- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02732678
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)
April 8, 2016 updated by: Assistance Publique Hopitaux De Marseille
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.
Study Overview
Study Type
Interventional
Enrollment (Anticipated)
24
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Sébastien SALAS, MD PhD
- Email: sebatien.salas@ap-hm.fr
Study Locations
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Marseill, France, 13354
- Assistance Publique Hopitaux de Marseille
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
15 years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Factorial Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Cohort of a dose of Propranolol 80 mg/day
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Experimental: Cohort of a dose of Propranolol 120 mg/day
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Experimental: Cohort of a dose of Propranolol 160 mg/day
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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1 month
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Non-progression rate
Time Frame: 3 month
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The efficacy criterion is defined as the non-progression rate at 3 months according to RECIST 1.1 guidelines and with central radiological review.
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3 month
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Sébatien SALAS, MD PhD, Assistance Publique Hopitaux de Marseille
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
May 1, 2016
Primary Completion (Anticipated)
May 1, 2018
Study Completion (Anticipated)
May 1, 2019
Study Registration Dates
First Submitted
March 29, 2016
First Submitted That Met QC Criteria
April 8, 2016
First Posted (Estimate)
April 11, 2016
Study Record Updates
Last Update Posted (Estimate)
April 11, 2016
Last Update Submitted That Met QC Criteria
April 8, 2016
Last Verified
April 1, 2016
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Sarcoma
- Neoplasms, Vascular Tissue
- Hemangiosarcoma
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Propranolol
Other Study ID Numbers
- 2015-005177-21
- 2015-29 (Other Identifier: AP-HM)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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