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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arcagy Gineco

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Apr 2022 → ongoing

Decision date (initial)

2024-03-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

GSK

External identifiers

EU CT number

2023-510097-14-00

EudraCT number

2021-002124-21

ClinicalTrials.gov

NCT05201547

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenomic, Safety, Therapy, Efficacy

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.

Secondary objectives 12

1. Overall survival (OS)
2. Progression Free Survival 2 (PFS2)
3. Quality of Life (QoL)
4. Best objective Response Rate (ORR)
5. Disease control rate (DCR)
6. Duration of Response Rate (DoR)
7. PFS, DoR as per investigator assessment
8. Safety and tolerability Assessed according to CTCAE v5.0 (by investigators) and assessed according to NCI PRO-CTCAE (by patients)
9. Time to first and second Subsequent Treatment (TFST and TSST)
10. Efficacy of second systemic therapies
11. To describe the pharmacokinetics of dostarlimab
12. To determine the immunogenicity of dostarlimab

Conditions and MedDRA coding

Patients with MMR deficient relapse or advanced / metastatic endometrial cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1. Female patient is at least 18 years of age
2. 2. Patient has signed the Informed Consent (ICF) and is able to comply with protocol requirements
3. 3. Patient with histologically proven endometrial adenocarcinoma with recurrent or advanced disease
4. 4. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
5. 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 – 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
6. 6. Patient with evaluable disease (measurable and not measurable disease) according to RECIST 1.1
7. 7. 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)
8. 8. All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H
9. 9. 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
10. 10. Availability of 1 block for MMR/MSI status centralized confirmation for IHC or PCR / NGS.
11. 11. Patient could have been previously treated with hormone therapy, for the metastatic/advanced disease
12. 12. Patient may have received pelvic and lombo-aortic external beam +/- vaginal brachytherapy
13. 13. 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
14. 14. 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
15. 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 site’s source documents).

Exclusion criteria 20

1. 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. 2. Patient has had > 1 recurrence of endometrial cancer, treated with chemotherapy. Surgery of the recurrence is allowed
3. 3. Patient previously treated with systemic chemotherapy for noncurable advanced disease or metastatic disease
4. 4. Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
5. 5. 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
6. 6. Patient with contraindication to chemotherapy or checkpoint inhibitor treatments
7. 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. 8. Patient has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both
9. 9. Patient has a known history of human immunodeficiency virus (HIV; HIV 1 or 2 antibodies)
10. 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. 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. 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. 13. 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
14. 14. Patient has not recovered adequately from AEs or complications from any major surgery prior to starting therapy
15. 15. Patient has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients
16. 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. 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. 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 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
19. 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. 20. Patients who had an allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS) assessed per BICR (Blinded Independent Central Review)

Secondary endpoints 12

1. Overall survival (OS)
2. Progression Free Survival 2 (PFS2)
3. Quality of Life (QoL)
4. Best objective Response Rate (ORR)
5. Disease control rate (DCR)
6. Duration of Response Rate (DoR)
7. PFS, DoR as per investigator assessment
8. Safety and tolerability
9. Time to first and second Subsequent Treatment
10. Efficacy of second systemic therapies
11. To describe the pharmacokinetics of dostarlimab
12. To determine the immunogenicity of dostarlimab

Investigational products

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

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arcagy Gineco

Sponsor organisation

Arcagy Gineco

Address

1 Parvis Notre Dame Place Jean Paul Ii

City

Paris

Postcode

75004

Country

France

Scientific contact point

Organisation

Arcagy Gineco

Contact name

Florence Joly

Public contact point

Organisation

Arcagy Gineco

Contact name

Florence Joly

Third parties 1

Locations

4 EU/EEA countries · 92 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 50 files

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

Application history

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