A Study Combining Eribulin Mesylate With Avelumab in Cisplatin Ineligible Metastatic Urothelial Cell Cancer Patients

This is a single arm, open-label phase Ib study of combining eribulin mesylate with avelumab. The initial 9-12 patients (MTD cohort) will be enrolled to determine safety of avelumab in combination with eribulin mesylate. Upon determination of maximum tolerated dose (MTD), 12 additional patients will be enrolled in an expansion cohort (efficacy cohort) to determine ORR at 6 months.

Dose Escalation Plan:

A standard "3+3" design will be used to determine the MTD of eribulin with avelumab.

The maximum tolerated dose is the dose of eribulin combined with avelumab with dose limiting toxicity of 0-1 of 6 patients in the first cycle of combination therapy. After the MTD has been determined, an additional 12 patients will be enrolled in an expansion cohort at the MTD to evaluate the efficacy of this combination.

After determination of MTD for eribulin mesylate, an additional 12 patients will be enrolled on the expansion cohort. Subjects on the expansion cohort will be assessed for adverse events but will not be assessed for DLTs.

Eligibility Criteria:
Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

* Written informed consent and HIPAA authorization for release of personal health information.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status of 0-2 at the time of enrollment.
* Life expectancy of \>12 weeks.
* Stage IV patients either locally advanced node positive (these patients must have N3 disease) or metastatic-M1 positive urothelial cancer of bladder and upper tract.
* Histologically proven urothelial carcinoma of bladder with predominant transitional cell component. Adenocarcinoma, squamous cell differentiation, or other atypical histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the study, provided they form \<50% of the histology.
* Presence of measurable disease per RECIST v1.1 for solid tumors.
* Patients who are cisplatin ineligible defined by the presence of one or more of the following:

  * Impaired renal function (GFR ≥ 30 but ≤ 60 cc/min). GFR should be assessed by direct measurement (i.e. creatinine clearance or ethylenediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine by Cockroft-Gault equation.
  * Grade ≥ 2 Hearing Loss (hearing loss measured by audiometry of 25 dB at two contiguous frequencies)
  * Grade ≥ 2 peripheral neuropathy (Please note that for enrollment on this trial patients must have peripheral neuropathy grade 2 or lower)
  * ECOG Performance Status of 2
  * NYHA Class III-IV CHF (Please note that for enrollment on this trial patients must have Ejection Fraction of \>35% measured on ECHO)
* Patients must be treatment naïve for metastatic disease. Use of chemotherapy in neoadjuvant or adjuvant form is allowed provided the time period between last dose of treatment and enrollment is \>12 months and subjects must have recovered from all reversible toxic effects of the regimen (other than alopecia) to ≤Grade 1 or baseline.
* Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to study registration:

Hematological:

* Platelet ≥ 100K/mm\^3
* Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm\^3
* Hemoglobin (Hgb) ≥ 9 g/dL

Renal:

* Calculated creatinine clearance

  * ≥ 30 cc/min using the Cockcroft-Gault formula (Cockcroft and Gault 1976)
  * or by equivalent criteria such as measured GFR by hospital's laboratory
  * or by 24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

Hepatic:

* Bilirubin ≤ 1.5 × upper limit of normal (ULN)
* Aspartate aminotransferase (AST) ≤ 2.5 × ULN
* Alanine aminotransferase (ALT) ≤ 2.5 × ULN

Coagulation:

* International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 1.5× ULN for patients who are not on any anticoagulants.

Patients who are on warfarin would require switching to either a short acting anticoagulant such as oral apixaban or lovenox injection. Prior to entry on the trial their INR should be \<2.0. Patients who are already on short acting anticoagulants would be allowed to enroll on the study provided their INR \<2.0

* Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to registration.
* Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use a highly effective method of contraception from the time of informed consent until 90 days after treatment discontinuation.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
* Availability of baseline tumor tissue (fresh biopsy or archival) prior to enrollment on the clinical trial. TURBT specimens are preferred but tissue from lymph node or visceral areas are also acceptable. If archival tissue is not available, the subject must be willing to consent to a fresh biopsy for research prior to registration for protocol therapy. If archival tissue is not available and there are no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a case by case basis.
* Palliative radiation therapy prior to or during the treatment is allowed if indicated. However, if prior to start of treatment, radiation therapy must complete at least 7 days prior to cycle 1 day 1 of treatment.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

* Participation in another clinical study with an investigational product within 2 weeks prior to registration.
* Any previous treatment with a PD1 or PD-L1 inhibitor, including Avelumab.
* Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.
* History of another primary malignancy except for:

  * Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence. However adequately treated prostate cancer \>3 years ago with no significant change in PSA for past 6 months can be included.
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  * Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ.
* Receipt of the last dose of anti-cancer therapy for local recurrence only and not for any systemic disease (immunotherapy, endocrine therapy, biologic therapy, tumor embolization, monoclonal antibodies, or other investigational agent) within14 days prior to study registration and within 6 weeks for intravesical BCG or mitomycin C .
* Mean QT interval corrected for heart rate (QTc) ≥470 ms on electrocardiogram (ECG) using Frediricia's Correction.
* Current or prior use of immunosuppressive medication within 28 days before study registration, with the exceptions of: a) intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) b) systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid, c) steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* Any unresolved toxicity (≥CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss). Alopecia, sensory neuropathy grade ≤ 2, or other grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
* Active or prior documented autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. NOTE: Subjects with diabetes type I, vitiligo, hypo- or hyperthyroid diseases, or psoriasis not requiring immunosuppressive systemic treatment are eligible. Patients with a history of completely resolved childhood asthma or atopy are also eligible.
* Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
* History of and/or confirmed pneumonitis.
* History of primary immunodeficiency.
* History of organ transplantation including allogeneic stem-cell transplant.
* History of hypersensitivity to Avelumab or Eribulin mesylate, including known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3).
* Uncontrolled intercurrent illness including, but not limited to:

  * ongoing or active infection requiring systemic therapy
  * active peptic ulcer disease or gastritis, or active bleeding diatheses,
  * psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
* Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
* Any subject known to have evidence of acute or chronic hepatitis B (positive HBV surface antigen), hepatitis C (perform HCV RNA if anti-HCV antibody screening test positive), or human immunodeficiency virus (HIV). Note: testing will be performed if applicable per physician discretion.
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of starting treatment with Avelumab. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
* Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control. For this study male or female patients of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 90 days after last dose of study drug.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
* Brain metastases or history of leptomeningeal carcinomatosis.
* Subjects with uncontrolled seizures.