Nab-paclitaxel Plus Gemcitabine as First-line Therapy for Cisplatin-ineligible or Cisplatin-incurable Advanced Urothelial Carcinoma

Study Overview
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Brief Summary
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The purpose of this trial is to determine the benefit of the combination of nab-paclitaxel plus gemcitabine given for 6 cycles, followed by maintenance nab-paclitaxel alone, in patients with cisplatin-ineligible or cisplatin-incurable advanced urothelial carcinoma (UC).

Detailed Description
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This open-label, non-randomized phase II trial evaluates the efficacy and toxicity of first-line treatment with a combination of gemcitabine and nab-paclitaxel, followed by maintenance therapy with nab-paclitaxel alone in patients with metastatic or locally advanced unresectable urothelial cancer. Two groups of patients are eligible: (1) patients who are poor candidates for treatment with cisplatin, and (2) patients with visceral metastases who are incurable and unlikely to derive long-term benefit from treatment with cisplatin-based regimens. Eligible patients will receive a minimum of 3 cycles and up to 6 cycles of treatment with the gemcitabine/nab-paclitaxel combination. Patients having an objective response or stable disease will continue maintenance treatment with single-agent nab-paclitaxel until disease progression, intolerable toxicity, or patient decision to discontinue treatment. Up to 55 patients are planned for enrollment.

Official Title
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Phase II Study of Nanoparticle Albumin-bound Paclitaxel Plus Gemcitabine as First-line Therapy for the Treatment of Cisplatin-ineligible or Cisplatin-incurable Advanced Urothelial Carcinoma

Conditions
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Urothelial Carcinoma, Bladder Cancer, Transitional Cell Carcinoma

Intervention / Treatment
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* Drug: nab-paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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KEY POINTS: Inclusion Criteria: Histologically confirmed diagnosis of urothelial carcinoma (UC) that is either metastatic (any N+ M1) or locally advanced and unresectable (T4bN0). A component of urothelial (transitional cell) carcinoma is required. Two groups of patients are eligible: Poor candidates for cisplatin-based chemotherapy based on the presence of ≥ 1 the following: Glomerular filtration rate of 30-60 ml/min (Cockcroft-Gault formula) ECOG performance status score of 2 Hearing loss (trouble communicating with hearing aids or hearing loss at ≤ 3 KHz) Grade ≥3 heart failure Age ≥80 years Other concurrent illness which may make the patient a poor candidate for receiving cisplatin. Note: Enrollment of patients with 2 or more of these criteria should occur only after careful consideration by the treating physician regarding the patient's ability to tolerate combination chemotherapy. OR Poor prognosis and defined as cisplatin-incurable due to the presence of metastasis to at least one visceral site (these patients are not required to have any of the cisplatin-ineligibility criteria). ECOG performance status score of 0, 1, or 2. Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with brain metastases are allowed if treatment was completed at least 4 weeks prior to study treatment, neurologic symptoms are minimal and stable during the preceding 4 weeks, and maintenance dexamethasone is not required. Adequate hematologic, liver and kidney function. Willingness and ability to comply with study requirements and give written informed consent. Exclusion Criteria: Previous systemic chemotherapy for UC with the exception of perioperative (neoadjuvant or adjuvant) treatment or treatment with concurrent chemoradiation for locally advanced disease. All of these treatments must have been completed more than 1 year previously. Presence of small-cell or sarcomatoid component in tumor histology. Women who are pregnant or breast-feeding. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement. Cardiac diseases currently or within the last 6 months: Inadequately controlled hypertension. Currently receiving treatment with therapeutic doses of warfarin sodium. (A maximum daily dose of 1 mg will be permitted for port line patency. Low molecular weight heparin is allowed.) Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C (screening for these diseases is not required.). Presence of other active cancers, or history of treatment for invasive cancer ≤5 years previously. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nab-paclitaxel+gemcitabine<br>Induction Phase: nab-paclitaxel (125 mg/m²) and gemcitabine (1000 mg/m²) by IV infusion on Days 1 and 8 of each 21-day cycle. Responding or stable patients will be treated with a minimum of 3 cycles and up to 6 cycles before starting the single agent maintenance therapy. Maintenance Phase: Patients completing 3-6 cycles of induction therapy with an objective response (complete or partial response) or stable disease will continue treatment with single agent nab-paclitaxel (260 mg/m²) by IV infusion every 21 days) until disease progression, intolerable toxicity or patient decision to discontinue treatment. | Drug: nab-paclitaxel<br>* Induction: 125 mg/m² by intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle for 3 to 6 cycles to be given with Gemcitabine. Maintenance: single agent nab-paclitaxel (260 mg/m²) by IV infusion every 21 days) until disease progression, intolerable toxicity or patient decision to discontinue treatment.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Induction: 1000 mg/m²) by IV infusion on Days 1 and 8 of each 21-day cycle for 3 to 6 cycles.<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Month Progression-free Survival (PFS6) | The percentage of treated patients who are progression-free at 6 months after start of treatment, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over sum. | up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The proportion of patients with a confirmed complete or partial response (CR or PR) according to RECIST v1.1. CR = disappearance of all target lesions. PR = at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | every 3 cycles (9 weeks) until treatment discontinuation, an expected average of 1 year. | 
| Clinical Benefit Rate | Defined as the proportion of patients with CR, PR, or stable disease (SD) according to RECIST v1.1. SD = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum of diameters since start of treatment. | every 3 cycles (9 weeks) until treatment discontinuation, an expected average of 1 year. | 
| Overall Survival | Defined as the time from Day 1 of study drug administration to disease progression or death on study. | every 9 weeks until disease progression or death on study, an expected average of 1 year. Patients with progressive disease will be followed every 3 months for the first year and every 6 months thereafter up to 5 years. | 
| The Number of Participants With Grade 3/4/5 Adverse Events (AEs) as a Measure of Safety. | The reported incidence of AEs with an onset on or after the initiation of therapy will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nab-paclitaxel, gemcitabine