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BRIEF TITLE: Eribulin Mesylate in Combination With Atezolizumab Compared to Atezolizumab Alone in Subjects With Locally Advanced or Metastatic Transitional Cell Urothelial Cancer Where Cisplatin-Based Treatment is Not an Option

A Randomized, Phase 2 Trial to Evaluate the Safety and Efficacy of Eribulin Mesylate in Combination With Atezolizumab Compared to Atezolizumab Alone in Subjects With Locally Advanced or Metastatic Transitional Cell Urothelial Cancer Where Cisplatin-Based Treatment is Not an Option


  • Org Study ID: NCI-2017-01388
  • Secondary ID: NCI-2017-01388,PHII-150,10100,10100,UM1CA186717
  • NCT ID: NCT03237780
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Cancer Institute (NCI)

Brief Summary

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.

Detailed Description


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.

Overal Status Start Date Phase Study Type
Recruiting January 19, 2018 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Incidence of adverse events

Primary Outcome 1 - Time Frame: Up to 52 weeks

Primary Outcome 2 - Measure: Objective tumor response

Primary Outcome 2 - Time Frame: Up to 52 weeks

Primary Outcome 3 - Measure: Overall response rate (probability of complete response [CR] or partial response [PR])

Primary Outcome 3 - Time Frame: Up to 52 weeks

Condition:

  • Locally Advanced Renal Pelvis Urothelial Carcinoma
  • Locally Advanced Ureter Urothelial Carcinoma
  • Locally Advanced Urethral Urothelial Carcinoma
  • Metastatic Renal Pelvis Urothelial Carcinoma
  • Metastatic Ureter Urothelial Carcinoma
  • Metastatic Urethral Urothelial Carcinoma
  • Recurrent Bladder Urothelial Carcinoma
  • Recurrent Renal Pelvis Urothelial Carcinoma
  • Recurrent Ureter Urothelial Carcinoma
  • Recurrent Urethral Urothelial Carcinoma
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Renal Pelvis Cancer AJCC v7
  • Stage III Ureter Cancer AJCC v7
  • Stage III Urethral Cancer AJCC v7
  • Stage IV Bladder Urothelial Carcinoma AJCC v7
  • Stage IV Renal Pelvis Cancer AJCC v7
  • Stage IV Ureter Cancer AJCC v7
  • Stage IV Urethral Cancer AJCC v7
  • Unresectable Renal Pelvis Urothelial Carcinoma
  • Unresectable Ureter Urothelial Carcinoma
  • Unresectable Urethral Urothelial Carcinoma

Eligibility

Criteria:
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
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: David I Quinn

Role: Principal Investigator

Affiliation: City of Hope Comprehensive Cancer Center LAO

Locations

Facility Status Contact
Los Angeles County-USC Medical Center
Los Angeles, California 90033
United States
Recruiting Site Public Contact
323-865-0451
USC / Norris Comprehensive Cancer Center
Los Angeles, California 90033
United States
Recruiting Site Public Contact
323-865-0451
Keck Medical Center of USC Pasadena
Pasadena, California 91105
United States
Recruiting Site Public Contact
323-865-0451
University of California Davis Comprehensive Cancer Center
Sacramento, California 95817
United States
Recruiting Site Public Contact
916-734-3089
University of Kansas Cancer Center
Kansas City, Kansas 66160
United States
Recruiting Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205
United States
Recruiting Site Public Contact
913-588-3671
KUCC_Navigation@kumc.edu
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania 15232
United States
Recruiting Site Public Contact
412-647-8073