Molecular Profiling of Advanced Soft-tissue Sarcomas

Randomized phase

Inclusion Criteria:

• Age ≥ 18 years,

• Histology: soft-tissue sarcoma confirmed by the RRePS Network, as recommended by theFrench NCI

• Unresectable locally advanced and/or metastatic STS

• No previous systemic treatment for advanced disease,

• ECOG ≤ 1

• Adequate hematological and metabolic functions: Hemoglobin > 9 g/dL and albumin > 30g/L

• Measurable disease according to RECIST 1.1. At least one site of disease must beuni-dimensionally > 10 mm,

• Availability of suitable frozen archive tumor material obtained from a metastaticlesion or advanced disease (not previously treated), or at least one lesion that canbe biopsied for research purpose,

• Archived FFPE block of specimen tumor sampling obtained anytime during diseasedevelopment for research purpose,

• Eligible to first-line systemic treatment,

• No prior or concurrent malignant disease diagnosed or treated in the last two yearsbefore inclusion. Note that patients with in situ carcinoma of the cervix, oradequately treated basal cell or squamous cell carcinoma of the skin, or adequatelytreated localized prostate cancer, or other localized cancer under maintenancetherapy can be included as long as they don't limit assessment of efficacy offirst-line systemic therapy,

• Participant with a social security in compliance with the French law,

• Voluntary signed and dated written informed consent prior to any study specificprocedure (ICF1)

Exclusion Criteria:

• Radiological evidence of symptomatic or progressive brain metastases,

• Inability to swallow,

• Major problem with intestinal absorption,

• Previous allogeneic bone marrow transplant,

• Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension,active bleeding diatheses, or active Hepatitis B, C and HIV or active autoimmunedisease),

• Any condition which in the Investigator's opinion makes it undesirable for thesubject to participate in the trial or which would jeopardize compliance with theprotocol,

• Individuals deprived of liberty or placed under guardianship

• Pregnant or breast feeding women,

• Men or women refusing contraception,

• Previous enrolment in the present study,

• Any contraindication to first-line chemotherapy treatment.

Phase II Sub-trials

Inclusion Criteria:

• Participants already enrolled in MULTISARC and randomized/switched in Arm "NGS",

• ECOG performance status < 1,

• Measurable disease according to RECIST v1.1,

• Molecular alteration identified by molecular profiling,

• Participants who have received a first-line systemic treatment at the inclusion,

• Participants must have advanced disease and must not be a candidate for otherapproved therapeutic regimen known to provide significant clinical benefit based oninvestigator judgement,

• Participants will have had a minimum of 21 days gap from last chemotherapy orimmunotherapy or any other pharmacological therapy and/or radiotherapy prior to thefirst dose of study treatment,

• Women of childbearing potential must have a negative serum pregnancy test within 3days of enrolment and serum/urine pregnancy test within 24 hours prior to theadministration of the study drug,

• Female with child bearing potential and male participants with partners of childbearing potential must be willing to use two effectives forms of contraception (1highly effective method and 1 barrier method), from beginning 3 weeks before thefirst dose of investigational product and until 3 months after discontinuing thestudy.

• Participant with a social security in compliance with the French law,

• Voluntary signed and dated written informed consent (ICF2) prior to any studyspecific procedure.

Main exclusion Criteria:

• Previous treatment with the targeted therapy,

• No "targetable" genomic alteration generated during the screening phase either dueto the lack of alteration or due to ineligible samples for genomic analysis (MULTISARC),

• Participants with total gastrectomy,

• Major surgery within 30 days prior to entry into the study (excluding placement ofvascular access) or minor surgery within 14 days of entry into the study,

• History of hypersensitivity to involved study drug(s) or of its excipients,

• Radiological evidence of symptomatic or progressive brain metastases,

• Participant with oral anticoagulation therapy,

• Inability to swallow,

• Major problem with intestinal absorption,

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria. Participants with Grade ≥2 neuropathy will be evaluated on a case-by-casebasis after consultation with the Sponsor.

• Previous allogeneic bone marrow transplant,

• Altered hematopoietic or organ function,

• Mean resting corrected QT interval (QTcF)>470msec obtained from 3 consecutive ECGs

• Previous or current maligancies of other histologies within the last 2 years, withthe exception of in situ carcinoma of the cervix, and adequately treated basal cellor squamous cell carcinoma of the skin and prostate cancer,

• Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension,active bleeding diatheses), active uncontrolled systemic bacterial, viral, or fungalinfection > Grade 2 as per NCI CTCAE v5.0

• Chronic or active hepatitis B or hepatitis C. Testing for hepatitis B surfaceantigen (HBs Ag) and hepatitis B core antibody (anti HBc) will be performed atscreening,

• Human immunodeficiency virus (HIV) positive,

• Any condition which in the Investigator's opinion makes it undesirable for thesubject to participate in the trial or which would jeopardize compliance with theprotocol,

• Individuals deprived of liberty or placed under guardianship,

• Pregnant or breast feeding women.