To determine the clinical and histologic response of propranolol monotherapy in patients with angiosarcoma.
ID
Bron
Verkorte titel
Aandoening
Angiosarcoma
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
The primary endpoint is the clinical response according to RECIST 1.1 criteria.
If propranolol leads to a response in ≥3 out of 14 patients, this treatment modality is highly interesting and should be tested further in a randomized trial. If propranolol leads to a response in ≥3 out of 14 patients, this treatment modality is highly interesting and should be tested further in a randomized trial. A response is defined as CR, PR, or SD with an improvement in clinical characteristics, like thickness, erythema, necrosis or edema of the inflicted area.
Achtergrond van het onderzoek
Rationale:
Propranolol hydrochloride, a β-blocker, has recently been repurposed against a benign vascular tumor called hemangioma with 88% complete or near complete resolution of the treated lesions. Also, several small case reports/series have suggested that propranolol could be repurposed to treat locally advanced or metastatic angiosarcoma. These patients were treated with propranolol, in combination with various chemotherapy regimens, such as cyclophosphamide and vinblastine. Preclinical studies have demonstrated synergy between propranolol in combination with vinblastine in in vitro angiosarcoma models. A reduction in proliferation index of angiosarcoma has also been reported in response to propranolol monotherapy in one patient.
In terms of safety in cancer patients, propranolol has been or is being used in more than 20 clinical oncology trials, including one clinical trial in advanced angiosarcoma in combination with cyclophosphamide (NCT02732678) with no major safety concerns when cardiovascular monitoring is performed (i.e. dose adapted to blood pressure and heart rate).
Since there is few data available regarding the activity and mechanism of action of propranolol as a single agent for angiosarcoma, both in the primary and metastatic setting, our goal is to evaluate the activity in a window study in angiosarcoma patients in a neoadjuvant setting before they proceed with the standard anti-cancer treatment.
The goal of this neoadjuvant window of opportunity study is therefore to prospectively evaluate the activity of propranolol in the clinical setting as monotherapy, where the neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in anti-cancer treatment.
Objectives:
The primary objective is to determine the clinical response of propranolol monotherapy in patients with angiosarcoma. The secondary endpoint is to assess the histologic response of propranolol monotherapy in patients with angiosarcoma.
Study design:
Single-arm neoadjuvant window of opportunity phase II study to explore the activity of propranolol monotherapy in angiosarcoma.
Treatment:
Propranolol monotherapy 40-80 mg BID or TID if tolerated.
Treatment plan*:
Dose escalation of propranolol before standard anti-cancer treatment Propranolol (tablet, 40 mg)
Day 1 – Day 7 1 x 40 mg, 2x/day
Day 8 – Day 14 2 x 40 mg, 2x/day
Day 15 – Day of surgery or biopsy 2 x 40 mg, 3x/day
Tapering of propranolol post- surgery/biopsy Propranolol (tablet, 40 mg)
Day 1 post-surgery/biopsy - Day 7 post-surgery/biopsy 2 x 40 mg, 2x/day
Day 8 post-surgery/biopsy - Day 14 post-surgery/biopsy 1 x 40 mg, 2x/day
*Propranolol will be increased to the next dose level if heart rate is >60, systolic blood pressure (BP) is >110 and previous dose is well tolerated.
Duration/schedule:
When patients are diagnosed, standard anti-cancer treatment must be scheduled within 6 weeks. Since propranolol treatment can start immediately after the diagnosis and will be continued until the day the patient starts with the standard anti-cancer treatment, this is a so-called window of opportunity study. The duration of study treatment will be 3-6 weeks.
Doel van het onderzoek
To determine the clinical and histologic response of propranolol monotherapy in patients with angiosarcoma.
Onderzoeksopzet
The primary and secondary endpoints will be determined after 3-6 weeks of study treatment.
Onderzoeksproduct en/of interventie
propranolol monotherapy
Publiek
Wetenschappelijk
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
o Histological proof of angiosarcoma
o Patients with primary, recurrent and metastasised disease are eligible;
o Patients with a window of at least 3 weeks before surgery or systemic therapy;
o Age ≥18 years;
o Able and willing to give written informed consent;
o WHO performance status of 0, 1 or 2;
o Evaluable disease according to RECIST 1.1 criteria; radiologic visible disease is not obligated
o Minimal acceptable safety laboratory values
o ANC of ≥ 1.5 x 109 /L
o Platelet count of ≥ 100 x 109 /L
o Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ASAT and ALAT ≤ 2.5 x ULN
o Renal function as defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula);
o At least one tumor lesion accessible to safely biopsy per clinical judgement of the treating physician
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
o Contraindication for propranolol therapy, like severe hypotension or bradycardia, sick-sinus syndrome, second or third grade heart block, cardiogenic shock, untreated heart failure, severe peripheral vascular disease asthma or other obstructive lung diseases, untreated pheochromocytoma, metabolic acidosis, prolonged fasting.
o Current treatment with β-blockade therapy.
o Any anticancer treatment within 30 days prior to receiving the first dose of investigational treatment; with the exception of hormonal therapy for breast cancer.
o Concurrent treatment with an anticancer therapy: with the exception of hormonal therapy for breast cancer.
o Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;
o Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications;
o Pregnancy;
o Legal incapacity.
Opzet
Deelname
Voornemen beschikbaar stellen Individuele Patiënten Data (IPD)
Toelichting
Opgevolgd door onderstaande (mogelijk meer actuele) registratie
Andere (mogelijk minder actuele) registraties in dit register
Geen registraties gevonden.
In overige registers
| Register | ID |
|---|---|
| NTR-new | NL8118 |
| CCMO | NL71090.031.19 |
| OMON | NL-OMON49514 |