Primary objective: 1) To evaluate the overall response rate (ORR) after 24 weeks of cemiplimab in secondary angiosarcomas, according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or daylight photography as per WHO Offset Publication…
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Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective:
1) To evaluate the overall response rate (ORR) after 24 weeks of cemiplimab in
secondary angiosarcomas, according to Response Evaluation Criteria in Solid
Tumours (RECIST) 1.1 or daylight photography as per WHO Offset Publication No.
48.
Secondary outcome
Secondary objectives:
1) To establish the best ORR of patients with secondary angiosarcomas receiving
cemiplimab.
2) To establish the median time to response (TTR) and duration of response
(DOR) in patients with secondary angiosarcomas receiving cemiplimab.
3) To assess the median progression-free survival (PFS) of patients with
secondary angiosarcomas receiving cemiplimab.
4) To establish the overall survival (OS) of patients with secondary
angiosarcomas receiving cemiplimab.
5) To investigate possible relations between response to cemiplimab and tumour
characteristics (i.e. PD-L1 expression, tumour infiltrating lymphocytes, MYC
status and tumour mutational burden).
6) To assess differences in response to cemiplimab between UV associated and
radiation induced secondary angiosarcomas.
7) To assess effects of cemiplimab on tumour tissue by comparing pre- and
post-treatment biopsies.
8) To quantify toxicity during cemiplimab treatment.
Background summary
Angiosarcomas are aggressive mesenchymal tumours arising from cells with
endothelial properties and belong to the group of soft tissue sarcomas (STS).
Angiosarcomas are rare with an incidence of only 0.1-0.2/100.000/year.
Prognosis is poor with a 5-years specific survival of 30-40% for all stages. In
selected trial patients with metastatic disease the range in median overall
survival was between 5.5-19.5 months. In our real life series, the median
overall survival of 203 primary metastatic angiosarcoma patients diagnosed
between 1989-2014, was only 5 months. For metastatic disease, only chemotherapy
(mostly doxorubicin or paclitaxel) and one targeted drug (pazopanib) is
available. There is need for more treatment options, and for a more effective
treatment.
Angiosarcomas encompass de novo (primary) angiosarcomas and secondary
angiosarcomas, which frequently are located in the skin and arise due to DNA
damaging noxes, like radiotherapy or UV radiation. The clinical behaviour,
genetic and molecular background and clinical outcomes of secondary
angiosarcomas differ from primary angiosarcomas and have similarities to
cutaneous squamous-cell carcinoma cSCC.
Cemiplimab showed impressive results in advanced cSCC. At the ASCO Annual
Meeting 2019, updates were presented of a phase II study. With a median follow
up of 9.3 months, 10 complete and 24 partial responses were observed in 78
patients with locally advanced disease (ORR 44%). Median time to response was
1.9 months and the median duration of response was not yet reached. For
metastatic disease, 10 complete responses and 19 partial responses were
observed in 59 patients (ORR 49%), which was prolonged (> 12 months) in 22
patients and again with a median time to response of 1.9 months. With a median
follow up of 16.5 months, median progression free survival (PFS) was 18.4
months and median overall survival (OS) was not yet reached (ASCO abstract
9526).
At the ASCO Annual Meeting 2020 the latest updates were presented after a
longer follow up of a phase II study. Of the 193 patients treated with
cemiplimab for locally advanced or metastatic cSCC with a median follow up of
15.7 months, ORR was 46.1%. Median DOR was not yet reached. In responding
patients, the estimated proportion of patients with ongoing response at 24
months was 69.4%. In 31 patients (16.1%) a complete response was reported with
a median time to complete response of 11.2 months. Partial response was
reported in 58 patients (30.1%). Median OS was not yet reached, estimated
median PFS was 18.4 months. (ASCO abstract 367) Cutaneous SCC are UV light
associated cancers with subsequently a high mutational load, which explains
this excellent efficacy.
There are anecdotical reports of responses to checkpoint inhibitors in UV
associated secondary angiosarcomas. Moreover, there are several reasons to
expect increased susceptibility of secondary angiosarcomas to immune checkpoint
inhibitors. Secondary angiosarcomas have an increased mutational load, which in
itself make them potentially more sensitive to immunotherapy. As in cSCC,
secondary angiosarcomas have high MYC expression, which is of interest given
the dependency of PD-L1 expression on MYC.
In our preliminary work (29 UV and 27 radiotherapy associated angiosarcomas),
28 (50%) were PD-L1+ (>10%) of which 11 strongly positive (>50%). In 19 samples
PD-1 was also positive. Furthermore, we found 12/56 (21%) MLH1-. 14/56 (25%)
MSH2-, 9/56 (16%) MSH6-, 11/56 (20%) PMS2- and 4/56 (7%) cases negative for all
four markers.
Since the similarities between cSCC and secondary angiosarcomas and the need
for more available and effective treatment options and we here propose a study
with cemiplimab in secondary angiosarcomas.
Study objective
Primary objective:
1) To evaluate the overall response rate (ORR) after 24 weeks of cemiplimab in
secondary angiosarcomas, according to Response Evaluation Criteria in Solid
Tumours (RECIST) 1.1 or daylight photography as per WHO Offset Publication No.
48.
Secondary objectives:
1) To establish the clinical benefit of patients with secondary angiosarcomas
receiving cemiplimab. Clinical benefit is defined as the combined number of
patients with a complete or partial response and stable disease.
2) To establish the median time to response (TTR) and duration of response
(DOR) in patients with secondary angiosarcomas receiving cemiplimab.
3) To assess the median progression-free survival (PFS) of patients with
secondary angiosarcomas receiving cemiplimab.
4) To establish the overall survival (OS) of patients with secondary
angiosarcomas receiving cemiplimab.
5) To investigate possible relations between response to cemiplimab and tumour
characteristics (i.e. PD-L1 expression, tumour infiltrating lymphocytes, MYC
status and tumour mutational burden).
6) To assess differences in response to cemiplimab between UV associated and
radiation induced secondary angiosarcomas.
7) To assess effects of cemiplimab on tumour tissue by comparing pre- and
post-treatment biopsies.
8) To quantify toxicity during cemiplimab treatment.
Study design
This single arm phase II study will be conducted at the Radboudumc and a
maximum of 3 other tertiary sarcoma centres. Patients with locally advanced or
metastatic angiosarcomas, in the first line of treatment unfit for chemotherapy
and patients in advanced lines of treatment can be included. All participating
patients will be treated with cemiplimab every three weeks. In total, 18
patients will be included in this study. After the first 13 patients are
included, a interim analysis will be conducted. If there are 1 or fewer
responses in these 13 patients, the study will be stopped due to ineffectivity.
Otherwise, 5 additional patients will be accrued for a total of 18 patients.
The expected time to include 18 patients is two years. During treatment,
patients will be frequently evaluated (as is also the case in regular
treatment), and side effects and treatment effect will be monitored. Patients
can continue the treatment as long as it effective in treating the disease,
with a maximum of 2 years as is common practice in patients treated with
immunotherapy. The maximum treatment duration is not a limiting factor of this
study, but common practice in treating patients with immunotherapy. Treatment
will be stopped preliminary in case of unacceptable toxicity or ift the
patients decides to stop participation in the study. In case of disease
progression, treatment will also be stopped.
Intervention
In this study we want to evaluate the effect cemiplimab, a known drug
registered for another type of cancer, in patients with locally advanced or
metastatic secondary angiosarcomas. Patients in the first line of treatment
unfit for chemotherapy and patients in advanced lines of treatment will be
included. Treatment will continue until disease progression, unacceptable
toxicity or until withdraw of informed consent.
Patients will be treated with cemiplimab 350mg every three weeks, the
registered dose and time intervall for patients with cutaneous squamous cell
carcinoma.
Study burden and risks
Adverse events of cemiplimab may occur. Cemiplimab is registered as a treatment
for cutaneous squamous cell carcinomas, and dosing and toxicity have been
evaluated in phase I-II studies for this indication. In our study we will treat
patients with the registered dose of cemiplimab. Follow up of the study during
therapy will include laboratory research, regular visits to the outpatient
clinic and evaluation using CT- or MRI-scan (if not possible, daylight
photography will be used). Additional research blood samples will be taken
during regular visits to the outpatient clinic, together with standard safety
lab. A tumour biopsy will be taken at baseline and after 12 weeks of treatment.
Due to the etiology of secondary angiosarcomas, this will usually be a
minimally invasive dermatological biopsy. Per biopsy, two tissue samples will
be collected. The risk is considered low. A tumour biopsy will be taken at end
of treatment if a patient specifically signed informed consent for this.
Follow-up after the end treatment (maximum 2 years as is common practice in
treating patients with immumotherapy), in case of disease progression or
discontinuation due to toxicity or after withdrawal of consent or other reason
will be every 12 weeks (to check for Adverse Events and survival). Additional
blood will be drawn for translational research purposes, Blood collection will
be done during regular treatment visits so no additional venapunctures are
required. Microbiome research requires that patients provide feces for
translational research purposes. This will be asked four times during the
treatment. It will be accompanied with by a questionaire asking about recent
medication use, diet and stool consistency. No lifestile interventions ore
other personal questons are part of this research. At several timepoints,
patients will be asked to fill out a questionnaire about the quality of life.
This is the QLQ-C30 validated questionnaire of the EORTC.
Geert Grooteplein Zuid 10
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
1. Adult patient aged >= 18 years.
2. Signed written informed consent.
3. Histologically confirmed diagnosis of progressive unresectable locally
advanced or metastatic secondary angiosarcoma.
4. Patients in the first line of systemic treatment unfit for chemotherapy and
patients in advanced lines of systemic treatment
5. Measurable disease per RECIST 1.1 or per physical examination / daylight
photography (WHO Offset Publication No. 48) as determined by the investigator.
6. Tumour tissue material available (archival or recent tumour biopsy).
7. WHO ECOG 0-2.
8. Hepatic function:
a. Total bilirubin <= 1.5 x ULN (if liver metastases: <= 3 x ULN).
b. Transaminases <= 3 x ULN (if liver metastases: <= 5 x ULN).
c. Patients with Gilbert*s Disease and total bilirubin up to 3x ULN may be
eligible after communication with and approval from the medical monitor
d. Alkaline phosphatase <= 2.5 x ULN (if liver OR bone metastases <=5 x ULN).
9. Renal function: serum creatinine <= 2 x ULN or estimated CrCl > 30 mL/min.
10. Creatine phosphokinase (CPK) (also known as CK [creatine kinase]) elevation
<= grade 2
11. Bone marrow function:
a. Hemoglobulin >= 9.0 g/dL.
b. ANC >= 1.5 x 109/L.
c. Platelet count >= 75 x 109/L.
12. Expected life expectancy of at least 3 months as judged by the
investigator.
Exclusion criteria
1. Ongoing or recent (within 5 years) evidence of significant autoimmune
disease that required treatment with systemic immunosuppressive treatments,
which may suggest risk for irAEs. The following are not exclusionary: vitiligo,
childhood asthma that has resolved, type 1 Diabetes mellitus, residual
hypothyroidism that required only hormone therapy, or psoriasis that does not
require systematic treatment.
2. Prior treatment with immune checkpoint inhibitors.
3. Continuous immunosuppressive corticosteroid treatment (doses > 10 mg
prednisone daily or equivalent) within 4 weeks prior to the first dose of
cemiplimab. Note: patients who require a brief course of steroids (e.g. as
prophylaxis for imaging studies) are not excluded.
4. Active uncontrolled infection requiring therapy, including infection with
HIV, active infection with HBV or HCV.
5. History of pneumonitis within the last 5 years.
6. Untreated brain metastasis(es) that may be considered active.
a. Note in clarification: Patients with previously treated brain metastases may
participate provided that the lesion(s) is (are) stable (without evidence of
progression for at least 6 weeks on imaging obtained in the screening period),
and there is no evidence of new or enlarging brain metastases, and the patients
do not require any immunosuppressive doses of systemic corticosteroids for
management of brain metastasis(es) within 28 days of the first dose of
cemiplimab.
7. Patients with allergy or hypersensitivity to cemiplimab or to any of the
excipients must be excluded. Specifically, because of the presence of trace
components in cemiplimab, patients with allergy or hypersensitivity to
doxycycline or tetracycline are excluded.
8. History of documented allergic reactions or acute hypersensitivity reaction
attributed to antibody treatments
9. Patients with a history of solid organ transplant (patients with prior
corneal transplants may be allowed to enroll after discussion with and approval
from the medical monitor).
10. Any anticancer treatment other than radiation therapy (chemotherapy,
targeted systemic therapy, imiquimod, photodynamic therapy), investigational or
standard of care, within 30 days of the initial administration of cemiplimab or
planned to occur during the study period
11. Receipt of live vaccines (including attenuated) within 30 days of first
study treatment
12. Prior use of PI3K-D inhibitors
13. Women of childbearing potential (WOCBP)*, or sexually active men, who are
unwilling to practice highly effective contraception prior to the initial
dose/start of the first treatment prior to the start of the first treatment,
during the study, and for at least 6 months after the last dose.
14. Breastfeeding
15. Positive serum pregnancy test (a false positive pregnancy test, if
demonstrated by serial measurements and negative ultrasound, will not be
exclusionary, upon communication with and approval from the medical monitor)
16. Any other condition that might interfere with experimental treatment and
the study procedures as judged by the investigator.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005465-13-NL |
| ClinicalTrials.gov | NCT04873375 |
| CCMO | NL74804.091.21 |