Randomized phase III trial in MMR deficient endometrial cancer patients comparing chemotherapy alone versus Dostarlimab in first line advanced/metastatic setting: DOMENICA STUDY

JRCT ID: jRCT2031240065

Registered date:07/05/2024

Basic Information

• Recruitment status: Pending
• Health condition(s) or Problem(s) studied: endometrial adenocarcinoma
• Date of first enrollment: 01/05/2024
• Target sample size: 6
• Countries of recruitment: France,Japan,Belgium,Japan,Spain,Japan,Italy,Japan,Germany,Japan,Canada,Japan,United Kingdom,Japan,Switzerland,Japan,South Korea,Japan,Singapore,Japan,Australia,Japan,Turkiye,Japan
• Study type: Interventional

Intervention(s)

Patients will be randomized 1:1 to receive either 4 cycles of dostarlimab followed by dostarlimab as maintenance
up to 2 years or 6 cycles of carboplatin-paclitaxel:
Arm A: Dostarlimab 500 mg, every 3 weeks, 4 cycles and then 1000 mg every 6 weeks until progression,
unacceptable toxicity, patient/investigator decision to withdrawal or completion of 2 years of treatment*
Arm B: Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2, every 3 weeks, 6 cycles.
A cross over is allowed at first progression.

Outcome(s)

Primary Outcome

Progression Free Survival (PFS) assessed per BICR (Blinded Independent
Central Review)
defined as the time from the date of randomization
until objective tumor progression based on RECIST 1.1 by BICR (Blinded
Independent Central Review), or death due to any cause, whichever
occurs first. Patients alive and free of progression will be censored at
the last disease assessment date.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Female

Include criteria

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 IIIA to C2 or Stage IV disease or first recurrent endometrial cancer (see International Federation of Gynecology and Obstetrics staging FIGO Staging 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 IIIA-IIIC1 with not 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 lumbo-aortic nodes after lumbo-aortic dissection, which cannot be treated by curative radiotherapy) or Stage IV disease.
c) Patient has recurrent disease and is chemotherapy naive for recurrence or advanced / metastatic setting.
d) Patient may have received prior irradiation for advanced endometrial cancer with or without radiosensitizing chemotherapy if > 2 weeks before the start of the study
6. Patient with evaluable disease (measurable and not measurable disease) according RECIST 1.1 criteria
7. 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).
8. All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H,
9. Patient with MMRd/MSI-H status (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), the MSI-H status will be assessed by PCR/NGS.
10. Availability of 1 block for MMR/MSI status centralized confirmation for IHC or NGS/PCR, and additional block(s) for Translational Research
11. Patient could have been previously treated with hormone therapy, for the metastatic/advanced disease
12. Patient may have received pelvic and lombo-aortic external beam +/- vaginal brachytherapy
13. Patient has adequate organ function, defined as follows:
a) Absolute neutrophil count >= 1,500 cells/uL
b) Platelets >= 100,000 cells/uL
c) Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
d) Serum creatinine =< 1.5x upper limit of normal (ULN) or calculated creatinine clearance >= 50 mL/min using the Cockcroft-Gault equation for patients with creatinine levels > 1.5 x institutional ULN
e) Total bilirubin =< 1.5 x ULN (=< 2.0 x ULN in patients with known Gilberts syndrome) or direct bilirubin =< 1 x ULN
f) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN unless liver metastases are present, in which case they must be =< 5 x ULN
g) International normalized ratio or prothrombin time (PT) =<1.5 x ULN and activated partial thromboplastin time =<1.5 x ULN. Patients receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants.
14. Patient must have a negative serum pregnancy test within 72 hours prior to 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 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 sites source documents.
15. 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 sites source documents).

Exclude criteria

1. 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.
2. Patient has had > 1 recurrence of endometrial cancer, treated with
chemotherapy. Surgery of the recurrence is allowed.
3. Patient previously treated with systemic chemotherapy for noncurable
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 for advanced or
metastatic disease (targeted therapies, hormonal therapy,
GINECO-EN105b/ENGOT-en13 - DOMENICA - Protocol - Version 3.0 - 08/03/2023
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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 greater than or equal to 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 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.
8. Patient has known uncontrolled central nervous system metastases,
carcinomatosis meningitis, or both. Note: Patients with previously
treated brain metastases may participate provided they are stable
(without evidence of disease progression by imaging [using the
identical imaging modality for each assessment, either MRI or CT scan]
for at least 4 weeks prior to the first dose of study treatment and any
neurologic symptoms have returned to baseline), have no evidence of
new or enlarging brain metastases, and have not been using steroids
for at least 7 days prior to study treatment. Carcinomatous meningitis
precludes a patient from study participation regardless of clinical
stability.
9. Patient has a known history of human immunodeficiency virus (HIV;
HIV 1 or 2 antibodies).
10. 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).
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 less than or equal to 1 or to baseline) from
cytotoxic therapy-induced adverse events (AEs).
Note: Patients with Grade less than or equal to 2 neuropathy, Grade less than or equal to 2 alopecia, or Grade
less than or equal to 2 fatigue are an exception to this criterion and may qualify for the
study.
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.
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 systemic corticoid use at higher dose,
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.
19. 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.
20. Patients who had an allogenic tissue/solid organ transplant.

Related Information

• Primary Sponsor: Hasegawa Kosei
• Source(s) of Monetary Support: ARCAGY -GINECO(Association de Recherche sur les CAncers dont GYnecologiques)