Phase III Randomized Trial of Dostarlimab Versus Chemotherapy in MMR-Deficient Advanced/Metastatic Endometrial Cancer

Trial ID: 2023-510097-14-00
Protocol: GINECO-EN105b
Sponsor: Asso De Recherche Cancers Gynecologiques

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Diseases & Conditions

Endometrial cancer

Objectives

The primary objective of this randomized phase III trial is to evaluate **Progression Free Survival (PFS)** in patients with MMR deficient endometrial cancer. This is assessed per Blinded Independent Central Review (BICR) and is defined as the time from randomization until objective tumor progression based on RECIST 1.1 criteria or death from any cause, whichever occurs first. This measure is clinically relevant as it provides insight into the efficacy of the treatment in delaying disease progression, which is crucial for improving patient outcomes in advanced or metastatic settings.

Secondary objectives include:

**Overall Survival (OS)**
**Progression Free Survival 2 (PFS2)**
**Quality of Life (QoL)**
**Best objective Response Rate (ORR)**
**Disease control rate (DCR)**
**Duration of Response Rate (DoR)**
PFS, DoR as per investigator assessment
Safety and tolerability assessed according to CTCAE v5.0 and NCI PRO-CTCAE
Time to first and second Subsequent Treatment (TFST and TSST)
Efficacy of second systemic therapies
To describe the pharmacokinetics of **dostarlimab**
To determine the immunogenicity of dostarlimab

These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on survival, disease control, patient quality of life, and safety, as well as to explore the pharmacokinetic and immunogenic properties of dostarlimab.

Participants

The clinical trial involves a total of **60 participants** who are exclusively **female** and at least **18 years of age**. The study population consists of patients diagnosed with **MMR deficient relapse or advanced/metastatic endometrial cancer**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of endometrial adenocarcinoma with recurrent or advanced disease, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. The trial does not include a vulnerable population. Participants may have previously undergone hormone therapy or radiation treatments, and they must have adequate organ function as defined by specific laboratory parameters. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial does not include male subjects, and there is no indication of any vulnerable populations being involved. The sponsor has not provided additional information regarding lifestyle considerations or other demographic details.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **controlled** study designed to evaluate the efficacy of **dostarlimab** in comparison to chemotherapy alone in patients with MMR deficient relapse or advanced/metastatic **endometrial cancer**. The trial aims to assess **progression-free survival** (PFS) as the primary endpoint, with secondary endpoints including overall survival, quality of life, and safety. The study is expected to run until December 31, 2029, with recruitment having commenced on March 1, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and organ function. Following randomization, participants will receive either dostarlimab or a combination of **carboplatin** and **paclitaxel** via **intravenous infusion**. The treatment period for dostarlimab is up to 24 months, while chemotherapy is administered for up to 18 months. Regular follow-up visits will be conducted to monitor disease progression, treatment response, and adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 24 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The trial is conducted in accordance with ethical guidelines, ensuring that all participants provide informed consent and are monitored for safety throughout the study duration.

Treatment

The clinical trial involves the administration of **CARBOPLATIN**, a chemical compound used as an antineoplastic and immunomodulator. It is provided in the form of a solution for intravenous injection or infusion. The maximum daily dose is 500 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of up to 18 weeks. The administration route is exclusively through intravenous infusion, and participant compliance will be monitored throughout the study.

**PACLITAXEL** is another chemical compound used in this trial, classified as an antineoplastic agent within the taxanes category. It is supplied as a concentrate for solution for infusion. The maximum daily dose is 175 mg/m², with a total maximum dose of 1050 mg/m², administered over a maximum treatment period of 18 weeks. The route of administration is intravenous infusion, and adherence to the dosing schedule will be closely monitored.

The experimental medication **DOSTARLIMAB** is a protein-based therapeutic agent provided as a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 100 mg and a total maximum dose of 1700 mg over a treatment period of up to 24 weeks. The administration schedule and participant compliance will be rigorously monitored to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial will be assessed primarily through **Progression Free Survival (PFS)**, as evaluated by a Blinded Independent Central Review (BICR). This is defined as the time from the date of randomization until objective tumor progression based on RECIST 1.1 criteria, or death due to any cause, whichever occurs first. Patients who are alive and free of progression will be censored at the last disease assessment date.

Secondary endpoints include Overall Survival (OS), Progression Free Survival 2 (PFS2), Quality of Life (QoL), Best Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response Rate (DoR), and PFS and DoR as per investigator assessment. Additional secondary endpoints involve safety and tolerability, time to first and second subsequent treatment, efficacy of second systemic therapies, pharmacokinetics, and immunogenicity of **dostarlimab**.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Female patient is at least 18 years of age
Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements
Patient with histologically proven endometrial adenocarcinoma with recurrent or advanced disease
Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
Patient must have primary Stage IIIA to C2 or Stage IV disease or first recurrent endometrial cancer (see International Federation of Gynecology and Obstetrics staging FIGO Staging – Appendix 18.1) without curative treatment by radiation therapy or surgery alone or in combination, and meet at least one of the following situations: a) Patient has Patient has primary Stage IIIA-IIIC1 with no amenable curative intent surgery or radiation b) Patient has primary Stage IIIC2 (with nodes involvement from the outset, not allowing a curative radiotherapy, or with remaining lumboaortic nodes after lumbo-aortic dissection, which cannot be treated by curative radiotherapy) or Stage IV disease. c) Patient has recurrent disease and is chemotherapy naïve for recurrence or advanced/metastatic setting. d) Patient may have received prior irradiation for advanced endometrial cancer with or without radio-sensitizing chemotherapy if > 3 weeks before the start of the study
Patient with evaluable disease (measurable and not measurable disease) according to RECIST 1.1
Patient may have received prior neo-adjuvant/adjuvant systemic chemotherapy for the primary cancer and had a recurrence ≥ 6 months after completing treatment (first recurrence only)
All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H
MMRd/MSI-H tumor (first diagnosed by routine local IHC performed either on primitive tumour tissue or on relapse/metastatic tumour sample), is mandatory for inclusion. A central confirmation will be done before inclusion; in case of ambiguous result of central IHC (lack of positive internal control, heterogeneous loss of MMR protein expression), MSI-H status will be assessed by PCR/NGS
Availability of 1 block for MMR/MSI status centralized confirmation for IHC or PCR / NGS.
Patient could have been previously treated with hormone therapy, for the metastatic/advanced disease
Patient may have received pelvic and lombo-aortic external beam +/- vaginal brachytherapy
Patient has adequate organ function, defined as follows: a) Absolute neutrophil count ≥ 1,500 cells/μL b) Platelets ≥ 100,000 cells/μL c) Haemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L d) Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault equation for patients with creatinine levels > 1.5× institutional ULN e) Total bilirubin ≤ 1.5× ULN (≤ 2.0 x ULN in patients with known Gilbert’s syndrome) or direct bilirubin ≤ 1× ULN f) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, in which case they must be ≤ 5× ULN GINECO-EN105b/ENGOT-en13 – DOMENICA – Protocol – Version 3.0 – 08/03/2023 (From FORM 113-02 : Protocol – Application date : 22/JUN/2020) Page 9 on 152 g) International normalized ratio or prothrombin time (PT) ≤1.5× ULN and activated partial thromboplastin time ≤1.5× ULN. Patients receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants
Patient must have a negative serum pregnancy test within 72 hours of the first dose of study medication, unless they are of non-childbearing potential. Non-childbearing potential is defined as follows: a) Patient is ≥ 45 years of age and has not had menses for > 1 year. b) A follicle-stimulating hormone value in the postmenopausal range upon screening evaluation if amenorrhoeic for < 2 years without a hysterectomy and oophorectomy. c) Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation: - Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, MRI, or CT scan. - Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the patient must fulfil the criteria in Inclusion Criterion 14. - Information must be captured appropriately within the site’s source documents
Patient of childbearing potential must agree to use a highly effective method of contraception (section 18.8) with their partners starting from time of consent through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient (Information must be captured appropriately within the site’s source documents).

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Exclusion Criteria

Patient has received neoadjuvant/adjuvant systemic chemotherapy for primary Stage III or IV disease and has had a recurrence or PD within 6 months of completing this chemotherapy treatment prior to entering the study. Note: Low-dose cisplatin given as a radiation sensitizer or hormonal therapies do not exclude patients from study participation
Patient has had > 1 recurrence of endometrial cancer, treated with chemotherapy. Surgery of the recurrence is allowed
Patient previously treated with systemic chemotherapy for noncurable advanced disease or metastatic disease
Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
Patient has received prior anticancer therapy for advanced or metastatic disease, (targeted therapies, hormonal therapy, radiotherapy) within 21 days or < 5 times the half-life of the most recent therapy prior to Study Day 1, whichever is shorter. Note: Palliative radiation therapy to a small field ≥ 1 week prior to Day 1 of study treatment may be allowed
Patient with contraindication to chemotherapy or checkpoint inhibitor treatments
Patient has a concomitant malignancy, or patient has a prior nonendometrial invasive malignancy who has been disease-free for < 3 years or who received any active treatment in the last 3 years for that malignancy. Non-melanoma skin cancer is allowed
Patient has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both
Patient has a known history of human immunodeficiency virus (HIV; HIV 1 or 2 antibodies)
Patient has known active viral infection of hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] detection)
Patient has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (eg, thyroid hormone or insulin)
Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment
Patient has not recovered (ie, to Grade ≤ 1 or to baseline) from cytotoxic therapy-induced adverse events (AEs). Note: Patients with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2 fatigue are an exception to this criterion and may qualify for the study
Patient has not recovered adequately from AEs or complications from any major surgery prior to starting therapy
Patient has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients
Patient is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment
Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent)
Use of any of the following immunomodulatory agents within 30 days prior to the first dose of study drug:  Systemic corticosteroids (at dose higher than 10 mg/day equivalent prednisone); if systemic corticoid use at higher dose than 10 mg/day, corticoid must be stopped at least 7 days before study treatment start  Interferons  Interleukins  Live vaccine Note: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed as other killed vaccines, if done at least 2 weeks prior the first dose of study drug; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
Patient is pregnant or breastfeeding or is expecting to conceive children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment, or lactating woman
Patients who had an allogenic tissue/solid organ transplant.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	01 Mar 2022	120
Italy	Not Recruiting	01 Mar 2022	60
Romania	Not Yet Recruiting	01 Mar 2022	10
Spain	Not Recruiting	01 Mar 2022	27

Sites & Investigators

Research sites

Azienda Usl Toscana nord ovest Institut de Cancérologie Hématologie Universitaire de Saint Etienne (iCHUSE)Clinique de l'Europe Centre Azuréen de Cancérologie

Investigators

Dana Lucia S.Raafet A.Sophie R.Anne-Claire H. B.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
CARBOPLATIN	Comparator	—	INTRAVENOUS INFUSION	500	18	SUB06614MIG
PACLITAXEL	Comparator	—	INTRAVENOUS INFUSION	175	18	SUB09583MIG
DOSTARLIMAB	Test	—	INTRAVENIOUS INFUSION	100	24	SUB195307