Atezolizumab With or Without Eribulin Mesylate in Treating Patients With Recurrent Locally Advanced or Metastatic Urothelial Cancer
Atezolizumab With or Without Eribulin Mesylate in Treating Patients With Recurrent Locally Advanced or Metastatic Urothelial Cancer
This phase II trial studies the side effects of atezolizumab with or without eribulin
 mesylate and how well they work in treating patients with urothelial cancer that has come
 back (recurrent), spread to nearby tissues and lymph nodes (locally advanced), or other
 places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as
 atezolizumab, may help the body's immune system attack the cancer, and may interfere with the
 ability of tumor cells to grow and spread. Chemotherapy drugs, such as eribulin mesylate,
 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. Giving atezolizumab and
 eribulin mesylate may work better at treating urothelial cancer compared to atezolizumab
 alone.
PRIMARY OBJECTIVES:

 I. To confirm that eribulin mesylate (eribulin), at or close to the single agent recommended
 phase 2 dose, and atezolizumab at the single agent recommended phase 2 dose, can be given
 together with an acceptable toxicity profile.

 II. To estimate the objective response rate (ORR) based on Response Evaluation Criteria in
 Solid Tumors (RECIST) 1.1 for eribulin and atezolizumab in combination, and compare that to
 the ORR of atezolizumab alone.

 SECONDARY OBJECTIVES:

 I. To summarize and characterize the toxicity associated with this 2-drug combination.

 II. To estimate the best overall response rate (immune-related best overall response [irBOR]
 rate) using the immune-related response criteria (irRC).

 III. To estimate the disease control rate (DCR: complete response [CR] + partial response
 [PR] + stable disease [SD]) based on RECIST 1.1.

 IV. To estimate the duration of response and the duration of stable disease. V. To summarize
 the progression-free survival (PFS). VI. To summarize the overall survival (OS). VII. To
 evaluate efficacy in subsets of patients determined by PD-L1, CD3 and CD8 expression.

 EXPLORATORY OBJECTIVES:

 I. To assess the pharmacodynamic (PD) profile of eribulin when it is given in combination
 with atezolizumab, specifically exploring the expression of putative tumor, circulating
 microenvironment and computed tomography (CT) radiomic correlatives of epithelial-mesenchymal
 transition (EMT)/ (mesenchymal-epithelial transition) MET phenotype at baseline and 6 weeks
 on therapy.

 II. To ascertain the role of expression of PD-L1 using the SP142 assay and potentially other
 methods as a predictive biomarker for response to treatment with atezolizumab in combination
 with eribulin.

 III. To identify clinical biomarkers that may predict for efficacy and toxicity in this
 population and with this treatment combination.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles
 repeat every 21 days in the absence of disease progression or unacceptable toxicity.

 ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1 and eribulin mesylate IV
 over 2-3 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 52 weeks.
Inclusion Criteria:

 -  Histologically- or cytologically-confirmed diagnosis of locally advanced/unresectable
 (inoperable or not amenable to surgical treatment) and/or metastatic transitional cell
 urothelial cancer of the renal pelvis, ureter, urinary bladder, or urethra

 -  Presence of measurable disease meeting the following criteria:

 -  At least one lesion of >= 1.0 cm in long axis diameter for non-lymph nodes or >=
 1.5 cm in short axis diameter for lymph nodes that is serially measurable
 according to RECIST 1.1 using either computerized tomography or magnetic
 resonance imaging or panoramic and close-up color photography with caliper
 measurement; if there is only one target lesion and it is a not a lymph node, it
 should have a long-axis diameter of at least 1.5 cm

 -  Lesions that have had radiotherapy must show radiographic evidence of disease
 progression based on RECIST 1.1 may be deemed a target lesion

 -  Archival paraffin-embedded invasive tumor tissue or newly obtained biopsy must be
 available prior to the first dose of study drug for biomarker analysis; patients must
 be offered sequential biopsies at baseline and 6 weeks unless in the opinion of the
 trial principal investigator (PI) this would be hazardous; recent data suggest
 discordance between primary tumor and tumor from recurrence or metastasis with high
 percentages of PD-L1 SP142 positive immune cells after recurrence

 -  PD-L1 status determined centrally by HistogeneX, which is funded by the study, must be
 available before randomization of the patient to allow for stratification; COMMERCIAL
 ASSESSMENT OF PD-L1 STATUS OBTAINED LOCALLY AT THE SITE WILL NOT SATISFY ELIGIBILITY
 CRITERIA

 -  New, progressive or recurrent disease occurring

 -  During or within 12 months of treatment with a platinum containing regimen
 (cisplatin or carboplatin or novel platinum) in either in the metastatic or
 perioperative setting

 -  In first-line patients defined as cisplatin-ineligible based on renal impairment
 (creatinine clearance calculated by Cockcroft-Gault method < 60 ml/min), grade 2
 hearing loss and/or Eastern Cooperative Oncology Group (ECOG) status of 2; these
 patients will be chemotherapy naive or have received platinum based therapy in
 the adjuvant or neoadjuvant setting more than 12 months prior to study entry

 -  May have received up to two prior lines of chemotherapy for advanced disease

 -  Adequate recovery from any adverse events resulting from prior anti-neoplastic
 treatment including chemotherapy, biological therapy, targeted small molecule therapy,
 radiation therapy, and surgery as determined by the investigator (and in consultation
 with the study PI); in most instances, adequate recovery is resolution to =< grade 1
 except for alopecia of any grade, grade 2 neuropathy and/ or any grade hearing loss

 -  Subjects with known brain metastases will be eligible if they have completed the
 primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or
 complete surgical resection) and if they have remained clinically stable,
 asymptomatic, and off of steroids for at least 28 days

 -  Life expectancy of >= 12 weeks

 -  Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
 0 to 2 (Karnofsky >= 60%)

 -  Leukocytes >= 2,500/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 75,000/mcL

 -  Hemoglobin >= 8 g/dL

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
 with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

 -  Aspartate aminotransferase (AST) (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 x ULN for patients with documented liver
 involvement or bone metastases)

 -  Creatinine clearance >= 20 mL/min/1.73 m^2 by Cockcroft-Gault

 -  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)

 -  All females must have a negative serum or urine pregnancy test (minimum sensitivity 25
 IU/L or equivalent units of beta-human chorionic gonadotropin [B-hCG]) at the
 screening visit and the baseline visit; a pregnancy test needs to be performed within
 72 hours of the first dose of study drug

 -  Administration of atezolizumab and eribulin may have an adverse effect on pregnancy
 and poses a risk to the human fetus, including embryo-lethality; women of
 child-bearing potential and men must agree to use adequate contraception (hormonal or
 barrier method of birth control; abstinence) prior to 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

 -  Male subjects who are partners of women of childbearing potential must use a condom
 and spermicide and their female partners if of childbearing potential must use a
 highly effective method of contraception beginning at least 1 menstrual cycle prior to
 starting study drug(s), throughout the entire study period, and for 150 days after the
 last dose of study drug, unless the male subjects are totally sexually abstinent or
 have undergone a successful vasectomy with confirmed azoospermia or unless the female
 partners have been sterilized surgically or are otherwise proven sterile

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Subject must be willing and able to comply with all aspects of the protocol

 -  Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
 HIV-positive patients must have:

 -  A stable regimen of highly active anti-retroviral therapy (HAART) using
 combination retroviral agents which are not CYP3A4 inducers or inhibitors

 -  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 within 3 weeks or radiotherapy or targeted therapy
 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those
 who have not recovered from adverse events (other than alopecia) due to agents
 administered more than 4 weeks earlier; however, the following therapies are allowed:

 -  Hormone-replacement therapy or oral contraceptives

 -  Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as
 anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)

 -  Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1

 -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
 pathway-targeting agents or eribulin

 -  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] version 5.0)

 -  Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1

 -  Treatment with systemic immunostimulatory agents (including, but not limited to,
 interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1

 -  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 prior to cycle 1, day 1

 -  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; use of
 bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
 allowed

 -  Patients requiring treatment with a receptor activator of nuclear factor kappa-B
 ligand (RANKL) inhibitor (e.g. denosumab) who cannot discontinue it before treatment
 with atezolizumab

 -  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 prior to cycle 1,
 day 1

 -  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 prior to
 cycle 1, day 1

 -  Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
 and >= 2 weeks from discontinuation of corticosteroids

 -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
 human antibodies

 -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins or eribulin

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to other agents used in study

 -  Known additional malignancy that is progressing or requires active treatment excepting
 basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has
 undergone potentially curative therapy, or in situ cancer; patients with another known
 malignancy are allowed as long that other cancer is in clinical remission for at least
 2 years prior to cycle 1 (C1) day 1 (D1)

 -  History of significant cardiovascular disease, defined as:

 -  Congestive heart failure greater than New York Heart Association (NYHA) class III
 according to the NYHA functional classification

 -  Unstable angina or myocardial infarction within 6 months of enrollment

 -  Serious cardiac arrhythmia

 -  A prolonged QT/corrected QT (QTc) interval (QTc > 500 ms) demonstrated on
 electrocardiogram (ECG) at screening or baseline; a history of risk factors for
 torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT
 syndrome) or the use of concomitant medications that prolonged the QT/QTc
 interval

 -  Autoimmune disease that has required systemic treatment in past 2 years

 -  Clinically significant illness that requires medical treatment within 8 weeks or a
 clinically significant infection that requires medical treatment within 4 weeks of
 dosing

 -  History of organ allograft

 -  Active hepatitis b virus (positive hepatitis b surface antigen) or active hepatitis c
 virus (measurable viral ribonucleic acid [RNA] load with polymerase chain reaction)
 infection

 -  Known intolerance to either of the study drugs (or any of the excipients)

 -  Any medical or other condition which, in the opinion of the investigator, would
 preclude participation in a clinical trial or the investigator's belief that the
 subject is medically unfit to receive eribulin mesylate and atezolizumab or unsuitable
 for any other reason

 -  Known clinically significant liver disease, including active viral, alcoholic, or
 other hepatitis; cirrhosis; fatty liver; 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 (PCR) is negative for HCV RNA

 -  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)

 -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
 organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
 pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
 tomography (CT) scan; history of radiation pneumonitis in the radiation field
 (fibrosis) is permitted

 -  Patients with active tuberculosis (TB) are excluded

 -  Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited
 to, hospitalization for complications of infect