HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas

This trial is a two-step Phase I/II study comprising: Part 1: A dose escalation part with the aim to assess the safety of the proposed combination (N= up to 30 patients). In the dose escalation part, eligible patients will be treated with a fixed dose of pazopanib and escalating doses of HDM201. Part 2: An extension part to collect preliminary data about the clinical activity of the proposed combination according to the 6M-PFR.

Inclusion Criteria: I1. Male or female patient ≥ 18 years of age I2. Histologically or cytologically confirmed diagnosis of soft tissue sarcoma with documented p53 wild-type (wt) status and known MDM2 status (amplification or no amplification). Note: p53 wt status has to be determined by Next-generation sequencing of the full coding sequence using a tumor sample collected no longer than 36 months before inclusion. I3. Previously treated by at least one prior chemotherapy line of treatment in the advanced/metastatic setting. I4. STS subtypes eligible to pazopanib treatment according to respective SmPC Note: The following tumour types are eligible: Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignant solitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma \[MFH\], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal muscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma, angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal sarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas not otherwise specified (NOS) and other types of sarcoma (not listed as ineligible)and liposarcoma. The following tumour types ARE NOT eligible: All rhabdomyosarcoma that are not alveolar or pleomorphic, chondrosarcoma, osteosarcoma, Ewing tumours/primitive neuroectodermal tumours (PNET), GIST, dermofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant mesothelioma and mixed mesodermal tumours of the uterus I5. Documented progressive disease and presence of at least one measurable lesion according to RECIST 1.1 (Appendix 01) based on screening tumor assessment. I6. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. I7. Adequate organ system function as assessed by the following minimal requirements (within 7 days prior to first administration of study drugs (C1D1)): Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L). Transfusion is not allowed within 2 weeks of screening assessment. aspartate transaminase and alanine aminotransferase ≤ 2.5x Upper limit of normal or up to 5 Upper limit of normal in case of liver metastasis Bilirubin ≤ 1.5 Upper limit of normal (except in the setting of isolated Gilbert syndrome) Serum creatinine clearance ≥ 30 mL/min (calculated by CKD-EPI -Appendix 03) Calcium, magnesium and potassium within normal limits. Urine Protein to Creatinine ratio (UPC) \