Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma

Study Description

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Brief Summary:

The purpose of this research study is to test the effectiveness of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in combination with pegfilgrastim followed by radical surgery in patients with muscle-invasive urothelial carcinoma.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer; Muscle-invasive Bladder Cancer	Drug: Methotrexate; Drug: Doxorubicin; Drug: vinblastine; Drug: cisplatin; Drug: Pegfilgrastim	Phase 2

Detailed Description:

• Participants will be given a study infusion schedule for each treatment cycle. Each treatment cycle lasts three weeks. The infusion of methotrexate will take place on the first day of each cycle. Infusions of vinblastine, doxorubicin and cisplatin will take place on the second day and an injection of pegfilgrastim will be given on the third day.
• During all treatment cycles participants will have a physical exam and will be asked questions about their general health and any problems they might be having and any medications they may be taking.
• Following completion of study treatment, but before surgery, participants will have an assessment of their tumor by CT scan of the chest and and MRI of the abdomen and pelvis.
• Following the participants surgery, we would like to keep track of their medical condition indefinitely, or until this study is officially completed. We would like to do this by calling the participants on the telephone once a year to see how they are doing.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	39 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Trial of Neoadjuvant Dose-Dense MVAC With Pegfilgrastim Support in Subjects With Muscle-Invasive Urothelial Carcinoma
Study Start Date :	December 2008
Actual Primary Completion Date :	December 2013
Actual Study Completion Date :	September 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Dose Dense MVAC; Chemo therapy with methotrexate, vinblastine, Adriamycin, Cisplatin	Drug: Methotrexate; intravenously 30mg/m2 over 30 minutes Drug: Doxorubicin; intravenously 30mg/ms over 15 minutes Drug: vinblastine; intravenously 3mg/m2 over 30 minutes Drug: cisplatin; intravenously 70mg/m2 in 1 liter NS with 12.5gm Mannitol over 2 hours after vinblastine completion Drug: Pegfilgrastim; Given subcutaneously 24 hours after last chemotherapy dose

Outcome Measures

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Primary Outcome Measures :

1. Number of Patients Achieving Pathologic Response [ Time Frame: After completion of 4 cycles of chemotherapy with pegfilgrastim support (cycle length 2 weeks) ]
   Pathological response is defined as down-staging to </=pT1, N0 after chemotherapy with pegfilgrastim support.

Secondary Outcome Measures :

1. Number of Patients Experiencing Febrile Neutropenia [ Time Frame: After completion of 4 cycles of chemotherapy with pegfilgrastim support (cycle length 2 weeks) ]
   Febrile neutropenia defined per CTCAEv3 as Grade 3 or higher and treatment attribution possibly, probably or definitely-related.
2. Number of Patients Experiencing Surgery-related Toxicity [ Time Frame: Surgery + 30 days ]
   Surgery-related toxicity defined per CTCAEv3 as Grade 2 or higher and treatment attribution possibly, probably or definitely-related.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Histologic proof of urothelial cancer. Patients with all histologic subtypes are eligible as long as transitional cell carcinoma is predominant, with the exception of more than a few clusters of small cell carcinoma, which is treated with different chemotherapy and thus are ineligible
• Patients with primary tumors arising in the bladder or urethra are eligible if they have clinical T2-T4a disease
• Patients with primary tumors arising in the ureter or renal pelvis are eligible if they have either grade 3 tumors, or radiographic abnormality large enough to be recognized as an abnormal mass by CT/imaging
• Evaluation by a urologist and be deemed to be acceptable surgical candidates within 3 months of registration
• Adequate physiologic reserves as outlined in the protocol
• Clinical or pathologic N1 lymph node involvement (involvement of a single lymph node < 2cm in greatest dimension) are eligible. Patients with N2-3 or M1 disease are ineligible
• Determination of LV function with an EF > 50%
• Women of child-bearing potential must have a negative pregnancy test
• Patients of child-bearing or father-bearing potential must agree to use an acceptable form of birth control while on the study
• Patients with prior malignancy are eligible provided that the expected outcome from the prior cancer is such that this will not interfere in the delivery of this therapy, or the assessment of response in the cystectomy specimen
• 18 years of age or older

Exclusion Criteria:

• Current, recent (within 3 weeks), or planned participation with other experimental anti-cancer medications as part of clinical trials
• Prior treatment with doxorubicin
• Prior systemic cytoreductive chemotherapy for bladder cancer
• Blood pressure of > 160/100 mmHg. Patients whose blood pressure can be controlled with oral medication are eligible
• NYHA Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to study enrollment
• History of stroke or transient ischemic attack within 6 months prior to study enrollment
• Clinically significant peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Known history of central nervous system or brain metastases
• Major surgical procedure, significant traumatic injury within 21 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study
• Lactating women
• Patients who are not candidates for surgery, or unwilling to undergo surgery
• Patients with significant fluid collection
• Known hypersensitivity to any component of cisplatin, methotrexate, vinblastine, doxorubicin or pegfilgrastim

Contacts and Locations

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Locations

United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Lahey Clinic
Burlington, Massachusetts, United States, 01805
United States, Pennsylvania
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232

Sponsors and Collaborators

Dana-Farber Cancer Institute

Beth Israel Deaconess Medical Center

Brigham and Women's Hospital

Amgen

Investigators

Principal Investigator:	Toni Choueiri, MD	Dana-Farber Cancer Institute

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. doi: 10.1200/JCO.2013.52.4785. Epub 2014 May 12.

Responsible Party:	Toni Choueiri, MD, Assistant Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT00808639 History of Changes
Other Study ID Numbers:	08-208
First Posted:	December 16, 2008
Results First Posted:	May 15, 2014
Last Update Posted:	October 24, 2016
Last Verified:	September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Toni Choueiri, MD, Dana-Farber Cancer Institute:

pegfilgrastim; MVAC

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; Cisplatin; Doxorubicin; Methotrexate; Vinblastine

Antineoplastic Agents; Antibiotics, Antineoplastic; 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; Immunosuppressive Agents