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

NCT03502681

Last updated date
Study Location
Univeristy of Iowa Hospital and Clinics
Iowa City, Iowa, 52242, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Metastatic Urothelial Cell Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


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.

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Metastatic Urothelial Cell CancerA Study Combining Eribulin Mesylate With Avelumab in Cisplatin Ineligible Metastatic Urothelial Cell Cancer Patients
NCT03502681
  1. Iowa City, Iowa
  2. Hershey, Pennsylvania
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE A Study Combining Eribulin Mesylate With Avelumab in Cisplatin Ineligible Metastatic Urothelial Cell Cancer Patients
Official Title  ICMJE Phase 1b Clinical Trial of Eribulin Mesylate and the PD-L1 Monoclonal Antibody, Avelumab, in Cisplatin Ineligible Metastatic Urothelial Cell Cancer Patients
Brief 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Urothelial Cell Cancer
Intervention  ICMJE
  • Drug: Eribulin Mesylate

    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

    Other Name: Halaven
  • Drug: Avelumab
    Days 1, 15 Avelumab (10mg/kg)
    Other Names:
    • MSB0010718C
    • BAVENCIO
Study Arms  ICMJE Experimental: Maximum tolerated dose (MTD) cohort

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 objective response rate (ORR) at 6 months.

Interventions:
  • Drug: Eribulin Mesylate
  • Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 12, 2020)
6
Original Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
24
Actual Study Completion Date  ICMJE October 25, 2019
Actual Primary Completion Date October 25, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03502681
Other Study ID Numbers  ICMJE BTCRC-GU16-051
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Monika Joshi, MD, Big Ten Cancer Research Consortium
Study Sponsor  ICMJE Monika Joshi, MD
Collaborators  ICMJE
  • Pfizer
  • Eisai Inc.
  • Big Ten Cancer Research Consortium
Investigators  ICMJE
Study Chair:Monika Joshi, M.D.Big Ten Cancer Research Consortium
PRS Account Big Ten Cancer Research Consortium
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP