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Risk Adapted Treatment for Muscle Invasive Bladder Cancer After Neoadjuvant Accelerated MVAC

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ClinicalTrials.gov Identifier: NCT02710734
Recruitment Status : Recruiting
First Posted : March 17, 2016
Last Update Posted : November 17, 2017
Sponsor:
Information provided by (Responsible Party):
Fox Chase Cancer Center

Brief Summary:
The aim of this study is to evaluate a risk-adapted approach to the treatment of muscle invasive bladder cancer. Each baseline transuretheral resection of bladder tumor (TURBT) sample will be sequenced while proceeding with neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) chemotherapy. Based on the mutational profile and the post AMVAC TURBT findings, patients will be treated with active surveillance (experimental arm), or standard of care intravesicle therapy, chemoradiation or surgery. We hypothesize that this approach will lead to non-inferior metastasis-free survival at 2 years, while preserving the bladder and thus quality-of-life for a proportion of patients.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma of the Bladder Drug: Methotrexate Drug: Vinblastine Drug: Doxorubicin Drug: Cisplatin Radiation: Intensity modulated radiation therapy (IMRT) Procedure: Transurethral Resection of Bladder tumor Drug: 5-FU Drug: Mitomycin C Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Risk Adapted Treatment for Muscle Invasive Bladder Cancer After Neoadjuvant Accelerated MVAC (RAT-MIBC)
Actual Study Start Date : February 24, 2016
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: CRT
Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then chemoradiation followed by TURBT#3
Drug: Methotrexate
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Vinblastine
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Doxorubicin
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Cisplatin
Administered Day 1 of each 14 day cycle for 3 cycles

Radiation: Intensity modulated radiation therapy (IMRT)
2.0 Gy per fraction to the whole bladder plus a margin for a total of 32 fractions (64.0 Gy). Radiation will be administered from Monday to Friday

Procedure: Transurethral Resection of Bladder tumor
Performed at before and after AMVAC and after chemoradiation and intravesicle therapy

Drug: 5-FU
Continuous 24hr Intravenous infusion days 1-5 and 16-20 with radiation treatment

Drug: Mitomycin C
Intravenous on day 1 with radiation treatment

Experimental: Surveillance
Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then active surveillance
Drug: Methotrexate
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Vinblastine
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Doxorubicin
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Cisplatin
Administered Day 1 of each 14 day cycle for 3 cycles

Procedure: Transurethral Resection of Bladder tumor
Performed at before and after AMVAC and after chemoradiation and intravesicle therapy

Experimental: Intravesicle therapy
Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then intravesicle therapy followed by TURBT#3
Drug: Methotrexate
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Vinblastine
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Doxorubicin
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Cisplatin
Administered Day 1 of each 14 day cycle for 3 cycles

Procedure: Transurethral Resection of Bladder tumor
Performed at before and after AMVAC and after chemoradiation and intravesicle therapy

Experimental: Radical Cystectomy
Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then cystectomy
Drug: Methotrexate
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Vinblastine
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Doxorubicin
Administered Day 1 of each 14 day cycle for 3 cycles

Drug: Cisplatin
Administered Day 1 of each 14 day cycle for 3 cycles

Procedure: Transurethral Resection of Bladder tumor
Performed at before and after AMVAC and after chemoradiation and intravesicle therapy




Primary Outcome Measures :
  1. Metastasis-free survival (MFS) at 2 years. [ Time Frame: 24 months ]

Secondary Outcome Measures :
  1. Ability to complete of 3 cycles of neoadjuvant AMVAC and chemoradiation therapy with 5-FU and mitomycin C. [ Time Frame: Up to 37 Weeks ]

Other Outcome Measures:
  1. Rate of urothelial carcinoma recurrence in active surveillance patients [ Time Frame: 60 months ]
  2. Overall survival and PFS of the entire cohort [ Time Frame: 60 months ]
  3. toxicity during each treatment arm according to NCI CTCAE v 4.01 criteria [ Time Frame: 24 months ]
  4. Proportion of patients with ≥cT1 disease after TURBT#2 [ Time Frame: up to 22 weeks ]
  5. Proportion of patients requiring a cystectomy, either immediately after TURBT#2 or as salvage after surveillance or CRT [ Time Frame: up to 24 months ]
  6. Endoscopic Tumor Quantification System score at each TURBT [ Time Frame: 24 months ]
    At each cystoscopic examination, the location and extent of tumor volume will be visually depicted and graded according to Endoscopic Tumor Quantification System

  7. Quality of life with neoadjuvant AMVAC and subsequent risk-adapted treatment [ Time Frame: 60 months ]
    American Urologic Association (AUA) Symptom Index Score, Sexual Health Inventory for Men (SHIM) score or Female Sexual Function Index (FSFI) score



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients ≥18 years.
  • Primary urothelial or predominantly urothelial carcinoma of the bladder.
  • Histologic evidence of muscularis propria invasion.
  • AJCC27 clinical stage T2-T4a .
  • No radiographic evidence of lymph node positivity (N0) or metastatic disease (M0). Clinical lymphadenopathy on staging CT greater than 1.5 cm in short axis must be biopsy proven negative.
  • ECOG performance status 0, 1, or 2.
  • Left ventricular ejection fraction ≥ 50% by MUGA or ECHO within 6 months of study entry.
  • Normal organ and bone marrow function as defined:

Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN Creatinine Creatinine Clearance ≥ 50 mL/min (calculated using the Cockroft-Gault formula or measured with 24 hour urine collection)

Exclusion Criteria:

  • Any component of small cell histology.
  • Prior pelvic radiation therapy or patients who have undergone prior radiation to greater than or equal to 25% of the bone marrow within the past year are excluded due to risk of life threatening myelosuppression
  • Prior systemic chemotherapy; patients who have received any previous systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible.
  • Prior or concurrent malignancy of any other site except for non-melanoma skin cancer, unless disease free interval ≥ 5 years.
  • Patients who have received experimental agents within 4 weeks of study entry.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to Methotrexate, Vinblastine, Adriamycin or Cisplatin or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects of cytotoxic chemotherapy.
  • Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cytotoxic chemotherapy. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Patients with hydronephrosis that has not been addressed with an intervention such as placement of a stent.
  • Pregnancy & Women of Childbearing Potential

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02710734


Contacts
Contact: Daniel Geynisman, MD 215-214-1515 Daniel.Geynisman@fccc.edu

Locations
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Daniel Geynisman, MD    215-728-4300    daniel.geynisman@fccc.edu   
Principal Investigator: Daniel Geynisman, MD         
Sponsors and Collaborators
Fox Chase Cancer Center

Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT02710734     History of Changes
Other Study ID Numbers: GU-086
15-1071 ( Other Identifier: Fox Chase Cancer Center IRB )
First Posted: March 17, 2016    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Fox Chase Cancer Center:
Urothelial

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Doxorubicin
Mitomycins
Mitomycin
Methotrexate
Vinblastine
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Folic Acid Antagonists