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.
Brief Title
Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA 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.
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.
Categories
Completion Date
Completion Date Type
Actual
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
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
* 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
Inclusion 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
* 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
Gender
Female
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01711515
Org Class
Nih
Org Full Name
National Cancer Institute (NCI)
Org Study Id
NCI-2012-01733
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Measure
DLTs occurring during adjuvant ipilimumab in the dose escalation phase
Outcome Time Frame
During first 2 courses of treatment
Outcome Measure
DLTs occurring in the feasibility phase
Outcome Time Frame
Over 4 courses of treatment
Outcome Measure
Toxicities as assessed by CTCAE version 4
Outcome Time Frame
Up to 2 years post-treatment
Secondary Ids
Secondary Id
NCI-2012-01733
Secondary Id
GOG-PIS1102
Secondary Id
GOG-9929
Secondary Id
GOG-9929
Secondary Id
GOG-9929
Secondary Id
U10CA180830
Secondary Id
U10CA180868
Secondary Id
U10CA027469
Secondary Outcomes
Outcome Description
Relationships of translational research endpoints to response will be explored if practical.
Outcome Time Frame
Up to 2 years post-treatment
Outcome Measure
Response rate in patients enrolled with measurable disease assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Outcome Description
Will be summarized using Kaplan-Meier plots. Relationships of translational research endpoints to PFS will be explored if practical.
Outcome Time Frame
From time of study entry to time of progression or death, whichever occurs first, assessed up to 1 year post-treatment
Outcome Measure
Progression-free survival (PFS)
Outcome Description
Will be summarized using Kaplan-Meier plots.
Outcome Time Frame
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
Outcome Measure
Overall survival
Outcome Time Frame
Up to 1 year post-treatment
Outcome Measure
Location of recurrence (loco-regional versus distant)
Outcome Time Frame
Up to 1 year post-treatment
Outcome Measure
Chronic toxicities experienced within one year of completion of therapy
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Mark Einstein
Investigator Email
meinstei@montefiore.org
Investigator Phone
Categories Mesh Debug
Prostate Cancer --- UROGENITAL NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Cancer --- NEOPLASMS
Gynecologic Cancers --- UTERINE CERVICAL DISEASES
Gynecologic Cancers --- UTERINE DISEASES
MeSH Terms
UTERINE CERVICAL NEOPLASMS
UTERINE NEOPLASMS
GENITAL NEOPLASMS, FEMALE
UROGENITAL NEOPLASMS
NEOPLASMS BY SITE
NEOPLASMS
UTERINE CERVICAL DISEASES
UTERINE DISEASES
GENITAL DISEASES, FEMALE
FEMALE UROGENITAL DISEASES
FEMALE UROGENITAL DISEASES AND PREGNANCY COMPLICATIONS
UROGENITAL DISEASES
GENITAL DISEASES
CISPLATIN
1,2-DIAMINOCYCLOHEXANEPLATINUM II CITRATE
PLATINUM
RADIATION
BRACHYTHERAPY
IPILIMUMAB
CHLORINE COMPOUNDS
INORGANIC CHEMICALS
NITROGEN COMPOUNDS
PLATINUM COMPOUNDS
METALS, HEAVY
ELEMENTS
TRANSITION ELEMENTS
METALS
PHYSICAL PHENOMENA
RADIOTHERAPY
THERAPEUTICS
ANTIBODIES, MONOCLONAL, HUMANIZED
ANTIBODIES, MONOCLONAL
ANTIBODIES
IMMUNOGLOBULINS
IMMUNOPROTEINS
BLOOD PROTEINS
PROTEINS
AMINO ACIDS, PEPTIDES, AND PROTEINS
SERUM GLOBULINS
GLOBULINS