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

Inclusion Criteria: I1. Male or female patient ≥ 18 years of age I2. Histologically or cytologically confirmed diagnosis of soft tissue sarcoma withdocumented p53 wild-type (wt) status and known MDM2 status (amplification or noamplification). Note: p53 wt status has to be determined by Next-generation sequencing of the full codingsequence 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 theadvanced/metastatic setting. I4. STS subtypes eligible to pazopanib treatment according to respective SmPC Note: Thefollowing tumour types are eligible: Fibroblastic (adult fibrosarcoma, myxofibrosarcoma,sclerosing epithelioid fibrosarcoma, malignant solitary fibrous tumours), so-calledfibrohistiocytic (pleomorphic malignant fibrous histiocytoma [MFH], giant cell MFH,inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal muscles (pleomorphicand 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 tissuesarcomas not otherwise specified (NOS) and other types of sarcoma (not listed asineligible)and liposarcoma. The following tumour types ARE NOT eligible: All rhabdomyosarcoma that are not alveolar orpleomorphic, 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 accordingto 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 5Upper 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) <1; if UPC ≥1, 24-hour urine protein must be <1g (use of urine dipstick for renal function assessment is not acceptable). I8. Adequate cardiovascular function: QTcF (corrected QT using Fridericia) ≤450ms, from 3 electrocardiograms on screening ECG,within 14 days prior to C1D1 Resting blood pressure systolic <140 mmHg and diastolic< 90mmHg, Left Ventricular Ejection Fraction ≥50% as determined by transthoracic echocardiogramor Multiple Gated acquisition. I9. Resolution (i.e. ≤ Grade 1 with the exception of alopecia all grades and Grade 2 forneuropathy, lab values presented in inclusion criteria) of any toxicities related toprevious anti-cancer treatment. I10. Patients able to swallow orally administered medication and do not have any clinicallysignificant gastrointestinal abnormalities that may alter absorption of study drugs such asmalabsorption syndrome or major resection of the stomach or bowels. I11. Availability of archival Formalin Fixed Paraffin Embedded tumor sample. This samplemust be sent to sponsor once eligibility is confirmed. I12. Expansion part only - Presence of at least one biopsiable lesion i.e. at least onelesion with a diameter ≥10 mm, visible by medical imaging and accessible to repeatablepercutaneous or endoscopic sampling that permit core needle biopsy without unacceptablerisk and suitable for retrieval of a minimum of three, but ideally four, cores using abiopsy needle of at least 16-gauge. Note: RECIST target lesion are not to be biopsied. I13. Women patient of child-bearing potential must have a negative serum pregnancy testbefore C1D1 and must agree to use effective forms of contraception from the time of thenegative pregnancy test up to 6 months after the last dose of study drugs I14. Sexually active and fertile men must agree to use contraceptive measures up to 100days after the last study drugs. I15. Written informed consent from patient before any study-specific screening procedures,and willingness to comply to study visits and procedures. I16. Patients must be covered by a medical insurance

Exclusion Criteria: Non-inclusion 1. Prior exposure to MMD2 inhibitors and/or pazopanib. Non-inclusion 2. Patients with significant active or uncontrolled cardiovascular disease orprior medical cardiac function disorders including for example uncontrolled hypertension,peripheral vascular disease, congestive heart failure (Class III-IV according to New YorkHeart Association scale), cardiac arrhythmia, or acute coronary syndrome within 6 months ofC1D1 or myocardial infarction, angina pectoris, symptomatic pericarditis, within 12 monthsof C1D1, congenital long QT syndrome or family history of long QT syndrome and patientswith drug eluting stents for cardiovascular purposes. Non-inclusion 3. Patients diagnosed with treatment-related interstitial lung disease orpneumonitis. Non-inclusion 4. Patients with secondary malignancy unless this malignancy is not expectedto interfere with the evaluation of study endpoints and is approved by the sponsor.Examples of the latter include: basal or squamous cell carcinoma of the skin, in-situcarcinoma of the cervix, localized prostate cancer, prior malignancy and no evidence ofdisease for ≥ 2 years. Non-inclusion 5. Patient with any condition (e.g., clinically significant gastrointestinalabnormality or disease resulting in an inability to take oral medication, prior surgicalprocedures affecting absorption, or active peptic ulcer disease) that impairs their abilityto swallow and retain tablets and may affect the absorption of the investigational productare excluded. Non-inclusion 6. Clinically significant gastrointestinal abnormalities that may increasethe risk for gastrointestinal bleeding including, but not limited to:

• Active peptic ulcer disease
• Known intraluminal metastatic lesion(s) with risk of bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or othergastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscesswithin 28 days prior to beginning study treatment. Non-inclusion 7. History of hemoptysis, cerebral hemorrhage or clinically significantgastrointestinal (GI) hemorrhage in the past 6 months. Non-inclusion 8. Hypersensitivity to the active substance or to any of the excipientslisted in section VII.1. Non-inclusion 9. Patients using, or requirement to use while on the study, or notrespecting the minimal wash-out period of medications listed below: Forbidden concomitant medications during the study period and Minimal wash-out periodbefore C1D1:

4 weeks - Any approved anti-cancer treatment (including hormonotherapy, chemotherapy,biological therapy, targeted therapy or immunotherapy) Note: Concurrent use of hormones fornon-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy)is acceptable. Or Any investigational therapy other than the specified therapies in presentprotocol

4 weeks - Radiotherapy - Note: Except palliative radiotherapy on non-target lesions afterdiscussion with the Sponsor

4 weeks - Surgery: Major surgical procedure, or significant traumatic injury. Note: If apatient underwent a major surgical procedure, he/she must have adequately recovered fromthe toxicity (i.e. wound healing) and/or complications from the intervention prior tostarting therapy.

4 weeks - Live vaccines. Note: Seasonal influenza vaccines for injection are generallyinactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g.,Flu-Mist®) are live attenuated vaccines, and are not allowed.

1 week - Medicinal products known to prolong the QT interval and/ or to induce "Torsades dePointes"

1 week - Strong and moderate inducers or inhibitors of CYP3A4/5

1. week - Strong inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) Forbidden concomitant medications during the DLT period: unless clinically indicated by institutional and/or American Society of ClinicalOncology (ASCO) guidelines - Growth factors targeting the myeloid lineage
2. weeks prior treatment start and during the DLT defined period - Prophylactic use ofred blood cells and platelet transfusions. Note: Therapeutic transfusions if clinically indicated by institutional and/or ASCOguidelines are permitted but may qualify as DLT. Transfusions outside the above specifiedtimeframe are permitted. Non-inclusion 10. Known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Non-inclusion 11. History of (non-infectious) pneumonitis that required steroids, evidenceof interstitial lung disease or active non-infectious pneumonitis. Non-inclusion 12. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)or active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] isdetected) Non-inclusion 13. Pregnant or breast-feeding female patients.