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PF-03446962 in Relapsed or Refractory Urothelial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01620970
Recruitment Status : Unknown
Verified June 2012 by Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano.
Recruitment status was:  Not yet recruiting
First Posted : June 15, 2012
Last Update Posted : June 15, 2012
Sponsor:
Information provided by (Responsible Party):
Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Tracking Information
First Submitted Date  ICMJE June 11, 2012
First Posted Date  ICMJE June 15, 2012
Last Update Posted Date June 15, 2012
Study Start Date  ICMJE July 2012
Estimated Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2012)
Progression-free survival. [ Time Frame: 2-month ]
Progression-free survival (PFS) is defined as the interval from the first dose of study drug to the date of the first documented disease progression or death for any reason, with censoring at the date of last contact for alive patients. A patient who has not progressed or died by the date of the analysis cut-off or when the patient received any further anticancer therapy would have the PFS censored at the time of last adequate tumor assessment before either cut-off date or the commencement of further anticancer therapy date, respectively.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2012)
  • Safety (CTCAE v.4.03) [ Time Frame: 2-month ]
    Incidence of adverse events (AEs), defined as any new untoward medical conditions occurrence or worsening of a pre-existing medical condition that does not necessarily have a causal relationship with the study drugs. AEs will be graded according to the NCI-CTC version 4.03 and the relationship of each AEs to study drugs will be assessed by the investigator.
  • RECIST response-rate [ Time Frame: 2-month ]
    Assessment of response-rate by RECIST v1.1 criteria. RR (%) = CR + PR
  • Overall Survival [ Time Frame: 6-month ]
    Overall Survival (OS) will be calculated as the interval from the date of the first dose of study drug to the date of death for any cause, with censoring at the date of last contact for patients alive. The Kaplan-Meier method will be used to estimate the OS curve (median and 95% confidence interval).
  • Circulating and Tissue Biomarkers [ Time Frame: Baseline and 2 months ]
    Tissue will be examined in terms of genotyping by high-resolution array comparative genome hybridization (aCGH) and expression of VEGFR, PDGFR, KIT, EGFR, HER2/neu, PTEN on tissue microarrays (TMAs). Circulating VEGF, soluble VEGFR-1, 2 and -3, soluble c-Kit, IL-6, 8, 12 and HGF will be evaluated by using multiplex ELISA plates. Circulating tumor cells will be evaluated as a potential response biomarkers.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PF-03446962 in Relapsed or Refractory Urothelial Cancer
Official Title  ICMJE Phase II Study of the Fully Human Monoclonal Antibody Against Transforming Growth Factor-beta (TGFβ) Receptor ALK1 (PF-03446962) in Relapsed or Refractory Urothelial Cancer (UC) Failing First-line Treatment.
Brief Summary

Salvage chemotherapy for advanced urothelial cancer (UC) yields suboptimal response rates of 15-40%, a median progression-free survival of 2-4 months and a median overall survival of 6 months. A rationale for targeting angiogenesis in UC is supported by preclinical evidences and early signals of clinical activity of anti-VEGF TKI as demonstrated by our group with the use of pazopanib.

Despite this activity, progression inevitably occurs and mechanisms determining resistance to conventional anti-angiogenic agents are under investigation.

PF-03446962 (Pfizer Inc) is a novel fully human monoclonal antibody (mAb) against ALK1 with dose-dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumor xenograft. The investigators suggest that PF-03446962 may increase current results for patients with advanced urothelial cancer failing upfront chemotherapy due to its mechanisms of action. Due to the lack of reliable and reproducible predictors of response as well as of imaging tools to assess tumor response, the trial will provide incorporation of 18FDG-PET/CT and contrast-enhanced ultrasound to stage and evaluate response of urothelial cancers, together with standard imaging modalities (RECIST criteria). Blood and tissue samples will be collected for translational purposes.

Detailed Description

This is an open-label, single arm, non randomised, phase II proof-of-concept study of the monoclonal antibody against TGF-beta receptor ALK1 (PF03446962) for patients with urothelial cancer relapsing/progressing after first line chemotherapy.

The study is planned according to Simon's Optimal two-stage design. The primary endpoint is the proportion of patients who are progression-free at 2-months. A 2-month PFS rate of 50% is not promising, while a 70% rate will be promising. In stage 1, 21 evaluable patients will be accrued. If 12 patients at least will be progression-free at 2 months, enrollment will be extended to the 2nd stage for further 24 patients. If, out of the total of 45 patients, 27 at least will be progression-free at 2 months, treatment will be declared worthy for further investigations.

Maximum overall accrual is 45 patients. Type I and type II error rates will be set both at the 10% level.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Transitional Cell Carcinoma of Bladder
Intervention  ICMJE Drug: PF03446962
PF-03446962 will be administered in 1hr intravenously at a dose of 10 mg/Kg on day 1, then every 2 weeks until the evidence of disease progression or onset of unacceptable toxicity.
Study Arms  ICMJE Experimental: PF03446962
Investigational study drug, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.
Intervention: Drug: PF03446962
Publications *

*   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 Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 13, 2012)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2013
Estimated Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age > 18 years.
  • ECOG Performance status of 0 or 1.
  • Life expectancy of at least 12 weeks.
  • Measurable disease criteria (RECIST v1.1).
  • Histological diagnosis of urothelial cancer.
  • Locally advanced or metastatic disease.
  • Failure of at least 1 prior chemotherapy regimen for metastatic disease.
  • Neoadjuvant/adjuvant therapy considered if relapse occurred within 6 months of the last cycle of chemotherapy.
  • Adequate bone marrow, liver and renal function requirements, to be conducted within 7 days prior to screening.

Exclusion Criteria:

  • Cardiovascular or CNS disease.
  • Previously untreated CNS metastases.
  • Active Hepatitis B, C, HIV infection.
  • Pregnant or breast-feeding patients.
  • GI abnormalities and any other clinical condition at high risk of bleeding.
  • Substance abuse and any other condition which may interfere with patient's participation in the study or evaluation of study results.
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 Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01620970
Other Study ID Numbers  ICMJE INT01/12
2011-005983-12 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Sponsor  ICMJE Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea Necchi, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Chair: Filippo G De Braud, MD filippo.debraud@istitutotumori.mi.it
Study Director: Alessandro M Gianni, MD University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori
PRS Account Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Verification Date June 2012

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