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)
Primary Purpose
Angiosarcoma
Status
Unknown status
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
PROPRANOLOL
Sponsored by
About this trial
This is an interventional treatment trial for Angiosarcoma
Eligibility Criteria
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
Sites / Locations
- Assistance Publique Hôpitaux de Marseille
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Cohort of a dose of Propranolol 80 mg/day
Cohort of a dose of Propranolol 120 mg/day
Cohort of a dose of Propranolol 160 mg/day
Arm Description
Outcomes
Primary Outcome Measures
toxicity of each tested propranolol dose level in association to cyclophosphamide assessed according to NCI-CTC AE Version 4.0
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
The efficacy criterion is defined as the non-progression rate at 3 months according to RECIST 1.1 guidelines and with central radiological review.
Secondary Outcome Measures
Full Information
NCT ID
NCT02732678
First Posted
March 29, 2016
Last Updated
April 8, 2016
Sponsor
Assistance Publique Hopitaux De Marseille
1. Study Identification
Unique Protocol Identification Number
NCT02732678
Brief Title
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)
Acronym
PROPAN
Study Type
Interventional
2. Study Status
Record Verification Date
April 2016
Overall Recruitment Status
Unknown status
Study Start Date
May 2016 (undefined)
Primary Completion Date
May 2018 (Anticipated)
Study Completion Date
May 2019 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique Hopitaux De Marseille
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Angiosarcoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort of a dose of Propranolol 80 mg/day
Arm Type
Experimental
Arm Title
Cohort of a dose of Propranolol 120 mg/day
Arm Type
Experimental
Arm Title
Cohort of a dose of Propranolol 160 mg/day
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
PROPRANOLOL
Primary Outcome Measure Information:
Title
toxicity of each tested propranolol dose level in association to cyclophosphamide assessed according to NCI-CTC AE Version 4.0
Description
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.
Time Frame
1 month
Title
Non-progression rate
Description
The efficacy criterion is defined as the non-progression rate at 3 months according to RECIST 1.1 guidelines and with central radiological review.
Time Frame
3 month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sébastien SALAS, MD PhD
Email
sebatien.salas@ap-hm.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Urielle Desalbres
Organizational Affiliation
Assistance Publique Hôpitaux de Marseille
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Sébatien SALAS, MD PhD
Organizational Affiliation
Assistance Publique Hôpitaux de Marseille
Official's Role
Principal Investigator
Facility Information:
Facility Name
Assistance Publique Hôpitaux de Marseille
City
Marseill
ZIP/Postal Code
13354
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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)
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