Comparing the New Anti-cancer Drug Eribulin With or Without Chemotherapy Against the Usual Chemotherapy Alone in Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This phase III trial compares the usual chemotherapy treatment to eribulin alone and to eribulin plus gemcitabine in treating patients with urothelial cancer that has spread to other places in the body (metastatic). Chemotherapy drugs, such as eribulin, gemcitabine, docetaxel, and paclitaxel, 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. This trial aims to see whether adding eribulin to standard of care chemotherapy may work better in treating patients with metastatic urothelial cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare overall survival (OS) in participants with metastatic urothelial carcinoma (mUC) who are randomized to standard treatment versus eribulin mesylate (eribulin) alone. II. To compare overall survival in participants with metastatic urothelial carcinoma (mUC) who are randomized to standard treatment versus eribulin plus gemcitabine hydrochloride (gemcitabine). III. To compare overall survival in participants with metastatic urothelial carcinoma (mUC) who are randomized to eribulin alone versus eribulin plus gemcitabine. SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS) in the standard treatment arm to the two experimental treatment arms in this population. II. To compare Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 overall response rate (ORR), both confirmed and unconfirmed, complete and partial responses (CR and PR), in the standard treatment arm to the two experimental treatment arms in the subset of participants with measurable disease in this population. III. To compare duration of response (DOR) in the standard treatment arm to the two experimental treatment arms in the subset of participants with measurable disease in this population. IV. To compare disease control rate (DCR) in the standard treatment arm to the two experimental treatment arms in the subset of participants with measurable disease in this population. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive 1 of the 3 standard of care chemotherapy regimens based on treating investigator's choice: Choice A: Patients receive docetaxel intravenously (IV) on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Choice B: Patients receive gemcitabine IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Choice C: Patients receive paclitaxel IV on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive eribulin IV over 2-5 minutes and gemcitabine IV 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 every 6 months for 2 years from the date of registration, then every 12 months until death or 3 years from the date of registration

Official Title
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A Phase III Randomized Trial of Eribulin (NSC #707389) With or Without Gemcitabine Versus Standard of Care (Physician's Choice) for Treatment of Metastatic Urothelial Carcinoma Refractory to, or Ineligible for, Anti PD1/PDL1 Therapy

Conditions
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Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Refractory Bladder Urothelial Carcinoma, Refractory Renal Pelvis Urothelial Carcinoma, Refractory Ureter Urothelial Carcinoma, Refractory Urethral Urothelial Carcinoma, Refractory Urothelial Carcinoma, Stage IV Bladder Cancer AJCC v8, Stage IV Renal Pelvis and Ureter Cancer AJCC v8, Stage IV Renal Pelvis Cancer AJCC v8, Stage IV Ureter Cancer AJCC v8, Stage IV Urethral Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Stage IVB Bladder Cancer AJCC v8

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Eribulin Mesylate
* Drug: Gemcitabine Hydrochloride
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have predominant histologically and cytologically proven urothelial carcinoma in a metastatic site Participant must have evidence of metastatic urothelial carcinoma based on computed tomography (CT) or magnetic resonance imaging (MRI) within 28 days prior to registration Participant must have had progression of disease following prior therapy at the discretion of the treating investigator Participant must meet ALL of the requirements listed below. There is no limit to the number or sequence of prior regimens participant may have received for urothelial carcinoma Participants must have received platinum based chemotherapy either in frontline metastatic setting or in the perioperative setting within 12 months prior to diagnosis of metastatic disease. Participants who have received a non-platinum systemic therapy within 12 months prior to diagnosis of metastatic disease are not required to have received platinum based chemotherapy Participant must have received PD1/PDL1 antibody systemic therapy either in frontline metastatic setting or in the perioperative setting within 12 months prior to diagnosis of metastatic disease. Participants who, in the opinion of the treating physician, are not candidates for PD1/PDL1 antibody systemic therapy are exempt Participant must have received enfortumab vedotin in a prior line of systemic therapy for urothelial carcinoma Participant must have received any planned surgery prior to registration Participant must have Zubrod performance status 0-2 Participant must have history and physical examination within 28 days prior to registration Participant must have complete blood count (CBC), complete metabolic panel including liver function tests, and lactate dehydrogenase (LDH) obtained with 28 days prior to registration Participant must have adequate kidney function as evidenced by measured or calculated creatinine clearance >= 30 mL/min within 28 days prior to registration Participant must have adequate hepatic function documented by either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x institutional upper limit of normal (IULN) within 28 days prior to registration. If both AST and ALT are performed, both must be =< 3 x IULN. For participants with liver metastases, AST or ALT must be =< 5 x IULN Participant must be on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration if they are known to have human immunodeficiency virus (HIV)-infection Participants must have undetectable hepatitis B virus (HBV) viral load within 28 days prior to registration if participant has known chronic hepatitis B virus (HBV) infection Participants with a known history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load within 28 days prior to registration Participants may have a prior or concurrent malignancy provided the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen per the opinion of the treating investigator Participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines Exclusion Criteria: Participants must not require immediate central nervous system (CNS)-specific treatment, in the opinion of the treating investigator if they have active brain metastases (defined as new or progressive brain metastases) or leptomeningeal disease Participant must not have progressed within 3 months following last dose of gemcitabine, if patient previously received gemcitabine Participant must not have unresolved toxicities from prior surgeries or radiation therapy > grade 1 at the time of registration Participants must not be planning to take strong or moderate CYP3A or CYP2C8 inhibitors or inducers if randomized to Arm 1 and standard of care (SOC) regimen chosen is paclitaxel or docetaxel. Participants receiving strong or moderate CYP3A or CYP2C8 inducers must discontinue use at least 2 weeks prior to randomization Participant must not have a known history of corrected QT (QTc) prolongation Participants must not be pregnant or nursing due to the risk of harm to a fetus or nursing infant. Women and men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study and 6 months (females) or 3.5 months (males) after the last dose. A woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (standard of care chemotherapy)<br>Patients receive 1 of the 3 standard of care chemotherapy regimens based on treating investigator's choice: Choice A: Patients receive docetaxel IV on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Choice B: Patients receive gemcitabine IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Choice C: Patients receive paclitaxel IV on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm II (eribulin)<br>Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Eribulin Mesylate<br>* Given IV<br>* Other names: Halichondrin B Analog;|
| Experimental: Arm III (eribulin, gemcitabine)<br>Patients receive eribulin IV over 2-5 minutes and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Eribulin Mesylate<br>* Given IV<br>* Other names: Halichondrin B Analog;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | From date of registration to date of death due to any cause, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | From date of registration to date of first documentation of progression or symptomatic deterioration (as defined in above), or death due to any cause, assessed up to 3 years | 
| Overall response rate |  | 3 years | 
| Duration of response | Assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. | Date from initial documentation of PR or CR to progression or death from any cause, whichever comes first, assessed up to 3 years | 
| Disease control rate | Percentage of patients achieving at least a stable disease as best response on imaging using RECIST 1.1 criteria during treatment. | Up to 3 years |