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Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

Descriptive Information
Brief Title † Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
Official Title † DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
Brief Summary This clinical trial studies nivolumab and ipilimumab in treating patients with rare tumors. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.
Detailed Description PRIMARY OBJECTIVES: I. To evaluate the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 overall response rate (ORR) in subsets of patients with advanced rare cancers treated with ipilimumab plus nivolumab combination immunotherapy. SECONDARY OBJECTIVES: I. To evaluate toxicities in each cohort. II. To estimate overall survival (OS), progression-free survival (PFS), clinical benefit rate; and to estimate immune-related ORR (irORR), and immune-related PFS (irPFS) by unidimensional immune-related response criteria. III. To collect specimens for banking for use in future correlative biomarker research studies. OUTLINE: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 10 years from registration.
Study Phase Phase 2
Study Type † Interventional
Study Design †
Primary Outcome Measure † ORR defined as confirmed and unconfirmed complete and partial response, assessed by RECIST 1.1
Secondary Outcome Measure † Best response calculated from the sequence of RECIST 1.1 and immune-related response criteria (irRC) objectives
Condition † Acinar Cell Carcinoma Adrenal Cortex Carcinoma Adrenal Gland Pheochromocytoma Anal Canal Neuroendocrine Carcinoma Anal Canal Undifferentiated Carcinoma Appendix Mucinous Adenocarcinoma Bartholin Gland Transitional Cell Carcinoma Bladder Adenocarcinoma Bronchioloalveolar Carcinoma Cervical Adenocarcinoma Cholangiocarcinoma Chordoma Colorectal Squamous Cell Carcinoma Dermoid Cyst Endometrial Transitional Cell Carcinoma Endometrioid Adenocarcinoma Esophageal Neuroendocrine Carcinoma Esophageal Undifferentiated Carcinoma Extrahepatic Bile Duct Carcinoma Fallopian Tube Adenocarcinoma Fallopian Tube Transitional Cell Carcinoma Fibromyxoid Tumor Gastric Neuroendocrine Carcinoma Gastric Squamous Cell Carcinoma Giant Cell Carcinoma Intestinal Neuroendocrine Carcinoma Intrahepatic Cholangiocarcinoma Lung Carcinoid Tumor Lung Sarcomatoid Carcinoma Major Salivary Gland Carcinoma Malignant Odontogenic Neoplasm Malignant Peripheral Nerve Sheath Tumor Malignant Testicular Sex Cord-Stromal Tumor Metastatic Malignant Neoplasm of Unknown Primary Origin Mixed Mesodermal (Mullerian) Tumor Mucinous Adenocarcinoma Mucinous Cystadenocarcinoma Nasal Cavity Adenocarcinoma Nasal Cavity Carcinoma Nasopharyngeal Carcinoma Nasopharyngeal Papillary Adenocarcinoma Nasopharyngeal Undifferentiated Carcinoma Oral Cavity Carcinoma Oropharyngeal Undifferentiated Carcinoma Ovarian Adenocarcinoma Ovarian Germ Cell Tumor Ovarian Mucinous Adenocarcinoma Ovarian Squamous Cell Carcinoma Ovarian Transitional Cell Carcinoma Pancreatic Acinar Cell Carcinoma Pancreatic Neuroendocrine Carcinoma Paraganglioma Paranasal Sinus Adenocarcinoma Paranasal Sinus Carcinoma Parathyroid Gland Carcinoma Pituitary Gland Carcinoma Placental Choriocarcinoma Placental-Site Gestational Trophoblastic Tumor Primary Peritoneal High Grade Serous Adenocarcinoma Pseudomyxoma Peritonei Scrotal Squamous Cell Carcinoma Seminal Vesicle Adenocarcinoma Seminoma Serous Cystadenocarcinoma Small Intestinal Adenocarcinoma Small Intestinal Squamous Cell Carcinoma Spindle Cell Neoplasm Squamous Cell Carcinoma of the Penis Teratoma With Malignant Transformation Testicular Non-Seminomatous Germ Cell Tumor Thyroid Gland Carcinoma Tracheal Carcinoma Transitional Cell Carcinoma Undifferentiated Gastric Carcinoma Ureter Adenocarcinoma Ureter Squamous Cell Carcinoma Urethral Adenocarcinoma Urethral Squamous Cell Carcinoma Vaginal Adenocarcinoma Vaginal Squamous Cell Carcinoma, Not Otherwise Specified Vulvar Adenocarcinoma Vulvar Squamous Cell Carcinoma
Intervention † ProcedureBiospecimen Collection
Study Arms / Comparison Groups Treatment (nivolumab, ipilimumab) Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Procedure
Estimated Enrollment † 334
Start Date † January 13, 2017
Completion Date
Primary Completion Date August 31, 2020
Eligibility Criteria † Inclusion Criteria: - Patients must have histologically confirmed rare cancer and/or cancer of unknown primary, that did not have a match to a molecularly-guided therapy on EAY131 "National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (MATCH)" protocol or who progressed on molecularly-matched therapy and have no further molecularly-matched treatment recommendations per EAY131, "NCI-MATCH" - All baseline assessments must have been completed within 28 days prior to registration - Patients that do not qualify for one of the histologic cohorts may be considered for registration in the "Not Otherwise Categorized" Rare Tumors cohort with confirmation of the study chairs via email - Patients that are determined to have a rare cancer with unknown primary site are eligible provided that there is histologic documentation of metastatic malignancy with no discernible primary site identified from histopathologic review, physical exam and associated cross-sectional imaging of the chest, abdomen, and pelvis - Patients must have a diagnostic quality computed tomography (CT) scan or magnetic resonance imaging (MRI), performed within 28 days prior to registration, which demonstrates measurable disease, as defined in RECIST v. 1.1; all disease must be assessed and documented on the S1609 Baseline Tumor Assessment Form - No other prior malignancy is allowed except for the following: - Adequately managed stage I or II cancer from which the patient is currently in complete remission - Any other cancer from which the patient has been disease free for five years - Adequately managed stage I or II follicular thyroid or prostate cancer is also eligible, wherein patient is not required to be in complete remission - Patients who have received prior anti-CTLA4 or other anti-PD-1/anti-PD-L1 therapy, not both, provided that it is completed >= 4 weeks prior to registration for monoclonal therapy, >= 8 weeks prior to registration if therapy involved immunestimulatory monoclonal antibody (mAb)s, and >= 28 days for all other immunotherapy - Patients who had prior immune-related adverse event (grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.) are not eligible - Patients with clinically controlled thyroiditis or pituitary disorders on stable replacement therapy are eligible - Patients are not eligible if they have had or are planned for solid organ transplant; patients who have received allogeneic hematopoietic stem cell transplant are eligible if the transplant occurred at least 90 days prior to registration, patient has no prior acute graft versus host disease (GVHD), and within 48 hours of registration, patient demonstrates at least 90% engraftment, defined as: absolute neutrophil count (ANC) >= 500 mcl, measured over 3 consecutive days or 1 day with an ANC >= 1,000 mcl, or platelets >= 50,000 mcl measured, wherein the patient did not receive any platelet transfusions within 7 days prior to laboratory assessment, patients with autoimmune disease who are otherwise eligible under criterion 5.3 k must not have received steroid and immunosuppressive therapy within 28 days prior to registration - Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 28 days prior to registration and have stable disease at time of registration; metastatic brain parenchymal disease must have been treated and patient must be off steroids for 7 days prior to registration - Patients must not currently be receiving any other investigational agents or any other systemic anti-cancer therapy (including radiation); in event patient recently received any other systemic anti-cancer therapy, patient must be off therapy at least 7 days prior to registration and any therapy-induced toxicity must have recovered to == 1,000/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 8 g/dL - Total bilirubin == 50 mL/min., as estimated by the Cockcroft and Gault formula; estimated creatinine clearance is based on actual body weight - Patients must have adequate thyroid function, as evidenced by thyroid-stimulating hormone (TSH), free thyroxine (T4) serum tests demonstrating values within the normal range, within 28 days prior to registration; Note: TSH, with reflex T4 is allowable if per institutional standard; otherwise, both TSH and free-T4 must be obtained - Patients must have adequate adrenal axis function, as evidenced by Adrenocorticotropic Hormone (ACTH) values within the normal ranges, within 28 days prior to registration - Females of childbearing potential must have negative serum pregnancy test 14 days prior to registration and agree to use birth control throughout study and for 23 weeks after completion of protocol therapy; patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Men of reproductive potential must have agreed to use birth control throughout the study and for 31 weeks after completion of protocol therapy; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (vasectomy); however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he is responsible for beginning contraceptive measures - Patients must not have known active hepatitis B virus (HBV) or hepatitis virus (HCV) infection at time of registration; patients with HBV or HCV that have an undetectable viral load, or in the opinion of the treating investigator is well-controlled, are eligible - Patients who are known to be human immunodeficiency virus (HIV)-positive at registration are eligible at the time of registration: 1. Cluster of differentiation (CD)4+ cell count greater or equal to 250 cells/mm^3 2. If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; once daily combinations that use pharmacologic boosters may not be used 3. No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts 4. Probable long-term survival with HIV if cancer were not present - Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10mg or equivalent). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory bowel disease, multiple sclerosis, vasculitis, or glomerulonephritis; patients with well-controlled systemic lupus erythematous or rheumatoid arthritis may be eligible after communication with the study chairs at S1609SC@swog.org; vitiligo, alopecia, hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not requiring systemic therapy within the past 3 years is permitted; short-term steroid premedication for contrast allergy is permitted - Patients must not have any uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4 grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= grade 3) - Note: Echocardiography (ECHO) and electrocardiogram (EKG) are clinically indicated at baseline for any patient with a history of CHF or a risk due to underlying cardiovascular disease or prior exposure to cardiotoxic drugs; if patient has any evidence of CHF, MI, cardiomyopathy, or myositis cardiac evaluation (NYHA I/II) patient, cardiology consultation is also clinically indicated at baseline (in addition to ECHO and EKG), with creatine phosphokinase (CPK) and troponin testing
Gender All
Ages 18 Years - N/A
Accepts Healthy Volunteers No
Contacts ††
Location Countries † United States
Administrative Information
NCT ID † NCT02834013
Organization ID NCI-2016-01041
Secondary IDs †† NCI-2016-01041, S1609, S1609, S1609, U10CA180888
Responsible Party Sponsor
Study Sponsor † National Cancer Institute (NCI)
Collaborators ††
Investigators † Principal Investigator: Sandip Patel, Southwest Oncology Group
Information Provided By
Verification Date May 2017
First Received Date † July 13, 2016
Last Updated Date June 16, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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