AngiosarcomaPhase 1/2PROPANNCT02732678
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)
A Phase 1/2 study testing PROPRANOLOL in people with Angiosarcoma, run by Assistance Publique Hopitaux De Marseille at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Angiosarcoma
- What is being tested?
- PROPRANOLOL
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteFrance
- Study dates
- May 2016to May 2019
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Sébastien SALAS, MD PhD contact
About this study
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.
- Conditions
- Angiosarcoma
- Being tested
- PROPRANOLOL
- Medical subject headings
- Hemangiosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PROPRANOLOLDrug
| Study group | Role | What they receive |
|---|---|---|
| Cohort of a dose of Propranolol 80 mg/day | Experimental | Not described Receives: Drug: PROPRANOLOL |
| Cohort of a dose of Propranolol 120 mg/day | Experimental | Not described Receives: Drug: PROPRANOLOL |
| Cohort of a dose of Propranolol 160 mg/day | Experimental | Not described Receives: Drug: PROPRANOLOL |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 1 month
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.
Measured: 3 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2016 (estimated)
- Study startMay 2016
- Primary completionMay 2018 (estimated)
- Study completionMay 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AngiosarcomaStudies of the same condition, open and under way.
- More trials run by Assistance Publique Hopitaux De MarseilleThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique Hopitaux De Marseille
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Urielle Desalbres, Study director, Assistance Publique Hôpitaux de MarseilleSébatien SALAS, MD PhD, Principal investigator, Assistance Publique Hôpitaux de Marseille
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02732678
- Sponsor's protocol ID
- 2015-005177-21
- Other IDs
- 2015-29, 2015
- Acronym
- PROPAN
- Status last verified
- Apr 2016
- First submitted
- 29 Mar 2016
- Last updated
- 11 Apr 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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)
- ClinicalTrials.gov ID
- NCT02732678
- Acronym / sponsor ID
- PROPAN / 2015-005177-21
- Conditions
- Angiosarcoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Assistance Publique Hopitaux De MarseilleUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- May 2018 (estimated)
- Study completion
- May 2019 (estimated)
- First posted
- 11 Apr 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort of a dose of Propranolol 80 mg/day | Experimental | Drug: PROPRANOLOL |
| Cohort of a dose of Propranolol 120 mg/day | Experimental | Drug: PROPRANOLOL |
| Cohort of a dose of Propranolol 160 mg/day | Experimental | Drug: PROPRANOLOL |
Who may qualify
- Ages
- 15 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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;
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PROPRANOLOL | Drug | Cohort of a dose of Propranolol 120 mg/day, Cohort of a dose of Propranolol 160 mg/day, Cohort of a dose of Propranolol 80 mg/day |
Primary outcome
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2016.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sébastien SALAS, MD PhD contact
Urielle Desalbres study director
Assistance Publique Hôpitaux de Marseille
Sébatien SALAS, MD PhD principal investigator
Assistance Publique Hôpitaux de Marseille
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PROPRANOLOL in people with Angiosarcoma, run by Assistance Publique Hopitaux De Marseille at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sébastien SALAS, MD PhD (sebatien.salas@ap-hm.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Apr 2016.