PRIMARY OBJECTIVE:
I. To determine the clinical efficacy of the investigational treatment combination.
SECONDARY OBJECTIVES:
I. To determine the clinical activity and toxicity of the investigational treatment
combination.
II. The clinical benefit rate (CBR), progression-free survival (PFS), duration of response
(DOR), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and
immune-related (ir) RECIST, and overall survival (OS).
III. The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression
levels in the tumor microenvironment.
IV. The safety and toxicity of addition of CYT107 to atezolizumab.
EXPLORATORY OBJECTIVES:
I. To determine the immune correlates of the clinical activity of the investigational
treatment combination.
II. Explore the effect of the investigational treatment combination on the number and
phenotype of tumor-specific T cells in the peripheral blood.
III. Investigate for evidence that the investigational treatment combination increases the
exposure of bladder cancer-specific antigens (e.g., cancer/testis antigens or neoantigens).
IV. Investigate changes in tumor microenvironment that correlate with response or provide
information on potential actionable causes for lack of clinical benefit.
V. Investigate the potential that administration of atezolizumab with CYT107 may perturb the
pharmacokinetics and immunogenicity of CYT107.
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP 1: Patients receive CYT107 intramuscularly (IM) on days 1, 8, 15, and 22, and
atezolizumab intravenously (IV) over 60 minutes on day 8 of cycle 1. Following cycle 1,
patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat
every 21 days for up to 2 years in the absence of disease progression or unacceptable
toxicity.
GROUP 2: Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21
days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks for up to 2 years.
Inclusion Criteria:
- Patients must have histologically or cytologically documented locally
advanced/inoperable or metastatic urothelial bladder carcinoma (UBC), including renal
pelvis, ureters, urinary bladder, and urethra
- Note: Mixed histology tumors allowed if predominant histology is urothelial
carcinoma
- Note: Small cell or neuroendocrine carcinoma is not allowed if predominant
- Patients must have recurrent disease after any prior platinum-based chemotherapy
regimen
- Patients must have measurable disease per RECIST 1.1 assessed by computed tomography
(CT) scan or magnetic resonance imaging (MRI)
- ECOG performance status =< 2 (Karnofsky >= 60%)
- Patients must have a life expectancy of greater or equal to 12 weeks
- Leukocytes >= 2,500/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 8 g/dL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
with known Gilbert's disease who have serum bilirubin level =< 3 x ULN may be
enrolled)
- Aspartate aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x ULN (AST and/or ALT=< 5 x ULN for patients with liver involvement)
- Alkaline phosphatase =< 2.5 x ULN (=< 5 +/- ULN for patients with documented liver
involvement or bone metastases)
- Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault
- At the discretion of the treating physician, a 24-hour urine creatinine clearance
could be obtained and utilized as the gold standard if creatinine clearance by
Cockcroft-Gault is < 30, and prevents patient enrollment on the trial
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
=< 1.5 x ULN (this applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation, such as
low-molecular-weight heparin or warfarin, should be on a stable dose)
- Patients must provide tissue from an archival tumor sample (obtained within 2 years
from screening visit) or newly obtained core, punch, or excisional biopsy of a tumor
lesion if deemed relatively safe and technically feasible
- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours before receiving the first dose of study agent(s); if
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required;
- Administration of atezolizumab may have an adverse effect on pregnancy and poses
a risk to the human fetus, including embryo-lethality; CYT107 has not been tested
for reproductive toxicity yet and may expose to the same risk; women of
child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) before study entry, for
the duration of study participation, and for 5 months (150 days) after the last
dose of study agent; should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately
- Patients must have the ability to understand and the willingness to sign a written
informed consent document
- Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
HIV-positive patients must have:
- A stable regimen of highly active antiretroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections
- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
- Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for
nitrosoureas or systemic mitomycin C) before the initiation of study treatment
- Patients who have received more than 2 systemic cytotoxic chemotherapy regimens for
metastatic urothelial carcinoma
- Note: Prior perioperative chemotherapy is allowed and is not counted as a line of
therapy if patient relapsed >= 12 months later and received additional
platinum-based chemotherapy for metastatic disease
- Patients who have not recovered from adverse events (other than alopecia) due to
agents administered more than 4 weeks earlier (i.e., have residual toxicities > grade
1); however, the following therapies are allowed:
- Hormone-replacement therapy or oral contraceptives
- Herbal therapy >= 1 week before initiation of study treatment (herbal therapy
intended as anticancer therapy must be discontinued at least 1 week before
initiation of study treatment)
- Palliative radiotherapy for bone metastases > 2 weeks before initiation of study
treatment
- Patients who have received prior treatment with anti-PD-1, or anti-PD-L1 therapeutic
antibody, or pathway -targeting agents
- Patients who have received prior treatment with anti-CTLA-4 may be enrolled,
provided the following requirements are met:
- Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from
the last dose
- No history of severe immune-related adverse effects from anti-CTLA-4
(National Cancer Institute [NCI] Common Terminology Criteria for Adverse
Events [CTCAE] grade 3 and 4)
- Patients who have received treatment with any other investigational agent within 4
weeks before initiation of study treatment
- Patients who have received treatment with systemic immunostimulatory agents
(including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6
weeks before initiation of study treatment
- Patients who have received treatment with systemic immunosuppressive medications
(including, but not limited to, prednisone, cyclophosphamide, azathioprine,
methotrexate, thalidomide, and anti-tumor necrosis factor [anti TNF] agents) within 2
weeks before initiation of study treatment
- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
- The use of inhaled corticosteroids, and mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension or adrenocortical
insufficiency is allowed
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia
- Note: Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
osteoporosis) is allowed
- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:
- Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
the following criteria are met:
- Evaluable or measurable disease outside the CNS
- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
10 mm of the optic apparatus (optic nerves and chiasm)
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No ongoing requirement for dexamethasone for CNS disease; patients on a
stable dose of anticonvulsants are permitted
- No neurosurgical resection or brain biopsy within 28 days before initiation
of study treatment
- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
the criteria listed above are met as well as the following:
- Radiographic demonstration of improvement upon the completion of CNS
directed therapy and no evidence of interim progression between the
completion of CNS directed therapy and the screening radiographic study
- No stereotactic radiation or whole-brain radiation within 28 days before
initiation of study treatment
- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
and >= 2 weeks from discontinuation of corticosteroids
- Note: Patients with CNS metastases enrolled on trial must also have a brain MRI
imaging at all standard radiologic evaluation timepoints
- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human antibodies
- Patients who have a history of severe allergic, anaphylactic, or other
hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Patients with known clinically significant liver disease, including active viral,
alcoholic, or other hepatitis; cirrhosis; fatty liver/nonalcoholic fatty liver disease
(NAFLD)/nonalcoholic steatohepatitis (NASH); and inherited liver disease
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Patient who have a history or risk of autoimmune disease, including, but not limited
to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
vascular thrombosis associated with antiphospholipid syndrome, Wegener's
granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple
sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
- Patients with a history of autoimmune hypothyroidism on a stable dose of
thyroid-replacement hormone may be eligible
- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may
be eligible
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)
- Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (including
drug induced), organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan;
history of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Patients who have known additional malignancies other than UBC within 2 years before
initiation of study treatment; exceptions include malignancies with a negligible risk
of metastasis or death and treated with expected curative outcome (e.g.,
non-melanomatous skin cancers), or localized prostate cancer treated with curative
intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate
cancer
- Patients with active tuberculosis (TB)
- Patients who have leptomeningeal disease
- Patients who have severe infections within 4 weeks before initiation of study
treatment, including, but not limited to, hospitalization for complications of
infection, bacteremia, or severe pneumonia;
- Exception: Uncomplicated urinary tract infection will not be considered as a
severe infection in these patients
- Patients who have signs or symptoms of infection within 2 weeks before initiation of
study treatment
- Patients who have received oral or IV antibiotics within 2 weeks before initiation of
study treatment; patients receiving prophylactic antibiotics (e.g., for prevention of
a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Patients who have major surgical procedure, other than for diagnosis, within 28 days
before initiation of study treatment or anticipation of need for a major surgical
procedure during the course of the study
- Patients who have had a live, attenuated vaccine within 4 weeks before initiation of
study treatment or anticipation that such a live, attenuated vaccine will be required
during the study and up to 5 months after the last dose of atezolizumab.
- Influenza vaccination should be given during influenza season only (approximately
October to March); patients must not receive live, attenuated influenza vaccine
within 4 weeks before initiation of study treatment or at any time during the
study
- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure (New York Heart Association class III or IV), unstable angina
pectoris, cardiac arrhythmia, recent myocardial infarction (within the last 6 months),
or psychiatric illness/social situations that would limit compliance with study
requirements
- Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or medical (e.g., infectious) illness
