Nivolumab with or without Ipilimumab in Treating Patients with Advanced or Metastatic Melanoma or Bladder Cancer
This phase II trial studies how well nivolumab works with or without ipilimumab in treating patients with melanoma or bladder cancer that has spread to other places in the body or has spread from the primary site to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
- Subjects must have signed and dated an Institutional Review Board (IRB) approved written informed consent in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care
- Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study
- Pathologically confirmed locally advanced or metastatic disease per the treating institution's standard of care of the following tumor types: * Subjects with histologically confirmed locally advanced/unresectable or metastatic melanoma who meet all of the following criteria: ** Subjects have received any number of prior lines of therapy or may be treatment naive ** If the subject has been treated with a prior line of therapy, they must have had disease progression or be refractory to treatment OR * Subjects with histologically or cytologically confirmed locally advanced/unresectable or metastatic urothelial carcinoma (including mixed histologies of urothelial carcinoma with elements of other subtypes) of the renal pelvis, ureter, bladder or urethra (referred to broadly in this protocol as “bladder cancer”) who meet the following criteria: ** Subjects must have disease progression or refractory disease after their prior line of therapy; subjects must have had at least 1 platinum based chemotherapy regimen for the treatment of metastatic or locally advanced unresectable disease; subjects may have received any number of prior lines of therapy OR ** Subjects with disease recurrence within 1 year of a platinum based neoadjuvant or adjuvant therapy for bladder cancer OR ** The subject actively refuses chemotherapy for the treatment of metastatic or locally advanced disease considered as standard treatment for this disease stage (i.e. a patient who has relapsed > 1 year after treatment with neoadjuvant or adjuvant chemotherapy), despite being informed by the investigator about the treatment options; the subject’s refusal must be documented
- Subjects must have measurable disease by computed tomography (CT) scans or magnetic resonance imaging (MRI) per RECIST 1.1 criteria; radiographic tumor assessment must be performed within 28 days prior to first dose of study drug
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Subjects must consent to allow for the acquisition of tumor sample prior to starting treatment on study (in most cases patients will require a tumor biopsy); this biopsy site may be the only site of measurable disease if the site is > 2 cm; the biopsy site must, in the opinion of the investigator, be likely to yield acceptable tumor sample for core biopsies; it is also acceptable if tumor sample is obtained by excision biopsy or during surgery (i.e. if procedure was previously planned), provided the tumor sample can be processed; in the case that a patient had a tumor sample acquired prior to consenting to the study and this tumor sample is acceptable for processing (i.e. frozen sample stored) and the tumor sample was acquired within 60 days of starting treatment, this is acceptable and a new biopsy will not be required
- Willingness to adhere to the study visit schedule and prohibitions as specified in this protocol
- Expected survival of at least 4 months
- At the time of day 1 of the study, patients must have completed chemotherapy, targeted therapy, investigational therapy, other immunotherapy, radiation therapy or major surgery (requiring general anesthesia) at least 28 days before administration of the first dose of nivolumab; patients undergoing minor surgical procedures and biopsies that do not require general anesthesia may begin receiving study therapy if sufficiently recovered as determined by the treating investigator; patients may have received prior focal radiotherapy for palliation of an isolated site of disease, which must be completed at least 14 days prior to day 1 of the study; palliative (limited-field) radiation therapy is permitted during treatment with study drug(s), if all of the following criteria are met: * The lesion being considered for palliative radiation is not a target lesion * Radiation treatment is administered 12 weeks or greater after their first dose of study drug
- White blood cells (WBCs) >= 2000/uL (obtained within 14 days of the first dose of study drug)
- Neutrophils >= 1000/uL (obtained within 14 days of the first dose of study drug)
- Platelets >= 100 x 10^3/uL (obtained within 14 days of the first dose of study drug)
- Hemoglobin >= 9.0 g/dL (obtained within 14 days of the first dose of study drug)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) (or glomerular filtration rate >= 40 mL/min) (obtained within 14 days of the first dose of study drug)
- Bilirubin =< 1.5 x ULN (except subjects with Gilbert’s syndrome who must have total bilirubin =< 3.0 mg/dL) (obtained within 14 days of the first dose of study drug)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (obtained within 14 days of the first dose of study drug)
- Albumin >= 3.0 g/dL (obtained within 14 days of the first dose of study drug)
- Active brain metastases or leptomeningeal metastases; subjects with treated brain metastases are eligible if they meet all of the following criteria: * Must be at least 28 days since craniotomy and resection, stereotactic radiosurgery, or whole brain radiotherapy * Must have no evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration * Must have no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy or interfere with the interpretation of study results
- Other prior malignancy active within the previous 2 years except for local or organ confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study
- Subjects with active autoimmune disease, symptoms or conditions; subjects with vitiligo, type I diabetes, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, asymptomatic laboratory evidence of autoimmune disease (e.g.: +antinuclear antibody [ANA], +rheumatoid factor [RF], antithyroglobulin antibodies), or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug; inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease
- Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-programmed cell death 1 (PD-1), anti-PD-L1, anti-programmed cell death 1 ligand 2 (PD-L2), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-cluster of differentiation (CD)137; or other medicines specifically targeting T cells are prohibited; prior therapy with Bacillus Calmette-Guerin (BCG) is permitted; prior interleukin (IL)-2 is permitted
- All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] version 4) or baseline before administration of study drug; subjects with toxicities attributed to prior anti-cancer therapy and which are not expected to resolve and result in long lasting sequelae such as neuropathy after platinum-based therapy, are permitted to enroll
- Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- History of allergy to study drug component or history of severe hypersensitivity reaction to any monoclonal antibody
- Women who are breast feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) done within 14 days of first dosing and urine test within 72 hours of first dosing
- Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle) * WOCBP are defined as those who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal; post-menopausal is defined as: ** Amenorrhea >= 12 consecutive months without another cause, or ** For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
- Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover)
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Locations & Contacts
Contact: Margaret Kathleen Callahan
Contact: Margaret Kathleen Callahan
Contact: Margaret Kathleen Callahan
Contact: Suresh G. Nair
Trial Objectives and Outline
I. Obtain preliminary prospective data on whether mutational load is associated with Response Evaluation Criteria in Solid Tumors (RECIST) response to immunotherapy.
I. Obtain preliminary prospective data on whether mutational load is associated with immune related response to immunotherapy.
II. Obtain preliminary prospective data on whether neo-antigen score is associated with RECIST response to immunotherapy.
III. Obtain preliminary prospective data on whether neo-antigen score is associated with immune related response to immunotherapy.
I. Evaluate duration of response (DOR), progression free survival (PFS), overall survival (OS), rate of grade 3/4 toxicity.
II. Compare tumor characteristic (mutation burden, neo-antigen score, programmed cell death 1 ligand 1 [PD-L1], T-cell receptor [TCR] repertoire, immune infiltrate) between pre-treatment and on-treatment (optional) tumor biopsies.
III. Evaluate tumor PD-L1 expression across range of mutation burden/predicted neo-antigens.
IV. Evaluate TCR repertoire across a range of mutation burdens/predicted neo-antigen scores.
V. Evaluate for the presence of predicted neo-antigen specific T cells in peripheral blood samples.
VI. Compare integrated mutation profiling of actionable cancer targets (IMPACT) assay to whole exome sequencing for the evaluation of patients according to mutation burden.
OUTLINE: Patients are assigned to 1 of 2 treatment arms based on disease.
ARM I (MELANOMA): Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 60 minutes every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with clinical benefit after combination therapy and disease progression after monotherapy may receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 courses and then nivolumab IV over 60 minutes every 2 weeks for up to 2 years from first dose of nivolumab in the absence of disease progression or unacceptable toxicity. Patients who are benefitting from treatment may continue beyond 2 years at the discretion of principal investigator.
ARM II (BLADDER CANCER): Patients receive nivolumab IV over 60 minutes every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with disease progression after 6 weeks may continue to receive nivolumab at the discretion of the treating physician and study Principal Investigator (PI). Patients achieving disease progression after 12 weeks, may also receive ipilimumab IV over 90 minutes every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with clinical benefit after combination therapy and disease progression after monotherapy may receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 courses and then nivolumab IV over 60 minutes every 2 weeks for up to 2 years from first dose of nivolumab in the absence of disease progression or unacceptable toxicity. Patients who are benefitting from treatment may continue beyond 2 years at the discretion of principal investigator.
After completion of study treatment, patients are followed up at 6 weeks and then every 12 weeks for 4 years.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Margaret Kathleen Callahan
Secondary IDs NCI-2015-01786
Clinicaltrials.gov ID NCT02553642