Clinical Trial 23362

• Overview

  Study Title:

  DESTINY-Endometrial01: An Open-Label, Sponsor-Blinded, Randomized, Controlled, Multicenter, Phase III Study of Trastuzumab Deruxtecan (T-DXd) Plus Rilvegostomig or Pembrolizumab vs Chemotherapy Plus Pembrolizumab as First-Line Therapy of HER2-Expressing (IHC 3+/2+), Mismatch Repair Proficient (pMMR), Primary Advanced or Recurrent Endometrial Cancer

  Summary:

  DESTINY-Endometrial01 will investigate the efficacy of first-line T-DXd + rilvegostomig (Arm A) and/or T-DXd+ pembrolizumab (Arm B) when compared to chemotherapy (carboplatin + paclitaxel) + pembrolizumab (Arm C), by assessment of progression free survival (PFS), as assessed by BICR, in participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC.

  Objective:

  Primary * To demonstrate the efficacy of first-line T-DXd + rilvegostomig (Arm A) and/or T-DXd + pembrolizumab (Arm B) when compared to chemotherapy (carboplatin + paclitaxel) + pembrolizumab (Arm C), by assessment of progression free survival (PFS), as assessed by blinded independent central review (BICR), in participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC. Key Secondary Objective * To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of overall survival (OS). * To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of PFS as assessed by the investigator. * To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of time from randomization to second progression or death (PFS2). * To assess the efficacy of Arm A and/or Arm B relative to Arm C in terms of the confirmed ORR according to BICR and investigator assessment. * To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of duration of response (DoR) according to BICR and investigator assessment. * To assess the efficacy of Arm A compared to Arm B in terms of PFS, as assessed by BICR. * To assess the efficacy of Arm A compared to Arm B in terms of OS. * To assess the safety and tolerability of Arm A and/or Arm B compared to Arm C. * To assess the PK of T-DXd, total anti-HER2 antibody, DXd, and rilvegostomig in serum. * To investigate the immunogenicity of T-DXd and rilvegostomig. * To describe patient-reported tolerability of Arm A and/or Arm B compared to Arm C. * To collect and assess tissue samples for development of regulated companion diagnostics for the detection of HER2 expression and MMR status

• Treatments

  Therapies:

  ADC consisting of a humanized anti-HER2 mAb.; Chemotherapy (NOS); humanized IgG1 antibody targeting PD-1 and TIGIT; mAb binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2.

  Medications:

  Paraplatin (carboplatin); Pembrolizumab (Keytruda); Rilvegostomig (); T-Dxd (); Taxol (paclitaxel); carboplatin (); paclitaxel ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Participants must be ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations.
  • Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies are allowed except for sarcomas (carcinosarcomas are allowed).
  • Following surgery or diagnostic biopsy, participant must have primary advanced disease (Stage III/IV) or first recurrent endometrial cancer and meet at least one of the following criteria: 1) Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment. 2) Primary Stage IV disease (per FIGO 2023) regardless of presence of measurable disease at baseline. 3) First recurrent disease regardless of presence of measurable disease at baseline.
  • Endometrial cancer with HER2 IHC expression of 3+ or 2+ as assessed by prospective central testing.
  • Endometrial cancer that is determined pMMR by prospective central IHC testing.
  • Provision of adequate FFPE tumor tissue sample of a tumor lesion that was not previously irradiated for central HER2, MMR, and PD-L1 IHC testing and valid central test results for randomization/ stratification.
  • Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
  • Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before randomization.
  • Adequate organ and bone marrow function within 14 days before randomization.
  • Additional criteria will apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • History of organ transplant
  • Uncontrolled intercurrent illness, including, but not limited to ongoing or active known infection, serious chronic gastrointestinal conditions associated with diarrhea and active non-infectious skin disease requiring systemic treatment.
  • Spinal cord compression or clinically active central nervous system metastases
  • Participants with a medical history of myocardial infarction (MI) within 6 months before randomization, or symptomatic congestive heart failure (CHF) (NYHA Class II to IV), clinically significant arrhythmia, or cardiomyopathy of any etiology. Participants with troponin levels above ULN at screening (as defined by the manufacturer), should have a cardiologic consultation before enrollment to rule out MI
  • History of (non-infectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
  • Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
  • Any concurrent anticancer treatment without an adequate washout period prior to the first dose of study intervention. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., HRT) is allowed.
  • Additional criteria will apply.

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