Targeting ATR in soft-tissue sarcomas: a randomized phase II study. TARSARC study

Phase 1

Conditions: ocally advanced/unresectable and/or metastatic soft-tissue leiomyosarcomas
MedDRA version: 20.0Level: HLTClassification code 10024190Term: LeiomyosarcomasSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-003835-31-FR

Lead Sponsor: Institut Bergonié

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 72

Inclusion Criteria

1. Histologically confirmed leiomyosarcomas. As recommended by the French NCI (Inca), diagnosis must be confirmed and reviewed by the RRePS Network.
2. Metastatic or unresectable locally advanced disease,
3. Documented progression according to RECIST v1.1 criteria, unless the patient has no received prior systemic treatment for advanced disease. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less than 6 months interval within the 12 months before randomization,
4. Age = 18 years,
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1,
6. Life expectancy > 3 months,
7. No more than 3 previous line of systemic therapy for advanced disease,
8. 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,
9. Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as = 10 mm with spiral CT scan.,
10. Patient must comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
11. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
12. Adequate hematological, renal, metabolic and hepatic function:
a. Hemoglobin = 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) = 1.5 G/l, and platelet count = 100 G/l.
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) = 2.5 x upper limit of normality (ULN) (< 5 in case of extensive liver involvement) and alkaline phosphatase (AP) = 2.5 x ULN
c. Total bilirubin = 1.5 x ULN (in case of Gilbert’s Syndrome, total bilirubin < 3 x ULN).
d. Albumin = 30 g/l
e. Calculated creatinine clearance (CrCl) > 40 ml/min (calculated as per institutional standard).
f. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
g. aPTT = 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. Pregnancy test (serum or urine) must be repeated within 72 hours prior to receiving the first dose of study medication.
14. 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 for women or from the screening visit for men, throughout the treatment period and for 6 months after discontinuation of treatment. Female subjects will be considered non-childbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years.
15. 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,
16. Recovery to grade = 1 from any adverse event (

Exclusion Criteria

1. Previous treatment with Gemcitabine, or berzosertib or other ATR inhibitor,
2. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
3. Women who are pregnant or breast feeding,
4. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
5. Previous enrolment in the present study,
6. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
7. Known hypersensitivity to any involved study drug or any of its formulation components,
8. Has known active hepatitis B or hepatitis C,
9. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS)
10. Any of the following cardiac or cardiovascular criteria :
- Congestive heart failure = New York Heart Association (NHYA) class 1,
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
- Myocardial infarction less than 6 months before start of study drug
- Uncontrolled cardiac arrhythmias,
11. Participants with Li Fraumeni syndrome and/or ataxia telangiectasia,
12. 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.
13. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication),
14. Patients with oral anticoagulation based on Vitamine K antagonist,
15. Treatment by potent inhibitors or inducers of CYP3A4
16. Vaccination with yellow fever or by any other live attenuated vaccine in the last 30 days,
17. Individuals deprived of liberty or placed under legual guardianship.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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