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Dose-Finding of Propranolol in Combination With Metronomic Fixed Oral Cyclophosphamide Based on Bivariate Efficacy-tolerability Outcome in Patients With Locally Advanced or Metastatic Angiosarcoma: A Collaborative and Innovative Phase I-II Sequential Trial by the French Sarcoma Group (GSF/GETO) (PROPAN)

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ClinicalTrials.gov Identifier: NCT02732678
Recruitment Status : Unknown
Verified April 2016 by Assistance Publique Hopitaux De Marseille.
Recruitment status was:  Not yet recruiting
First Posted : April 11, 2016
Last Update Posted : April 11, 2016
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille

Tracking Information
First Submitted Date  ICMJE March 29, 2016
First Posted Date  ICMJE April 11, 2016
Last Update Posted Date April 11, 2016
Study Start Date  ICMJE May 2016
Estimated Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2016)
  • toxicity of each tested propranolol dose level in association to cyclophosphamide assessed according to NCI-CTC AE Version 4.0 [ Time Frame: 1 month ]
    The toxicity of propranolol is well described on humans as well as its pharmacokinetic (Peak plasma concentrations occur about 1 to 4 hours) after oral dose and pharmacodynamics characteristics with the main target on beta-adrenergic receptor (blocking agent possessing no other autonomic nervous system activity). In this study the toxicity of each tested propranolol dose level in association to cyclophosphamide will be assessed according to NCI-CTC AE Version 4.0 at 1 month (Recording AE, Blood pressure, and electrocardiography). A dose-limiting toxicity (DLT) will be considered as any grade 3 or higher specially cardiac and hematologic but also non-hematologic toxicity that is probably or definitely related to treatment.
  • Non-progression rate [ Time Frame: 3 month ]
    The efficacy criterion is defined as the non-progression rate at 3 months according to RECIST 1.1 guidelines and with central radiological review.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-Finding of Propranolol in Combination With Metronomic Fixed Oral Cyclophosphamide Based on Bivariate Efficacy-tolerability Outcome in Patients With Locally Advanced or Metastatic Angiosarcoma: A Collaborative and Innovative Phase I-II Sequential Trial by the French Sarcoma Group (GSF/GETO)
Official Title  ICMJE Not Provided
Brief Summary Adrenergic processes stimulated by epinephrine and norepinephrine drive to the development of tumor growth and metastasis. Beta-adrenergic receptor (BAR) antagonists have shown efficacy against melanoma, breast cancer and prostate cancer. The non-specific BAR inhibitor propranolol has been used as the gold standard treatment in pediatric patients with benign infantile hemangioma which express high levels of beta adrenergic receptors potentially explaining their sensitively to propranolol. BAR have been shown to be expressed across a diverse panel of vascular tumors, with the highest expression in malignant vascular tumors including angiosarcoma. Several reports indicate positive results from beta-blockade in patients with moderately threatening vascular tumors. It remains to be determined if more malignant vascular tumor such as the angiosarcomas are susceptible to propranolol. Besides, due to the lack of adequate therapies for angiosarcoma (doxorubicin or paclitaxel and finally cyclophosphamide in third line) and to the poor prognosis of this rare and aggressive tumor, there is a strong need for the development of treatments against this tumor type. Recently using a panel of angiosarcoma cell lines. demonstrate that beta-adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Moreover, using in vivo tumor models they demonstrate that propanolol shows remarkable efficacy in reducing the growth of angiosarcoma tumors. Based on these proofs of mechanisms in vitro and in vivo and due to the well established safety propranolol in humans, investigators propose to determine among a wide range of propranolol dose (80 mg/d ; 120 mg/d and 160 mg/d) the optimal one based on bivariate efficacy-toxicity outcome in patients with angiosarcoma treated by cyclophosphamide. Because these two drugs have different pharmacological mechanisms, the aim is to determine the optimal dose of propranolol having the best systemic cardiovascular tolerability and the best potential antiangiogenic effect in addition with cyclophosphamide.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Angiosarcoma
Intervention  ICMJE Drug: PROPRANOLOL
Study Arms  ICMJE
  • Experimental: Cohort of a dose of Propranolol 80 mg/day
    Intervention: Drug: PROPRANOLOL
  • Experimental: Cohort of a dose of Propranolol 120 mg/day
    Intervention: Drug: PROPRANOLOL
  • Experimental: Cohort of a dose of Propranolol 160 mg/day
    Intervention: Drug: PROPRANOLOL
Publications * Not Provided

*   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: April 8, 2016)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2019
Estimated Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adolescent > 15 years with a body surface >1,6 m2
  • Histologically proven angiosarcoma, reviewed by an independent pathologist, with metastasis or locally advanced stage not amenable to radiotherapy or curative-intent surgery after multidisciplinary decision ;
  • Prior systemic treatment with paclitaxel or doxorubicin
  • At least one lesion measurable according to the RECIST, version 1.1;
  • No brain or meningeal metastasis;
  • No more than two prior lines of chemotherapy (whatever the indication);
  • A World Health Organization performance status score ≤2;
  • Neutrophils count > 1000 /mm3, platelets count ≥100,000/mm3, hemoglobin level ≥ 8 g/Dl, liver transaminases ≤1.5 XULN, total bilirubin ≤1.5X ULN, serum creatinine≤1.5XULN, and amylase and lipase≤1.5XULN

Exclusion Criteria:

  • Pregnant or breast-feeding women.
  • Subject with a contraindication to propranolol (ie cardiogenic shock; sinus bradycardia and greater than first-degree block; Chronic Obstructive Pulmonary Disease and bronchial asthma; patients with known hypersensitivity to Propranolol; assessed by cardiovascular and pulmonary history and examinations including blood pressure, ECG; untreated Pheochromocytoma, Congestive heart failure not controlled by treatment, Prinzmetal's angina)
  • Subject with Severe Raynaud Phenomena or Raynaud Disease
  • Subject with Prior systemic treatment with Cyclophosphamide as 1st or 2nd line
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, 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 France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02732678
Other Study ID Numbers  ICMJE 2015-005177-21
2015-29 ( Other Identifier: AP-HM )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique Hopitaux De Marseille
Study Sponsor  ICMJE Assistance Publique Hopitaux De Marseille
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Urielle Desalbres Assistance Publique Hôpitaux de Marseille
Principal Investigator: Sébatien SALAS, MD PhD Assistance Publique Hôpitaux de Marseille
PRS Account Assistance Publique Hopitaux De Marseille
Verification Date April 2016

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