PF-03446962 in Relapsed or Refractory Urothelial Cancer

NCT ID: NCT01620970

Last Updated: 2021-05-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-01
• Study Completion Date: 2013-06-01

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.

Conditions

Transitional Cell Carcinoma of Bladder

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PF03446962

Investigational study drug, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

PF03446962

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

OTHER

Sponsor Role: lead

Responsible Party

Andrea Necchi

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea Necchi, MD

Role: PRINCIPAL_INVESTIGATOR

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Filippo G De Braud, MD

Role: STUDY_CHAIR

filippo.debraud@istitutotumori.mi.it

Alessandro M Gianni, MD

Role: STUDY_DIRECTOR

University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori

Locations

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

Countries

Italy

References

Hu-Lowe DD, Chen E, Zhang L, Watson KD, Mancuso P, Lappin P, Wickman G, Chen JH, Wang J, Jiang X, Amundson K, Simon R, Erbersdobler A, Bergqvist S, Feng Z, Swanson TA, Simmons BH, Lippincott J, Casperson GF, Levin WJ, Stampino CG, Shalinsky DR, Ferrara KW, Fiedler W, Bertolini F. Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Res. 2011 Feb 15;71(4):1362-73. doi: 10.1158/0008-5472.CAN-10-1451. Epub 2011 Jan 6.

Reference Type: BACKGROUND

PMID: 21212415 (View on PubMed)

Necchi A, Giannatempo P, Mariani L, Fare E, Raggi D, Pennati M, Zaffaroni N, Crippa F, Marchiano A, Nicolai N, Maffezzini M, Togliardi E, Daidone MG, Gianni AM, Salvioni R, De Braud F. PF-03446962, a fully-human monoclonal antibody against transforming growth-factor beta (TGFbeta) receptor ALK1, in pre-treated patients with urothelial cancer: an open label, single-group, phase 2 trial. Invest New Drugs. 2014 Jun;32(3):555-60. doi: 10.1007/s10637-014-0074-9. Epub 2014 Feb 26.

Reference Type: DERIVED

PMID: 24566706 (View on PubMed)

Other Identifiers

2011-005983-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

INT01/12

Identifier Type: -

Identifier Source: org_study_id