Randomized phase III trial in MMR deficient endometrial cancer patients comparing chemotherapy alone versus Dostarlimab in first line advanced/metastatic setting: DOMENICA STUDY (GINECO-EN105b/ENGOT-en13 study)
- Conditions
- Endometrial cancerMedDRA version: 21.0Level: PTClassification code 10014733Term: Endometrial cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-002124-21-ES
- Lead Sponsor
- ARCAGY-GINECO
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Female
- Target Recruitment
- 142
1. Female patient is at least 18 years of age,
2. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements.
3. Patient with histologically proven endometrial adenocarcinoma with recurrent or advanced disease.
4. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
5. Patient must have primary Stage IIIC2 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 primary Stage IIIC2 (with nodes involvement from the outset, not allowing a curative radiotherapy, or with remaining measurable lumbo-aortic nodes after lumbo-aortic dissection, which cannot be treated by curative radiotherapy) or Stage IV disease.
b) Patient has first recurrent disease and is chemotherapy naïve for this 1st recurrence or metastatic setting.
c) Patient may have received prior neo-adjuvant/adjuvant systemic chemotherapy or loco-regional concomitant radio-chemotherapy for the primary cancer and had a recurrence = 6 months after completing treatment (first recurrence only).
6. All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H,
7. MMRd/MSI-H tumor (defined in routine local IHC), is mandatory for inclusion. In case of ambiguous result of IHC (lack of positive internal control, heterogeneous loss of MMR protein expression), the MMRd/MSI-H status will be assessed by PCR/NGS.
8. Availability of 1 block for MMR/MSI status centralized confirmation for IHC or PCR/ NGS, and additional block(s) for Translational Research
9. Patient with measurable disease according RECIST 1.1 criteria 10. Patient could have been previously treated with hormone therapy, for the metastatic/advanced disease
11. Patient may have received pelvic and lombo-aortic external beam +/- vaginal brachytherapy.
12. Patient has adequate organ function, defined as follows:
a) Absolute neutrophil count = 1,500 cells/µL
b) Platelets = 100,000 cells/µL
c) Hemoglobin = 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
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.
13. Patient must have a negative serum pregnancy test within 72 hours of the first dose of study medication, unless they are of nonchildbearing potential. Nonchildbearing 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 oophorecto
1. Patient has received neoadjuvant/adjuvant systemic chemotherapy for primary Stage IIIc2 or IV disease and has had a recurrence or PD within 6 months of completing 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.
2. Patient has had > 1 recurrence of endometrial cancer, treated with chemotherapy. Surgery of the recurrence is allowed.
3. Patient previously treated with chemotherapy for non-curable advanced disease or metastatic disease.
4. Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
5. Patient has received prior anticancer therapy (chemotherapy, 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.
6. Patient with contraindication to chemotherapy or checkpoint inhibitor treatments
7. Patient has a concomitant malignancy, or patient has a prior non-endometrial 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.
8. Patient has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both.
9. Patient has a known history of human immunodeficiency virus (HIV; HIV ½ antibodies).
10. Patient has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
11. 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).
12. 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.
13. Patient has not recovered (ie, to Grade = 1 or to baseline) from cytotoxic therapy-induced adverse events (AEs).
14. Patient has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
15. Patient has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
16. 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.
17. 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).
18. 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 systemi
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Progression Free Survival (PFS) defined as the time from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first;Primary end point(s): Progression Free Survival (PFS);Timepoint(s) of evaluation of this end point: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first.;Secondary Objective: • Quality of Life (QoL) <br>• Objective Response Rate (ORR)<br>• Overall survival (OS) <br>• Duration of Response Rate (DoR)<br>• Safety and tolerability Assessed by CTCAE v5.0 (by investigators) and assessed by NCI PRO-CTCAE (by patients)<br>• Time to first and second Subsequent Treatment (TFST and TSST)
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Quality of Life (QoL)<br>• Objective Response Rate (ORR)<br>• Overall survival (OS)<br>• Duration of Response Rate (DoR)<br>• Safety and tolerability<br>• Time to first and second Subsequent Treatment;Timepoint(s) of evaluation of this end point: A COMPLETER