Leiomyosarcoma, Adult
Conditions
Keywords
ATR inhibition, soft-tissue sarcoma, advanced/metastatic
Brief summary
Multicenter, prospective, open-labeled, 2-arm, non-comparative randomized phase II trial to assess the antitumor activity of berzosertib in association with gemcitabine
Detailed description
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.
Interventions
DRUGAssociation of berzosertib with gemcitabine
Gemcitabine will be administered by intravenous 30-minutes infusion on days 1 and 8 every 3 weeks, at a fixed dose of 1000 mg/m². Berzosertib will be administered intravenously on days 2 and 9 every 3 weeks (210 mg/m²). A treatment cycle consists of 3 weeks (i.e., 21 days) and will be administered during hospitalization.
DRUGGemcitabine
Gemcitabine will be administered by intravenous 30-minutes infusion on days 1 and 8 every 3 weeks, at a fixed dose of 1000 mg/m². A treatment cycle consists of 3 weeks (i.e., 21 days) and will be administered during hospitalization.
Sponsors
Institut Bergonié
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed leiomyosarcomas. 2. Metastatic or unresectable locally advanced disease, 3. Documented progression according to RECIST v1.1 confirmed by central review, 4. Age ≥ 18 years, 5. ECOG ≤ 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 defined as per RECIST v1.1 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 13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. 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 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 (AE) derived from previous treatment 17. Voluntarily signed and dated written informed consent prior to any study specific procedure, 18. Patients with a social security in compliance with the French law.
Exclusion criteria
1. Previous treatment with Gemcitabine, or berzosertib or other ATR inhibitor, 2. Evidence of progressive or symptomatic central nervous system 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 or known acquired immunodeficiency syndrome 10. 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, 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 , deep vein thrombosis or pulmonary embolism within 6 months 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the antitumor activity of berzosertib combined with gemcitabine | 6 months | Antitumor activity will be assessed in terms of 6-month progression-free rate and is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. |
| Assessment of the antitumor activity of gemcitabine | 6 months | Antitumor activity will be assessed in terms of 6-month progression-free rate and is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-month objective response rate (ORR) for patients treated by berzosertib in association with gemcitabine | 6 months | Objective response is defined as complete response (CR) or partial response (PR) as per adapted RECIST v1.1. |
| 6-month objective response rate (ORR) for patients treated by gemcitabine alone | 6 months | Objective response is defined as complete response (CR) or partial response (PR) as per adapted RECIST v1.1. |
| Best overall response for patients treated by berzosertib in association with gemcitabine | throughout the treatment period, an expected average of 6 months | Best overall response is defined as the best reponse across all time points (RECIST v1.1). The best overall response rate is determined once all the data for the patient is known |
| Best overall response for patients treated by gemcitabine alone | throughout the treatment period, an expected average of 6 months | Best overall response is defined as the best reponse across all time points (RECIST v1.1). The best overall response rate is determined once all the data for the patient is known |
| 1-year progression-free survival for patients treated by berzosertib in association with gemcitabine | 1 year | Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first |
| 1-year progression-free survival for patients treated by gemcitabine alone | 1 year | Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first |
| 2-year progression-free survival for patients treated by berzosertib in association with gemcitabine | 2 years | Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first |
| 2-year progression-free survival for patients treated by gemcitabine alone | 2 years | Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first |
| 1-year overall survival for patients treated by berzosertib in association with gemcitabine | 1 year | Overall survival is defined as the delay between the start date of treatment and the date of death (from any cause) |
| 1-year overall survival for patients treated by gemcitabine alone | 1 year | Overall survival is defined as the delay between the start date of treatment and the date of death (from any cause) |
| 2-year overall survival for patients treated by berzosertib in association with gemcitabine | 2 years | Overall survival is defined as the delay between the start date of treatment and the date of death (from any cause) |
| 2-year overall survival for patients treated by gemcitabine alone | 2 years | Overall survival is defined as the delay between the start date of treatment and the date of death (from any cause) |
| 6-month objective response according to CHOI criteria, independently for each arm | 6 months | Objective response is defined as complete response (CR) or partial response (PR) as per CHOI criteria. |
| Best overall response according to CHOI criteria, independently for each arm | throughout the treatment period, an expected average of 6 months | Best overall response is defined as the best reponse across all time points (CHOI criteria). The best overall response rate is determined once all the data for the patient is known |
| Safety profile independently for each arm: Common Terminology Criteria for Adverse Event version 5 | throughout the treatment period, an expected average of 6 months | Toxicity graded using the Common Terminology Criteria for Adverse Events version 5 |
| Tumor immune cells levels | before treatment onset and cycle 2 day 1 (each cycle is 21 days) | Levels of immune cells (CD4, CD8, PDL1)in tumor will be measured by immunohistochemistry |
| Blood cytokines levels | baseline, cycle 2 day 1, cycle 6 day 1 and progression (each cycle is 21 days) | Levels of cytokines (tryptophane, interleukine) in blood will be measured by ELISA |
| Blood lymphocytes levels | baseline, cycle 2 day 1, cycle 6 day 1 and progression (each cycle is 21 days) | Levels of fixed PBMC (peripheral blood mononucear cells) in blood will be measured by flow cytometry |
| Blood kynurenine levels | baseline, cycle 2 day 1, cycle 6 day 1 and progression (each cycle is 21 days) | Levels of kynurenine in blood will be measured by ELISA |
Countries
France
Outcome results
None listed