Cemiplimab for Secondary Angiosarcomas

Study design: A prospective, interventional, non-randomized, multicenter, phase II clinical trial.

Hypothesis:

Cemiplimab is registered for the use in patients with cutaneous squamous-cell carcinoma. In these patient groups cemiplimab showed impressive results. There are numerous similarities between cutaneous squamous-cell carcinoma and secondary angiosarcomas. Based on these similarities, including a complex genetic background, PD-L1 expression and MYC expression, the investigators hypothesize that cemiplimab might be an effective treatment for locally advanced and metastatic secondary angiosarcomas.

Primary Objective:

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:

Secondary objectives include the establishment of the best ORR, median time to response, duration of response and progression free survival. The secondary objectives also comprise safety and toxicity quantification and to investigate the relation between response to cemiplimab and various tumor characteristics.

Study Population:

Patients eligible for inclusion are at least 18 years of age, with adequate organ function, who have a histologically confirmed diagnosis of progressive unresectable locally advanced or metastatic secondary angiosarcoma. Patients eligible are patients in the first line of treatment if they are unfit for chemotherapy and patients in advanced lines of systemic treatment. Major exclusion criteria include significant ongoing autoimmune disease that requires immunosuppressive treatment, prior treatment with immune checkpoint inhibitors, active uncontrolled infections or recent pneumonitis. All patients will provide Informed Consent prior to inclusion in the study and during the course of the trial, al relevant data will be stored in electronic Case Report Forms (eCRF).

Treatment Schedule:

After study inclusion, patients will be treated with Cemiplimab 350mg intravenously every three weeks. Patients will receive treatment until disease progression or discontinuation due to unacceptable toxic effects, withdrawal of consent or other reasons. The maximum treatment period will be two years, as is standard of care for patients treated with immunotherapy.

Inclusion criteria

• Adult patient aged ≥ 18 years.
• Signed written informed consent.
• Histologically confirmed diagnosis of progressive unresectable locally advanced or metastatic secondary angiosarcoma.
• Patients in the first line of systemic treatment unfit for chemotherapy and patients in advanced lines of systemic treatment.
• Measurable disease per RECIST 1.1 or per physical examination / daylight photography (WHO Offset Publication No. 48) as determined by the investigator.
• Tumour tissue material available (archival or recent tumour biopsy).
• WHO ECOG 0-2.
• Hepatic function:

• Total bilirubin ≤ 1.5 x ULN (if liver metastases: ≤ 3 x ULN).
• Transaminases ≤ 3 x ULN (if liver metastases: ≤ 5 x ULN).
• Patients with Gilbert's Disease and total bilirubin up to 3x ULN may be eligible after communication with and approval from the medical monitor
• Alkaline phosphatase ≤ 2.5 x ULN (if liver OR bone metastases ≤5 x ULN).
• Renal function: serum creatinine ≤ 2 x ULN or estimated CrCl > 30 mL/min.
• Creatine phosphokinase (CPK) (also known as CK [creatine kinase]) elevation ≤ grade 2
• Bone marrow function:

• Hemoglobulin ≥ 9.0 g/dL.
• ANC ≥ 1.5 x 109/L.
• Platelet count ≥ 75 x 109/L.
• Expected life expectancy of at least 3 months as judged by the investigator.

Exclusion criteria

• 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.
• Prior treatment with immune checkpoint inhibitors.
• 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.
• Active uncontrolled infection requiring therapy, including infection with HIV, active infection with HBV or HCV.
• History of pneumonitis within the last 5 years.
• 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.

• 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.
• History of documented allergic reactions or acute hypersensitivity reaction attributed to antibody treatments
• 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).
• 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
• Receipt of live vaccines (including attenuated) within 30 days of first study treatment
• Prior use of PI3K-D inhibitors
• 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.
• Breastfeeding
• 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)
• Any other condition that might interfere with experimental treatment and the study procedures as judged by the investigator.