rate in patients enrolled with measurable disease assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	Relationships of translational research endpoints to response will be explored if practical.	Up to 2 years post-treatment
Secondary	Progression-free survival (PFS)	Will be summarized using Kaplan-Meier plots. Relationships of translational research endpoints to PFS will be explored if practical.	From time of study entry to time of progression or death, whichever occurs first, assessed up to 1 year post-treatment
Secondary	Overall survival	Will be summarized using Kaplan-Meier plots.	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
Secondary	Location of recurrence (loco-regional versus distant)		Up to 1 year post-treatment
Secondary	Chronic toxicities experienced within one year of completion of therapy		Up to 1 year post-treatment