Pasireotide as Maintenance Treatment in Synovial Sarcoma and Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma. It originates from the serosal surface of the abdominal cavity and the hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. Synovial sarcoma (SySa) is also a rare fusion-gene driven (SS18-SSX1, SS18-SSX2, or rarely, SS18-SSX4) soft-tissue sarcoma.

Selected somatostatin receptor (SSTR) family members, i.e., SSTR2, SSTR3 and SSTR5, were highly expressed in patients with available transcriptome data, providing the basis for treatment with a somatostatin analog such as pasireotide with high affinity for SSTR1, 2, 3, and 5.

The primary aim of the study is to assess the clinical efficacy of pasireotide maintenance therapy for prolonging progression-free (PFS) and overall survival (OS) in patients with SSTR2/3/5-expressing advanced SySa and DSRCT. Furthermore measurable residual disease (MRD) before, during, and after pasireotide maintenance therapy are assessed. Pasireotide is applied in adults with 60 mg and in adolescents 60 mg (body surface area [BSA] >1.6 m²) or 40 mg (BSA 1.1-1.6 m²) via intragluteal via intragluteal depot injection every 28±3 days. The sample size is planned for the entire study population with subsequent sensitivity analysis in two subgroups, i.e., adolescents and adults. The primary efficacy analysis is be based on a two-sided, one-sample log-rank test using a significance level of 5%. The sample size was calculated assuming exponential data, planning for a power of 90% to detect a hazard ratio of 0.5. With a sample size of n=28, the expected number of events during the study is 22. Safety is assessed continuously according to CTCAE v5.0. The recruitment period is planned for 2 years starting in 2024 followed by a minimal follow-up of the last patient of 6 months leading to estimated trial completion in 2027.

Inclusion criteria

Patients meeting all of the following criteria are considered for enrolment into the trial:

• Reference pathological proven diagnosis of DSRCT in any stage; or Reference pathological proven diagnosis of SySa, IRS III, metastatic or relapsed disease
• High SSTR2/3/5 mRNA expression, as determined by RNA sequencing in the DKFZ/NCT/DKTK MASTER (ClinicalTrials.gov ID: NCT05852522) or INFORM programs.
• Stable disease, partial or complete response after completion of standard treatment
• Age from 13 to 50 years
• For patients (≥16 years): Karnofsky-Index ≥ 80% For patients (<16 years): Lansky-Index ≥ 80%
• No curative treatment option
• Bodyweight ≥ 30kg and BSA ≥ 1.1m²
• Time from last chemotherapy (at least 2 chemotherapy cycles) to enrollment <8 weeks
• Ability of patient to understand character and individual consequences of the clinical trial
• Written informed consent (for individuals <18 years of age an ICF for adolescents and their parents is needed)
• For women of childbearing potential negative urine pregnancy test at screening as well as highly effective forms of contraception have to be in place thereafter

• Evidence of childbearing potential is defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile
• Postmenopausal or evidence of non-childbearing status is defined as:

• Amenorrhea for 1 year or more without an alternative medical cause following cessation of exogenous hormonal treatments plus follicle stimulating hormone (FSH) levels in the postmenopausal range in women not using hormonal contraception or hormonal replacement therapy.
• Chemotherapy-induced menopause
• Surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, total hysterectomy or tubal ligation at least 6 weeks before IMP treatment)
• A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy
• Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two forms of contraception in combination (male condom and one highly effective method). These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus 3 months for female and male patients . Male patients should refrain from fathering a child or donating sperm during the trial and for at least 3 months following the last dose.
• Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:

• Hemoglobin ≥ 10 g/dl
• Neutrophil count ≥ 1,500/mm3
• Platelet count ≥ 100,000/µl
• Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• ALT and AST ≤ 2.5 x ULN
• Alkaline phosphatase ≤ 2.5 x ULN
• PT-INR/PTT ≤ 1.5 x ULN
• Albumin ≥ 25 g/l
• Creatine kinase ≤ 2.5 x ULN
• Serum creatinine < or = 1.5 mg/dl or creatinine clearance = or > 51 ml/min (calculation according to Crockroft-Gault)

Exclusion criteria

Patients presenting with any of the following criteria are not included in the trial:

• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
• Concurrent or previous treatment within 30 days in another interventional clinical trial / Participation in other ongoing clinical trials.
• Uncontrolled concurrent disease, in particular diabetes mellitus
• Bleeding disorder
• Therapeutic anticoagulation which cannot be paused temporarily in order to ensure safe intramuscular injection
• Is taking or requiring any of the prohibited medication listed in Table 5 (6.4.2)
• Heart rate at rest < 60/min
• fasting glucose level > 110mg/dl
• Severe neurologic or psychiatric disorder
• Pregnancy/lactation
• Prior treatment with somatostatin analog

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