The primary objective is to determine the clinical response of propranolol monotherapy in patients with angiosarcoma. The secondary endpoint is to assess the pathologic response of propranolol monotherapy in patients with angiosarcoma.
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the clinical response according to RECIST 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. A response is defined as SD, PR or CR with improvement in clinical
characterstics.
Secondary outcome
The secondary endpoint is the histologic response defined as a decrease of >30%
of Ki-67 index between pre- and post-propranolol treatment biopsies.
Background summary
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
malignant vascular tumor, angiosarcoma. These patients with locally advanced or
metastatic angiosarcoma were treated with propranolol, in combination with
various chemotherapy regimens, including combination therapy with
cyclophosphamide and vinblastine based chemotherapy. 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 cutaneous 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 pathological response, without
a significant delay in anti-cancer treatment.
Study objective
The primary objective is to determine the clinical response of propranolol
monotherapy in patients with angiosarcoma. The secondary endpoint is to assess
the pathologic response of propranolol monotherapy in patients with
angiosarcoma.
Study design
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.
In case of hypotension (BP < 90/60 mmHg) or bradycardia (heart rate < 55bpm),
or symptoms of bradycardia or hypotension (dizziness, syncope) the dose will be
reduced to the previous level. In case of serious bradycardia (heart rate <
50bpm) the treatment will be put on hold until an acceptable heart rate > 55
bpm is reached, at which point the dose of the previous level will be
administered.
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.
Intervention
3-6 weeks treatment with propranolol according to the treatment plan as stated
in "study design".
Study burden and risks
Patients will be evaluated on the outpatient clinic on a weekly basis with only
minimal blood draws for safety assessments. Additional burden consist of extra
visits (3-6) including blood draws and physical examination, a dairy for study
medication needs to be filled in, extra biopsy or radiologic assessments will
be done if applicable. The patients are treated with propranolol with a
well-known safety profile.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
oHistological proof of angiosarcoma
oPatients with primary, recurrent and metastasised disease are eligible;
oPatients with a window of at least 3 weeks before surgery or systemic therapy
oAge of 18 years or more;
oAble and willing to give written informed consent;
oWHO performance status of 0, 1 or 2;
oEvaluable disease according to RECIST 1.1 criteria; radiologic visible disease
is not obligated in patients with cutaneous angiosarcoma
oAt least one tumor lesion accessible to safely biopsy per clinical judgement
of the treating physician
Exclusion criteria
o Contraindication for propranolol therapy,
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 Pregnancy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002947-41-NL |
| CCMO | NL71090.031.19 |
| OMON | NL-OMON23603 |