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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Feb 2022 → 21 Apr 2026

Decision date (initial)

2024-03-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509499-41-00

EudraCT number

2018-003835-31

ClinicalTrials.gov

NCT04807816

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Efficacy, Pharmacodynamic, Therapy, Safety

To evaluate the antitumor activity of berzosertib in association with gemcitabine in terms of 6-month progression-free rate (rate of complete or partial responses or stable disease more than 24 weeks, as per RECIST v1.1) after centralized radiological review, in patients with advanced/metastatic leiomyosarcomas.

Secondary objectives 6

1. To evaluate the antitumor activity of berzosertib in association with gemcitabine in terms of 6-month objective response, best overall response, 1 and 2-year progression free survival (PFS) (as per RECIST v1.1 criteria) and 1 and 2-year overall survival (OS).
2. SM-1 (MSA3) suppression
3. To evaluate the toxicity of berzosertib in association with gemcitabine (NCI-CTCAE v5).
4. To evaluate the antitumor activity and toxicity of berzosertib alone, using the same evaluation criteria as for the assessment of the association berzosertib + gemcitabine.
5. Biomarker study: to perform pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis.
6. To perform exploratory analysis of ctDNA for mutations relating to resistance to ATR inhibitor therapy.

Conditions and MedDRA coding

Adult patients with locally advanced/unresectable and/or metastatic soft-tissue leiomyosarcomas.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

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 7 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 12 months.
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 (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0),
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 17

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy of berzosertib in association with gemcitabine (Arm A) as well of efficacy of gemcitabine alone (Arm B) will be assessed, independently for each arm, in terms of 6-month progression-free rate (PFR). PFR is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. This endpoint is a validated endpoint in STS. Radiological centralized review data will be used for the primary endpoint analysis.

Secondary endpoints 9

1. 1. Antitumor activity of the association will be assessed as well in terms of:
2. a) Objective response defined as complete response (CR) or partial response (PR) as per adapted RECIST v1.1. The objective response rate (ORR) at 6 months will be reported independently for each arm.
3. b) Best overall response defined as the best response across all time points (RECIST v1.1). Best overall response rate will be reported independently for each arm.
4. c) Progression-free survival (PFS) 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. Median PFS, 1- and 2-year PFS rates will be reported independently for each arm.
5. d) Overall survival (OS) defined as the delay between the start date of treatment and the date of death (of any cause). Median OS, 1- and 2-year OS rates will be reported independently for each arm.
6. e) SM-1 (MSA3) suppression
7. f) Safety profile of berzosertib in association with gemcitabine. Events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
8. 2. Biomarker study: To perform pharmacodynamic (PD)/mechanism of action(MOA) biomarkers analysis as well as predictive biomarkers analysis, in blood and tumor tissue sample at different time points. This may include butnot limited to the following: analysis of fixed PBMCs using immunofluorescence and confocal microscopy inorder of priority: pSer296 Chk1, total Chk1, gammaH2AX, RAD51, pS317 Chk1 and pS345 Chk1, immune profiling, markers of genetic instability including microsatellite instability)
9. 3. Exploratory analyses of ctDNA for mutations relating to resistance to ATR inhibitor therapy in blood samples collected at baseline.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine Italiano

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore Barthod Malat

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications