Clinical trial NCT05201547: Endometrial Cancer Patientes MMR Deficient Comparing Chemotherapy vs Dostarlimab in First Line
Official title: Randomized Phase III Trial in MMR Deficient Endometrial Cancer Patients Comparing Chemotherapy Alone Versus Dostarlimab in First Line Advanced/Metastatic Setting
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Endometrial Cancer
Keywords: MMR
first line
metastatic
dostarlimab
Lead sponsor: ARCAGY/ GINECO GROUP
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2022-01-21
Enrollment: 260
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase 3, randomized, multicentre study to evaluate the efficacy and safety of dostarlimab versus carboplatin-paclitaxel in patients with MMR deficient relapse or advanced endometrial cancer.

Detailed description: Phase III, randomized, open label, multi-centre study.

Randomization on a 1:1 ratio, stratification performed according to:

* Prior adjuvant chemotherapy (yes or no)
* Prior pelvic radiotherapy (yes or no)
* Disease status: newly diagnosed advanced / metastatic disease versus relapse

Eligibility criteria: Inclusion Criteria:

* Patients must fulfil all the following 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:

     1. Patient has patient has primary Stage IIIA-IIIC1 with no amenable curative intent surgery or radiation.
     2. Patient has first recurrent disease and is chemotherapy naïve for this 1st recurrence or metastatic setting.
     3. Patient has recurrent disease and is chemotherapy naïve for recurrence or advanced /metastatic setting.
     4. 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. Patient with evaluable disease (measurable and not measurable disease) according to RECIST 1.1
  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. All histologic subtypes of endometrial adenocarcinoma could be included if MMRd/MSI-H
  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. Availability of 1 block for MMR/MSI status centralized confirmation for IHC or PCR/ NGS
  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/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 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. 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:
  1. Patient is ≥ 45 years of age and has not had menses for \> 1 year.
  2. A follicle-stimulating hormone value in the postmenopausal range upon screening evaluation if amenorrhoeic for \< 2 years without a hysterectomy and oophorectomy.
  3. 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. Patient of childbearing potential must agree to use a highly effective method of contraception (section 18.9) with their partners starting from time of consent through 150 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:

* Patients are to be excluded from the study if they meet any of the following 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 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 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. 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. 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 ≤ 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. 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 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. 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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: from the date of randomization until objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 5 years.
Secondary outcomes:
measure: Overall Survival (OS) (key secondary endpoint)
timeFrame: from the date of randomization until death due to any cause, assessed up to 5 years
measure: Progression Free Survival 2 (PFS2)
timeFrame: from the date of randomization until second objective tumor progression based on RECIST 1.1, or death due to any cause, whichever occurs first assessed up to 5 years
measure: Quality Of Life evaluation based on Quality of Life Questionnaire EQ5D5L (The 5-level EQ-5D version)
timeFrame: through study completion, an average of 5 years
measure: To assess the effects of Dostarlimab on Health related quality of Life (QoL) based on EORTC QLQ C30 (Quality of Life questionnaire-core 30)
timeFrame: Defined as the Global Health Status score from the EORTC QLQ C30 at 18 weeks, assessed up to 5 years
measure: To assess the quantity of peripheral neuropathy event induced by chemotherapy based on EORTC QLQ-CIPN 20 (Quality of Life questionnaire-Chemotherapy induced peripheral neuropathy 20)
timeFrame: Defined as the Global Health Status score from the EORTC QLQ-CIP20 at 18 weeks, assessed up to 5 years
measure: To assess the effects of treatment on health-related quality of life (HRQoL) as measure by determining time to deterioration in Quality of life, based EORTC QLQ-EN24 (Quality of Life Questionnaire - Endometrial Cancer Module)
timeFrame: Defined as the Global Health Status score from the EORTC QLQ-EN24 at 18 weeks, assessed up to 5 years
measure: To assess the status of health for patients with endometrial cancer based on EUROQOL EQ-5D (Descriptive system)
timeFrame: Defined as the Global Health Status score from the EUROQOL EQ-5D at 18 weeks, assessed up to 5 years
measure: Best Objective Response Rate (ORR)
timeFrame: from the date of randomization until best objective response based on RECIST 1.1, assessed up to 5 years
measure: Disease Control Rate (DCR)
timeFrame: from the date of randomization until response or stable disease per RECIST 1.1, assessed up to 5 years
measure: Duration of Response Rate (DoR)
timeFrame: from the time of initial response until documented tumor progression ,assessed up to 5 years
measure: Safety and number of adverse events
timeFrame: From date of randomization until end of study, assessed up to 6 years
measure: Tolerability to the treatment
timeFrame: From date of randomization until end of study, assessed up to 6 years
measure: Time to first and second Subsequent Treatment
timeFrame: from the date of randomization to date of event, assessed up to an average of 5 years
measure: To determine the immunogenicity of dostarlimab
timeFrame: from randomisation to 12 weeks after end of treatment, assessed at study end
Other outcomes:
Locations:
city: Garran
country: Australia
facility: Canberra Hospital
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Amiens
country: France
facility: CHU d'Amiens - Hôpital Sud
city: Amiens
country: France
facility: Clinique de l'Europe
city: Angers
country: France
facility: ICO Paul Papin
city: Auxerre
country: France
facility: Centre Hospitalier d'Auxerre
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Beauvais
country: France
facility: CH Simone Veil de Beauvais
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: Centre François Baclesse
city: Chalon-sur-Saône
country: France
facility: Centre Hospitalier William Morey
city: Chambray-lès-Tours
country: France
facility: ROC 37
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Creil
country: France
facility: GHPSO
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Dijon
country: France
facility: CHU de Dijon
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: APHM - Hôpital de la Timone
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: Hôpital Saint-Joseph
city: Mont de Marsan
country: France
facility: Hôpital de Mont-de-Marsan
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Nancy
country: France
facility: Médipôle de NANCY SAS
city: Nantes
country: France
facility: Hôpital Privé du Confluent S.A.S.
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: Institut de cancérologie du gard
city: Orléans
country: France
facility: Centre Hospitalier Régional
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: AP-HP Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses-Croix Saint-Simon
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Pau
country: France
facility: Centre Hospitalier Général de Pau
city: Plérin
country: France
facility: Centre CARIO - HPCA
city: Poitiers
country: France
facility: CHU de Poitiers - Hôpital de la Milétrie
city: Quimper
country: France
facility: CHI de Cornouaille
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Grégoire
country: France
facility: Centre Hospitalier Privé de Saint-Grégoire
city: Saint-Herblain
country: France
facility: ICO - Centre René Gauducheau
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne - Pôle de Cancérologie
city: Strasbourg
country: France
facility: Institut de Cancérologie de Strasbourg Europe - ICANS
city: Toulouse
country: France
facility: Institut Claudius Régaud
city: Tours
country: France
facility: CHU Bretonneau
city: Vandœuvre-lès-Nancy
country: France
facility: ICL - Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Biella
country: Italy
facility: Ospedale degli Infermi
city: Brescia
country: Italy
facility: Spedali Civili-Università di Brescia
city: Faenza
country: Italy
facility: Ospedale Civile degli Infermi
city: Lugo
country: Italy
facility: Ospedale "Umberto I"
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Ravenna
country: Italy
facility: Ospedale "Santa Maria delle Croci"
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale
city: Ehime
country: Japan
facility: Ehime University Hospital
city: Fukuoka
country: Japan
facility: Kurume University Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Koto-Ku
country: Japan
facility: The Cancer Institute Hospital Of JFCR
city: Niigata
country: Japan
facility: Niigata Cancer Center Hospital
city: Saitama
country: Japan
facility: Saitama Medical University International Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei Medical Center Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Singapore
country: Singapore
facility: National University Hospital (NUH)
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore (NCCS)
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol / ICO Badalona
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: León
country: Spain
facility: Hospital Universitario de León
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llátzer
city: Palma
country: Spain
facility: Hospital Universitario Son Espases
city: Santiago De Compostela
country: Spain
facility: Hospital Clínico Universitario Santiago de Compostela
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital NHS Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Centre François Baclesse
name: Florence JOLY, Pr
role: PRINCIPAL_INVESTIGATOR
References: