PRIMARY OBJECTIVE:
I. To estimate objective response rate (ORR) and overall survival (OS) in patients with
ARID1A mutations receiving nivolumab therapy.
II. To estimate objective response rate (ORR) and overall survival (OS) in patients with
ARID1A mutations plus CXCL13-high expression and ARID1A mutations plus CXCL13-low expression,
receiving nivolumab therapy.
SECONDARY OBJECTIVES:
I. To estimate progression free survival (PFS) in subjects with harboring ARID1A mutation
treated with nivolumab monotherapy.
II. To estimate progression free survival (PFS) in subjects with ARID1A mutations plus
CXCL13-high expression and ARID1A mutations plus CXCL13-low expression, treated with
nivolumab monotherapy.
III. To assess peripheral and tumor infiltrating immune cell sub-populations in patients with
ARID1A mutations, ARID1A plus CXCL13-high and ARID1A plus CXCL13-low expression, to determine
predictors of response and resistance.
IV. To determine expression pattern of CXCL13 in ARID1A mutant tumors.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeats 28
days (4 weeks) for up to 2 years in the absence of disease or unacceptable toxicity.
After the completion of study treatment, patients are followed up for 100 days, then every
3-6 months thereafter.
Inclusion Criteria:
- Patient will have a tumor harboring genomic mutation of ARID1A. ARID1A mutation
testing will be performed as standard of care
- Histological or cytological evidence of metastatic or surgically unresectable
urothelial cell carcinoma of the urothelial involving the bladder, urethra, ureter, or
renal pelvis. Minor histologic variants (< 50% overall) are acceptable
- Subjects must have progression or recurrence after treatment
- With at least 1 platinum-containing chemotherapy regimen for metastatic or
surgically unresectable locally advanced urothelial cancer, or
- Within 12 months of peri-operative (neo-adjuvant or adjuvant) treatment with
platinum agent in the setting of cystectomy for localized muscle-invasive
urothelial cancer
- Are ineligible or refused frontline chemotherapy
- All subjects must have measurable disease by computed tomography (CT) or magnetic
resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria
- Evaluable tumor tissue (archived or new biopsy) must be provided for biomarker
analysis as formalin-fixed paraffin-embedded (FFPE) tumor block or minimum of 10
slides. Archived tissue may be from prior biopsy of unresectable or metastatic disease
or from prior surgical resection
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Prior palliative radiotherapy must have been completed at least 2 weeks prior to study
drug administration. Patients must have measurable disease outside the radiation field
to be eligible. Patients with progression in a previously radiated field will also be
eligible
- White blood cell count (WBC) >= 2000/uL (obtained within 7 days prior to first dose)
- Neutrophils >= 1500/uL (obtained within 7 days prior to first dose)
- Platelets >= 100 x1 x10^3/uL (obtained within 7 days prior to first dose)
- Hemoglobin >= 9.0 g/dL (obtained within 7 days prior to first dose)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit
of normal (ULN) (or =< 5 X ULN for participants with liver metastases) (obtained
within 7 days prior to first dose)
- Total Bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL (obtained within 7 days prior to first dose)
- Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 30 mL/min (using the
Cockcroft-Gault formula) (obtained within 7 days prior to first dose)
- Re-enrollment: This study permits the re-enrollment of a subject that has discontinued
the study as a pre-treatment failure (ie, subject has not been treated). If
re-enrolled, the subject must be re-consented and inclusion/exclusion criteria
reassessed
- Patients are required to participate in PA13-0291 for correlative studies. Patients
will need to consent for biopsy and peripheral blood collection as documented in the
study calendar
Exclusion Criteria:
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways
- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
are eligible if these have been treated and there is no magnetic resonance imaging
(MRI) evidence of progression for at least 4 weeks after treatment is complete and
within 28 days prior to first dose of study drug administration. Where MRI is
contraindicated CT scan is acceptable. Cases must be discussed with the medical
monitor. Brain lesions are not considered measurable disease. There must also be 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
- Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, prostate
cancer without evidence of prostate specific antigen (PSA) progression or carcinoma in
situ such as the following: gastric, prostate, cervix, colon, melanoma, or breast for
example
- Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism, due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, 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 equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease
- All toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia
and fatigue must have resolved to grade 1 (National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events [CTCAE] version 5) or baseline before
administration of study drug. Subjects with toxicities attributed to prior anti-cancer
therapy which are not expected to resolve and result in long lasting sequelae, such as
neuropathy after platinum based therapy, are permitted to enroll. Neuropathy must have
resolved to grade 2 (NCI CTCAE version 5)
- Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
investigational therapy within 28 days of first administration of study treatment.
Prior palliative radiotherapy must have been completed at least 2 weeks prior to study
drug administration
- Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or
chronic infection
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)