A Phase 3, Open-label, Multicenter, Randomized Trial of Trastuzumab Deruxtecan with Bevacizumab Versus Bevacizumab Monotherapy as First-line Maintenance Therapy in HER2-Expressing Ovarian Cancer. (DESTINY-Ovarian01/ENGOT-ov89/GEICO144-O/GOG-3112)

This
is a global, multicenter, open-label, phase 3 trial to evaluate the efficacy
and safety of T-DXd in combination with bevacizumab versus bevacizumab monotherapy as
first-line maintenance therapy, in participants with human epidermal growth
factor 2 (HER2)-expressing (immunohistochemistry [IHC] 3+/2+/1+) advanced
high-grade epithelial ovarian cancer.

 The primary endpoint for the randomization phase of efficacy is progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the IHC 3+/2+ population.

 A non-randomized safety run-in phase will be established to assess the safety of T-DXd in combination with bevacizumab. Analysis of safety run-in will be conducted after approximately 20 participants have completed at least 2 cycles of trial intervention. Enrollment will be temporally paused until safety assessment is completed. All participants will receive T-DXd (5.4 mg/kg intravenous (IV) every 3 weeks (Q3W) up to a maximum of 34 cycles in combination with bevacizumab (15 mg/kg Q3W up to 16 cycles in the maintenance setting is allowed; NOTE: A maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with front-line chemotherapy).

The safety run-in phase will be divided into the following periods:

•            Tissue Prescreening Period: The Tissue Prescreening Period will occur before the Main Screening Period and upon signature of the tissue prescreening informed consent. Tissue prescreening will be optional for participants in the safety run-in phase. For participants in the safety run-in phase without local HER2 IHC test results (require using American Society of Clinical Oncology [ASCO]-College of American Pathologists [CAP] gastric cancer IHC scoring [IHC 3+/2+/1+] guidelines1), archived or newly obtained formalin-fixed, paraffin embedded tumor tissue samples or wet tissue as appropriate for tissue prescreening will be collected and sent to central laboratory for HER2 confirmation of eligibility. Tumor tissue block or sufficient tissue slides are required for HER2 testing.

•            Screening Period: A 28-day Screening Period starts after collection of safety run-in informed consent for eligible participants. Participants will be enrolled once all eligibility criteria have been met and will then enter the Treatment Period. A maximum of 3 days is allowed between enrollment and the first dose of the trial intervention. HER2 expression (IHC 3+/2+/1+) assessed by either local (require using ASCO-CAP gastric cancer IHC scoring [3+/2+/1+] guidelines) or central assessment (if available) will be acceptable for participants in the safety run-in phase.

 •            Treatment Period: During the Treatment Period, participants will receive the trial intervention(s) until progressive disease  (PD), completion of the trial intervention,  unacceptable toxicity, death, or discontinuation from the trial intervention for any other reason up to a maximum of 34 cycles for T-DXd and up to 16 cycles for bevacizumab (a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with chemotherapy). Trial intervention is to start within 3 to 12 weeks of the last dose of front-line chemotherapy. Radiographic evaluations will be performed. BICR assessment will not be implemented for participants in the safety run-in phase.

 •            Follow-up Period: The Follow-up Period begins upon the permanent discontinuation of the trial interventions at any time. Participants will be followed 40 days (+7 days) after the last trial intervention administration or before starting subsequent anticancer treatment, whichever comes first. After completion of the 40-Day Follow-up Visit, subsequent long-term survival follow-up (LTSFU) visits will occur at the following frequencies to assess survival and collect information on anticancer treatments: every 3 months (plus minus 14 days) for the first 2 years and every 6 months (plus minus  14 days) thereafter until death, withdrawal of consent, lost to follow-up, or trial termination by the Sponsor, whichever occurs first. Participants without radiographic tumor progression per investigator assessment will continue radiographic. BICR assessment will not be implemented for participants in the safety run-in phase. Participants will be followed for survival regardless of trial intervention discontinuation for any reasons (except if consent is withdrawn from the trial).

 Enrollment of the randomization phase will start when a decision has been made to proceed with the randomization phase based on the safety run-in assessment, approximately 562 eligible participants (which will include a minimum of 168 [30 percent ] participants who are HER2 IHC 3+ and a maximum of 82 [15%]

participants who are HER2 IHC 1+) will be randomized in a 1:1 ratio to T-DXd in combination with bevacizumab or bevacizumab monotherapy as first-line maintenance therapy after first-line platinum-based chemotherapy. No crossover between treatment arms within trial will be allowed.

•            Treatment Arm A (experimental arm): T-DXd (5.4 mg/kg IV Q3W up to a maximum of 34 cycles) in combination with bevacizumab (15 mg/kg Q3W up to 16 cycles in the maintenance setting is allowed; NOTE: a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with front-line chemotherapy).

 •            Treatment Arm B (control arm): Bevacizumab monotherapy as first-line maintenance therapy (15 mg/kg IV Q3W up to 16 cycles; a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with front-line chemotherapy).

Participants will be stratified by:

•            HER2 status: IHC 3+ versus 2+ versus 1+

•            Outcome of surgery: No residual disease after PDS versus other

Note: “Other” will include participants with either residual disease after primary debulking

surgery (PDS) or interval debulking surgery (IDS) or no surgery.

•            Histology: high-grade serous versus non-serous histology.

 The randomization phase will be divided into the following periods:

•            Tissue Prescreening Period: The Prescreening Period will occur before the Main Screening Period and upon signature of the tissue prescreening informed consent. Archived or newly obtained formalin-fixed, paraffin- embedded tumor tissue samples or wet tissue as appropriate for tissue prescreening will be collected and sent to central laboratory for HER2 confirmation of eligibility. Tumor tissue block or sufficient tissue slides are required  for  HER2  testing  and  retrospective  homologous  recombination  deficiency  (HRD) determination.

 •            Main Screening Period: A 28-day Screening Period starts after collection of main informed consent for eligible participants based on HER2 central testing results from the Tissue Prescreening Period. Participants will be randomized once all eligibility criteria have been met and will then enter the Treatment Period. A maximum of 3 days is allowed between randomization and the first dose of the trial intervention.

•            Treatment Period: During the Treatment Period, participants will receive the trial intervention(s) until PD, completion of the trial intervention, unacceptable toxicity, death, or discontinuation from the trial intervention for any other reason up to a maximum of 34 cycles for T-DXd and up to 16 cycles for bevacizumab (a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with chemotherapy). Trial intervention is to start within 3 to 12 weeks of the last dose of front-line chemotherapy. Radiographic evaluations will be performed as described in the SoA

 •            Follow-up Period: The Follow-up Period begins upon the permanent discontinuation of the trial interventions at any time. Participants will be followed 40 days (+7 days) after the last trial intervention, administration or before starting subsequent anticancer treatment, whichever comes first. After completion of the 40-Day Follow-up Visit, subsequent- LTSFU visits will occur at the following frequencies to assess survival and collect information on anticancer treatments: every 3 months (plus minus 14 days) for the first 2 years and every 6 months (plus minus 14 days) thereafter until death, withdrawal of consent, lost to follow-up, or trial termination by the Sponsor, whichever occurs first. Participants without radiographic disease progression confirmed by BICR will continue to undergo tumor assessments every 6 weeks (plus minus 7 days) for the first 6 months and every 9 weeks (plus minus 7 days) (irrespective of starting new anticancer therapy treatment) thereafter until both the investigator and BICR determine radiographic disease progression or until the participant withdraws from trial. Participants will be followed for survival regardless of trial intervention discontinuation for any reasons (except if consents withdrawn from the trial).