Clinical trial NCT01711515: Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA Cervical Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2012-10-22
Enrollment: 34
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: DLTs occurring during adjuvant ipilimumab in the dose escalation phase
timeFrame: During first 2 courses of treatment
measure: DLTs occurring in the feasibility phase
timeFrame: Over 4 courses of treatment
measure: Toxicities as assessed by CTCAE version 4
timeFrame: Up to 2 years post-treatment
Secondary outcomes:
measure: Response rate in patients enrolled with measurable disease assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
timeFrame: Up to 2 years post-treatment
measure: Progression-free survival (PFS)
timeFrame: From time of study entry to time of progression or death, whichever occurs first, assessed up to 1 year post-treatment
measure: Overall survival
timeFrame: 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
measure: Location of recurrence (loco-regional versus distant)
timeFrame: Up to 1 year post-treatment
measure: Chronic toxicities experienced within one year of completion of therapy
timeFrame: Up to 1 year post-treatment
Other outcomes:
measure: Enumeration of HPV-specific T-cells
timeFrame: Up to 2 years
measure: Kinetics of HPV-specific T-cell expansion
timeFrame: Up to 2 years
measure: Characterization of differential activated T-cell responses based on HLA-subtype A*0201
timeFrame: Up to 2 years
measure: 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
timeFrame: Up to 2 years
Locations:
city: Los Angeles
country: United States
facility: Los Angeles County-USC Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: NRG Oncology
name: Jyoti S Mayadev
role: PRINCIPAL_INVESTIGATOR
References:
citation: Da Silva DM, Enserro DM, Mayadev JS, Skeate JG, Matsuo K, Pham HQ, Lankes HA, Moxley KM, Ghamande SA, Lin YG, Schilder RJ, Birrer MJ, Kast WM. Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929). Clin Cancer Res. 2020 Nov 1;26(21):5621-5630. doi: 10.1158/1078-0432.CCR-20-0776. Epub 2020 Aug 18.