A Study Combining Eribulin Mesylate With Avelumab in Cisplatin Ineligible Metastatic Urothelial Cell Cancer Patients
Condition: Metastatic Urothelial Cell Cancer
Intervention: Eribulin Mesylate; Avelumab
Intervention description: Days 1, 15
Eribulin mesylate:
Dose level -1: 0.7mg/m^2;
Dose level 0: 1.1 mg/m^2;
Dose level +1: 1.4 mg/m^2; Days 1, 15 Avelumab (10mg/kg)
Intervention MeSH terms: Avelumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cisplatin-Ineligible; Avelumab; PD-L1 Monoclonal Antibody; Eribulin Mesylate

Summary:

      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.
    

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.