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An Exploratory Phase I Study With Sorafenib in Addition to Vinflunine in Progressive Locally Advanced or Metastatic Transitional Cell Carcinoma of the Urothelial Tract


Phase 1
18 Years
80 Years
Open (Enrolling)
Both
Urothelial Cancer, Bladder Cancer, Renal Pelvis Cancer, Ureter Cancer, Urethra Cancer

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Trial Information

An Exploratory Phase I Study With Sorafenib in Addition to Vinflunine in Progressive Locally Advanced or Metastatic Transitional Cell Carcinoma of the Urothelial Tract


Objectives

- To explore the safety of sorafenib in combination with vinflunine in patients with
transitional cell carcinoma of the urothelial tract and to define a recommended phase
II dose for this treatment combination

- To correlate early tracer 18F-FDG-PET/CT functional imaging readouts with standard
RECIST (version 1.1) evaluations with the intention to explore new endpoints for
targeted therapy

- To find predictive tumour tissue biomarkers for sorafenib/vinflunine treatment

- To evaluate serum and urine markers of apoptosis as potential markers of
sorafenib/vinflunine treatment

Rationale/Goal

To evaluate the tolerability and activity of sorafenib combined with vinflunine in patients
with advanced or metastatic urothelial cancer.

Tumour biopsies will be collected before and after one cycle of therapy. The translational
part of this study aims to explore the predictive value of a number of biomarkers related to
the targeted properties of sorafenib and presumptive markers for vinflunine treatment.

In addition, the predictive value of an early functional imaging tracer 18F-FDG-PET/CT will
be evaluated.


Inclusion Criteria:



- signed informed consent;

- histologically confirmed transitional cell (pure or mixed histology including
transitional cell carcinoma are allowed) carcinoma of the urothelial tract;

- patients who have received neoadjuvant or adjuvant platinum-containing chemotherapy
and who are diagnosed with locoregional recurrent or metastatic disease prior to or
at the 6-months‟ visit , are eligible or

- patients who have received palliative platinum-containing chemotherapy and who are
diagnosed with progression prior to or at the 6-months‟ visit, are eligible or

- patients who have contraindication to platinum-containing chemotherapy;

- previous systemic chemotherapy must have been stopped 14 days before the inclusion
with recovery (G1 or less) from any treatment related toxicity;

- measurable and/or non-measurable disease using RECIST and defined as: Measurable
disease: lesions that can be measured in at least one dimension and which have not
been previously irradiated. Longest diameter 20 mm with conventional techniques or 10
mm with spiral CT scan or MRI. Non-measurable disease: lesions which have not been
previously irradiated, or longest diameter <20 mm with conventional techniques or <10
mm with spiral CT scan or MRI, or truly non measurable lesions including bone
lesions, ascites, pleural/pericardial effusion, and lymphangitis cutis/pulmonitis;

- age 18 up to 80 years;

- ECOG / WHO Performance Status (PS) ≤1;

- haematological function: haemoglobin ≥100 g/L absolute neutrophil count 1.0 x LL
(lower limit of normal value) platelets 100 x 109/L;

- hepatic function: bilirubin <1.5 x ULN*, transaminases <2.5 x ULN*

*ULN = upper limit of normal value

- renal function: creatinine clearance 40 ml/min (measured by either iohexol clearance
or Cr-EDTA technique);

- Clinically normal cardiac function based on ejection fraction (LVEF assessed by MUGA
or ECHO, LVEF ≥50%);

- able to swallow and retain oral medication;

- previous treatment related toxicity must be grade ≤1 at time of inclusion and no
presence of asthenia, hand-foot skin reaction or rash grade >1 (NCI CTCAE v4.0) at
enrolment;

- no known or suspected allergy to the investigational agent or any agents given in
association with this trial;

Exclusion Criteria:

- non-transitional cell carcinoma of the urothelial tract (e.g. pure adenocarcinoma or
squamous cell carcinoma);

- prior treatment with vinflunine;

- diagnosed brain metastases or leptomeningeal involvement. Brain CT-scans or MRI are
not required unless there is clinical suspicion of central nervous system
involvement.

- peripheral neuropathy G3 (NCI CTCAE v4.0);

- history of serious or concurrent illness or uncontrolled medical disorder; any
medical condition that might be aggravated by treatment or which could not be
controlled: active infection requiring antibiotics within 2 weeks before the study
inclusion, unstable diabetes mellitus, uncontrolled hypercalcaemia >2.9 mmol/L (or
>G2 NCI CTCAE v4.0), concurrent congestive heart failure NYHA (class III-IV) or any
type of angina pectoris and/or a diagnosis of myocardial infarction during the
previous 6 months and/or poorly controlled hypertension will be excluded, QTc >450 ms
at baseline, additional risk factors for Torsade de Pointes (heart failure and
hypokalemia (≥G1, i.e. P-K cardiac arrhythmias requiring anti-arrhythmics (excluding beta-blockers or digoxin
for chronic atrial fibrillation);

- patients having received more than one previous systemic chemotherapy for advanced or
metastatic disease;

- patients who have received any other investigational or anti-cancer therapy 14 days
before the inclusion;

- other malignancies, except adequately treated basal carcinoma of the skin or in-situ
cervix carcinoma or incidental prostate cancer (T1a, Gleason score ≤6, PSA <0.5
ng/ml), or any other tumour with a disease free survival of ≥5 years;

- pregnant or lactating women;

- men or women of childbearing potential not employing adequate contraception;

- any psychological, familial, sociological, or geographical condition which does not
permit protocol compliance and medical follow-up.

- poorly controlled hypertension. At baseline, blood pressure >150/90 is defined as
poorly controlled.

- renal dysfunction: creatinine clearance <40 ml/min measured by either iohexol
clearance or Cr-EDTA technique.

- ECOG / WHO Performance Status ≥2

- presence of hand-foot skin reaction or rash >G1 at enrolment;

- known or suspected allergy to the investigational agent or any agents given in
association with this trial;

- current medical treatment with any compound that prolongs QTc

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of patients with adverse events

Outcome Description:

Primary endpoint: Define the recommended phase II dose (RPTD) by the number of dose limiting toxicity events (recorded during treatment cycle 1 and 2)

Outcome Time Frame:

6 weeks

Safety Issue:

Yes

Principal Investigator

Anders Ullén, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dept of Oncology, Karolinska University Hospital

Authority:

Sweden: Medical Products Agency

Study ID:

NUCOG III

NCT ID:

NCT01844947

Start Date:

June 2012

Completion Date:

September 2014

Related Keywords:

  • Urothelial Cancer
  • Bladder Cancer
  • Renal Pelvis Cancer
  • Ureter Cancer
  • Urethra Cancer
  • Urinary Bladder Neoplasms
  • Carcinoma
  • Carcinoma, Transitional Cell
  • Kidney Neoplasms
  • Ureteral Neoplasms
  • Urethral Neoplasms
  • Pelvic Neoplasms

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