RUBY ENGOT-EN6

Samenvatting

A Phase 3, Randomized, Double-blind, Multicenter Study of Dostarlimab (TSR-042) plus Carboplatin-paclitaxel versus Placebo plus Carboplatin-paclitaxel in Patients with Recurrent or Primary Advanced Endometrial Cancer.

Primair eindpunt: PFS (RECIST) bij alle ptn en bij ptn met MSI-H

Secundair: OS, ORR, DOR, DCR, PROs, safety, exploratory

Aantal benodigde patiënten: 470

Deelnemende centra: 200 (Erasmus MC, Amsterdam UMC, MUMC, MST, UMCG, Catharina)

Inclusie criteria

  1. Female subject at least 18 years of age, who is able to understand the study procedures and agrees to participate in the study by providing written informed consent.
  2. Subject has histologically or cytologically proven endometrial cancer with recurrent or advanced disease.
  3. Subject must provide adequate tumor tissue sample at Screening for MSI status testingNote: The quality of the tumor tissue sample must be confirmed by the central laboratory during screening. Subjects should not be randomized without central laboratory confirmation.
  4. Subject must have primary Stage III or Stage IV disease or first recurrent endometrial cancer (see International Federation of Gynecology and Obstetrics staging in Appendix 4) with a low potential for cure by radiation therapy or surgery alone or in combination, and meet at least one of the following criteria:
    a. Subject has primary Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per RECIST v.1.1 based on Investigator’s assessment. Lesions that are equivocal or can be representative of postoperational change should be biopsied and confirmed for the presence of tumor.
    b. Subject has primary Stage IIIC1 disease with carcinosarcoma, clear cell, serous, or mixed histology (containing = 10% carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging.
    c. Subject has primary Stage IIIC2 or Stage IV disease.
    d. Subject has first recurrent disease and is chemotherapy naïve.
    e. Subject has received prior neo-adjuvant/adjuvant systemic chemotherapy and had a recurrence or PD = 6 months after completing treatment (first recurrence).
  5. Subject has an ECOG performance status of 0 or 1.
  6. Subject 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 subjects with creatinine levels > 1.5 × institutional ULN
    e. Total bilirubin ≤ 1.5× ULN and direct bilirubin ≤ 1× ULN
    f. Aspartate aminotransferase and alanine aminotransferase ≤ 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. Subjects receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of the intended use of anticoagulants.
  7. Subject 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. Subject 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 amenorrheic for < 2 years without a hysterectomy and oophorectomy.
    c. Posthysterectomy, postbilateral oophorectomy, or posttubal ligation.

Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT) scan.

Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the subject must fulfill the criteria in Inclusion Criterion 8.

en verder: zie protocol.

Exclusie criteria

Subject has received neo-adjuvant/adjuvant systemic chemotherapy for primary Stage III or IV disease and:
a. has not had a recurrence or PD prior to entering the study
OR
b. 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 subjects from study participation.

  1. Subject has had > 1 recurrence of endometrial cancer.
  2. Subject has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1, or anti- programmed cell death-ligand 2 agent.
  3. Subject has received prior anticancer therapy (chemotherapy, targeted therapies, hormonal therapy, radiotherapy, or immunotherapy) 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.
  4. Subject has a concomitant malignancy, or subject 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.
  5. Subject has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of PD 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 subject from study participation regardless of clinical stability.
  6. Subject has a known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
  7. Subject has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
  8. Subject 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)
  9. Subject 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.
  10. Subject has not recovered (ie, to Grade ≤ 1 or to baseline) from cytotoxic therapy-induced AEs. Note: Subjects with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2 fatigue are an exception to this criterion and may qualify for the study.
  11. Subject has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
  12. Subject has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
  13. Subject 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.
  14. Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, noninfectious 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)

Randomisatie

Ja

Aanvullende onderzoeken bij randomisatie of tijdens de studie

anamnese, Lichamelijk onderzoek, voorgeschiedenis, medicatie, ECOG
ECG
LAB
urine
CT scans
biomarker
tumorweefsel
PROs

Contactgegevens

PI Ingrid Boere, Erasmus MC