Targeting ATR in Soft-tissue Sarcomas

This is a multicenter, prospective, open-labeled, 2-arm, non-comparative randomized (2:1) phase II trial. Patients will be randomized between arm A (gemcitabine + berzosertib) and arm B (gemcitabine) with two patients randomized in arm A for one patient randomized in arm B.

Inclusion criteria

• Histologically confirmed leiomyosarcomas.
• Metastatic or unresectable locally advanced disease,
• Documented progression according to RECIST v1.1 confirmed by central review,
• Age ≥ 18 years,
• ECOG ≤ 1,
• Life expectancy > 3 months,
• No more than 3 previous line of systemic therapy for advanced disease,
• Patients must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement,
• Patients must have measurable disease defined as per RECIST v1.1
• Patient must comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
• At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
• Adequate hematological, renal, metabolic and hepatic function
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
• Both women of childbearing potential and men must agree to use a highly effective method of contraception 28 days before start of first dose of study drug
• No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
• Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment
• Voluntarily signed and dated written informed consent prior to any study specific procedure,
• Patients with a social security in compliance with the French law.

Exclusion criteria

• Previous treatment with Gemcitabine, or berzosertib or other ATR inhibitor,
• Evidence of progressive or symptomatic central nervous system or leptomeningeal metastases,
• Women who are pregnant or breast feeding,
• Participation to a study involving a medical or therapeutic intervention in the last 30 days,
• Previous enrolment in the present study,
• Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
• Known hypersensitivity to any involved study drug or any of its formulation components,
• Has known active hepatitis B or hepatitis C,
• Has a known history of Human Immunodeficiency Virus or known acquired immunodeficiency syndrome
• Any of the following cardiac or cardiovascular criteria :

• Congestive heart failure ≥ New York Heart Association (NHYA) class 1,
• Unstable angina , new-onset angina
• Myocardial infarction less than 6 months before start of study drug
• Uncontrolled cardiac arrhythmias,
• Participants with Li Fraumeni syndrome and/or ataxia telangiectasia,
• Active autoimmune disease:

• Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible,
• Patients requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at dose ≤ 10 mg or 10 mg equivalent prednisone day,
• Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular or inhalation) are acceptable.
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident , deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication,
• Patients with oral anticoagulation based on Vitamine K antagonist,
• Treatment by potent inhibitors or inducers of CYP3A4
• Vaccination with yellow fever or by any other live attenuated vaccine in the last 30 days,
• Individuals deprived of liberty or placed under legual guardianship.