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A Phase IIa Open Multicenter, Trial, of Treatment With Pazopanib (Multi Tyrosine Kinase Inhibitor) in Dermatofibrosarcomas (DFSP), Unresectable Locally Advanced (Potentially Mutilating Surgery), Primary or Relapsing , Transformed or Not.


Phase 2
20 Years
N/A
Open (Enrolling)
Both
Dermatofibrosarcomas of DARIER FERRAND(DFSP)

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Trial Information

A Phase IIa Open Multicenter, Trial, of Treatment With Pazopanib (Multi Tyrosine Kinase Inhibitor) in Dermatofibrosarcomas (DFSP), Unresectable Locally Advanced (Potentially Mutilating Surgery), Primary or Relapsing , Transformed or Not.


Dermatofibrosarcoma protuberance (DFSP) is a rare soft tissue sarcoma of intermediate
malignant potential. Treatment relies on a wide local excision with negative margin and with
frequent need of reconstructive surgery. A translocation between chromosomes 17 and 22 that
places the platelet-derived growth factor-B (PDGFB) under the control of the collagen 1A1
promoter is present in > 90 % of the cases leading to an up regulation of PDGF-β expression
and activation of the tyrosinase kinase PDGFRβ. Imatinib mesylate has been approved in
unresectable and metastatic DFSP due to its activity on PDGFR. This study will evaluate the
benefit of pazopanib, a multikinase inhibitor in advanced DFSP. Administration of pazopanib
per os 800mg/ qd during 6 months until stable response according to primary endpoint , and
for a period of study not exceeding one year.In case of progression evaluated according to
the primary endpoint after a period of treatment superior to one month, or in the absence of
response at 3 months, the patient will be withdrawn from study, in order to get alternative
therapeutics. These patients will be considered as failures for analysis. After a 6-month
treatment period, and reaching a stable response, treatment continuation decision will be
based on the operability of patients.

Administration of pazopanib per os 800mg/ qd during 6 months until stable response
according to primary endpoint, with 3 monthly successive examinations, and for a period of
study not exceeding 18 months.In case of progression evaluated according to the primary
endpoint after a period of treatment superior to one month, or in the absence of response at
3 months, the patient will be withdrawn from study, in order to get alternative
therapeutics. These patients will be considered as failures for analysis. After a 6-month
treatment period, and reaching a stable response, treatment continuation decision will be
based on the operability of patients Statistical analysis : The trial has been planned using
a one-stage design (Fleming TR. Et al) Analysis of the main endpoint will rely on a
one-sided binomial test comparing the observed response rate to the expected response rate
under the null hypothesis . The type I error rate is fixed at 0.025.For the main endpoint, a
point estimate and a two-sided 90% confidence interval will be presented, which will be
consistent with the one-sided test at a 0.025 level. For secondary endpoints, point
estimates and 95% confidence intervals will be presented.We intend to estimate the
probability of tumour size reduction of at least 30%. The sample size was calculated by
FLEMMING method : Ho will be defined by a RR ≤20% (decrease in tumour size of at least 30%)
, H1 , response rate, 26 patients must be included in order to demonstrate an efficacy as
defined by a RR≥50%, with a 90% power and alfa 2.5% one side.


Inclusion Criteria:



- Primitive unresectable DFSP, locally advanced (potentially mutilating surgery), or in
relapse or transformed.

- Histologic confirmation of the Darier-FERRAND tumour (transformed types will be
accepted provided a previous caryotype confirming the translocation (17,22)

- Age > or equal to 20 years

- Signed informed consent

- Appropriate contraception

- No evolutive tumoural disease except baso-cellular carcinoma

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

Exclusion Criteria:

- Patient refusal to participate

- Age < 20 years

- Pregnant or lactating women

- Other evolutive tumour disease except baso-cellular carcinoma

- Haematologic abnormalities:Hemoglobin < 9g/dl, PNN <

- 1500/mm3, Platelets <100000/mm3

- AST and ALT > 2N

- Bilirubin > 1.5N

- Creatinin > 1.5mg/dL or creatinin clearance <30ml/mn

- Proteinuria >1g/24h

- Serum albumin< 2.5g/dL

- Hepatitis B, C and/or HIV known Infection

- Treatment interfering with pazopanib

- Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks
prior to beginning therapy, or anticipation of the need for a major surgical
procedure during the course of the study.

- Clinically significant gastrointestinal abnormalities including, but not limited
to:Malabsorption syndromeDisease significantly affecting gastrointestinal function or
major resection of the stomach or small bowel that could affect the absorption of
study drug.Active peptic ulcer diseaseInflammatory bowel diseaseUlcerative colitis,
erosive esophagitis or gastritis, infectious or inflammatory bowel disease,
diverticulitis or other gastrointestinal condition increasing the risk of
perforation.History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within 28 days prior to beginning study treatment· Presence
of active or uncontrolled infection.

- Evidence of active bleeding or bleeding diathesis.

- History of any one or more of the following cardiovascular conditions within the past
6 months:Coronary/peripheral artery bypass graft, cardiac angioplasty or
stenting.Myocardial infarction.Severe/unstable angina pectoris.Symptomatic peripheral
vascular disease pulmonary embolism, thromboembolic event, cerebrovascular accident
or transient ischemic attack.Class III or IV congestive heart failure, as defined by
the New York Heart Association

- Cardiovascular disease with NYHA > II

- Poorly controlled hypertension (defined as a systolic blood pressure (SBP) of ≥140
mmHg or diastolic blood pressure (DBP) ≥90 mmHg.

- Following abnormalities on ECG : Q wave, ischemia, QTc > 450 msec, atrioventricular
block 2 or 3, atrial fibrillation

- Therapeutic anticoagulation treatment.

- Chronic daily treatment with aspirin (≥ 100 mg/day) or non-steroidal
anti-inflammatory agents known to inhibit platelet function. Treatment with
dipyridamole, ticlopidine, clopidogrel and/or cilostazol is also not allowed..
Concurrent treatment with an investigational agent or participation in another
clinical trial.

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib.

- Taken by the order treatment anti cancerous concomittants within 4 weeks previous
inclusion

- Radiotherapy on the hurt within 3 months previous inclusion

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Decrease of at least 30% of the biggest diameter measured clinically at 6 months preceded by clinical response

Outcome Time Frame:

at 3 months

Safety Issue:

Yes

Principal Investigator

Celeste LEBBE, MD-PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris

Authority:

France: Ministry of Health

Study ID:

P090402

NCT ID:

NCT01059656

Start Date:

July 2010

Completion Date:

January 2015

Related Keywords:

  • Dermatofibrosarcomas of DARIER FERRAND(DFSP)
  • Dermatofibrosarcoma
  • Pazopanib¨
  • Phase II
  • Dermatofibrosarcoma

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