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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. 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
Information provided by (Responsible Party):
Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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.

Condition or disease Intervention/treatment Phase
Transitional Cell Carcinoma of Bladder Drug: PF03446962 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Study Start Date : July 2012
Estimated Primary Completion Date : January 2013
Estimated Study Completion Date : October 2013

Arm Intervention/treatment
Experimental: PF03446962
Investigational study drug, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.
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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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.

  2. RECIST response-rate [ Time Frame: 2-month ]
    Assessment of response-rate by RECIST v1.1 criteria. RR (%) = CR + PR

  3. 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).

  4. 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.

Information from the National Library of Medicine

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

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.

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 identifier (NCT number): NCT01620970

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Contact: Andrea Necchi, MD +39-02-2390-2402
Contact: Patrizia Giannatempo, MD +39-02-2390-2407

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Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, Italy, 20133
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
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Principal Investigator: Andrea Necchi, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Chair: Filippo G De Braud, MD
Study Director: Alessandro M Gianni, MD University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Andrea Necchi, Principal Investigator, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Identifier: NCT01620970    
Other Study ID Numbers: INT01/12
2011-005983-12 ( EudraCT Number )
First Posted: June 15, 2012    Key Record Dates
Last Update Posted: June 15, 2012
Last Verified: June 2012
Keywords provided by Andrea Necchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
Transitional Cell Carcinoma
Metastatic disease
Bladder tumors, Recurrent
Transforming growth factor beta
Activin receptor like kinase 1
Monoclonal Antibody
Locally advanced or metastatic disease
Failure of one platinum-based chemotherapy
Measurable disease
Additional relevant MeSH terms:
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Carcinoma, Transitional Cell
Urinary Bladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases