Phase 3 Randomized Trial of Trastuzumab Deruxtecan and Bevacizumab Versus Bevacizumab Monotherapy in HER2-Expressing Ovarian Cancer Maintenance Therapy
- Trial ID
- 2024-516982-35-00
- Protocol
- DS8201-772
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of Trastuzumab Deruxtecan (T-DXd) in combination with Bevacizumab during the Safety Run-in phase. Additionally, the study aims to compare the efficacy of T-DXd combined with Bevacizumab (Arm A) versus Bevacizumab monotherapy (Arm B) by measuring **Progression Free Survival** (PFS), as assessed by Blinded Independent Central Review (BICR) in the HER2 IHC 3+/2+ population during the Randomized phase. This is clinically relevant as it seeks to determine the potential benefits of combining T-DXd with Bevacizumab in treating HER2-expressing **ovarian cancer**, potentially offering a more effective first-line maintenance therapy.
The secondary objectives include:
- Comparing the efficacy of Arm A versus Arm B as measured by Overall Survival (OS) in both HER2 IHC 3+/2+ and HER2 IHC 3+/2+/1+ populations.
- Evaluating the efficacy of Arm A versus Arm B as measured by Progression Free Survival (PFS), as assessed by BICR and by the investigator in both HER2 IHC 3+/2+ and HER2 IHC 3+/2+/1+ populations.
- Assessing the efficacy of Arm A versus Arm B as measured by PFS2, Overall Response Rate (ORR), Duration of Response (DoR), Time to First Subsequent Therapy (TFST), and Time to Second Subsequent Therapy (TSST) in both HER2 IHC 3+/2+ and HER2 IHC 3+/2+/1+ populations.
- Evaluating the safety and tolerability of Arm A versus Arm B.
- Assessing patient-reported outcomes for overall health status, functioning, and symptom burden in participants treated with Arm A versus Arm B.
Participants
The clinical trial involves a total of **401 participants** diagnosed with **ovarian cancer**. The study population consists exclusively of **female subjects** who are adults aged 18 years and older. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube, or primary peritoneal carcinoma, and newly diagnosed FIGO Stage III or IV. All participants have HER2 expression as per IHC scoring guidelines and have received standard care with bevacizumab in combination with frontline platinum-based chemotherapy. The trial does not include male subjects and involves a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have adequate tumor tissue samples for HER2 assessment and have undergone local HRD or BRCA testing, with eligibility to continue bevacizumab maintenance therapy. The sponsor has not provided additional information regarding other lifestyle considerations or health status beyond the specified criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the safety and efficacy of **trastuzumab deruxtecan** in combination with **bevacizumab** versus bevacizumab monotherapy as first-line maintenance therapy in patients with HER2-expressing **ovarian cancer**. The trial is structured into two phases: a safety run-in phase and a randomized phase. The primary objective is to assess progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) in the HER2 IHC 3+/2+ population. Secondary endpoints include overall survival and PFS in the HER2 IHC 3+/2+/1+ population, both assessed by BICR and investigators.
The trial is expected to commence recruitment on November 20, 2025, and conclude by December 17, 2031. Participants will be involved in the study for a maximum treatment period of 24 months for those receiving trastuzumab deruxtecan and 12 months for those on bevacizumab monotherapy. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. Participants will be required to provide informed consent prior to any trial-specific procedures, including tissue pre-screening for HER2 testing.
Inclusion criteria stipulate that participants must be adults aged 18 years or older with a histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube, or primary peritoneal carcinoma, newly diagnosed at FIGO Stage III or IV, and with HER2 expression as per IHC scoring guidelines. Participants must have received standard care bevacizumab in combination with frontline platinum-based chemotherapy and be eligible for single-agent bevacizumab maintenance. Conditions for early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent.
Treatment
The clinical trial involves the administration of **trastuzumab deruxtecan**, marketed under the product name DS-8201a, which is an **Antibody-Drug-Conjugate (ADC)**. This experimental medication is provided as a **solution for infusion** and is administered **intravenously**. The dosing regimen for trastuzumab deruxtecan is set at a maximum daily dose of 0.26 mg/kg, with a total maximum dose of 5.4 mg/kg. The treatment period for this medication extends up to 24 months. The active substance, trastuzumab deruxtecan, is a protein-based compound developed by Daiichi Sankyo, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
The comparator treatment in this study is **bevacizumab**, marketed as VEGZELMA 25 mg/mL concentrate for solution for infusion. Bevacizumab is also administered **intravenously** and is provided in a concentrate form that is prepared into a solution for infusion. The dosing for bevacizumab is set at a maximum daily dose of 15 mg/kg, with a total maximum dose of 15 mg/kg. The treatment duration for bevacizumab is up to 12 months. Bevacizumab is a protein-based therapeutic developed by Celltrion Healthcare Hungary Kft. Participant compliance with the administration schedule is closely monitored to ensure the integrity of the trial data.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the combination of **Trastuzumab Deruxtecan** and bevacizumab (Arm A) with bevacizumab monotherapy (Arm B) in patients with HER2-expressing ovarian cancer. The primary endpoint for evaluating efficacy is **Progression-Free Survival (PFS)**, as assessed by Blinded Independent Central Review (BICR) in the HER2 IHC 3+/2+ population. This will measure the time from randomization to the time of objective radiographic disease progression or death due to any cause, based on RECIST v1.1 criteria.
Secondary endpoints include Overall Survival (OS) in both the HER2 IHC 3+/2+ and HER2 IHC 3+/2+/1+ populations, as well as PFS by BICR and by the investigator in these populations. The time interval for OS is from the date of randomization to the date of death due to any cause. PFS by the investigator will also be assessed based on RECIST v1.1 criteria. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on disease progression and survival outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sign and date the tissue pre-screening ICF, prior to HER2 central testing. Sign and date the main ICF, prior to the start of any trial- specific qualification procedures. Consent to optional PGx prior to any PGx procedures. For participants in the safety run-in phase, a safety run-in ICF needs to be signed and dated prior to the start of any trial-specific qualification procedures.
- Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.
- Has histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube or primary peritoneal carcinoma per local assessment (including but not limiting to serous, endometrioid, clear cell, carcinosarcoma, mucinous).
- Is newly diagnosed FIGO Stage III or IV.
- Has HER2 expression per IHC scoring (3+/2+/1+) guidelines by prospective central testing. For participants in the safety run-in phase, HER2 expression assessed by either local (require using IHC scoring [IHC 3+/2+/1+] guidelines) or central assessment (if available) is acceptable. Submission of the pathology report is required for participants enrolled based on local HER2 IHC results.
- Has adequate tumor tissue sample available for assessment of HER2 by central laboratory. Tumor tissue block or sufficient tissue slides are required for HER2 testing and retrospective HRD status determination. Note: Participants in the safety run-in phase who are enrolled based on local HER2 IHC results are recommended to provide a tumor tissue sample from the same specimen for central assessment.
- Has a local HRD or BRCA test result available. Participants with BRCA wildtype will have a local HRD test results, as applicable.
- Has received up to 6 cycles of standard of care bevacizumab in combination with front line platinum based chemotherapy as per approved indication and clinical guidelines and is eligible to continue single agent bevacizumab maintenance per standard of care and investigator discretion.
Exclusion Criteria
- Has ovarian, fallopian tube, or peritoneal cancer of non-epithelial origin.
- Has a known or suspected deleterious BRCA alteration as per local test that makes the patient eligible for PARP inhibitor treatment.
- Participant to receive PARP inhibitor as maintenance per standard of care and investigator discretion. Reasons for which the participant is not eligible for PARP inhibitor will be recorded in the eCRF as follows: • HRD negative • HRD positive with SD as best response after platinum • HRD positive non-serous histology • HRD tested, but inconclusive • HRD positive but safety concern (safety concern to be specified).
- Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products and other monoclonal antibodies.
- Previous Cerebral-Vascular Accident, Transient Ischemic Attack or Sub- Arachnoids Hemorrhage within 6 months prior to randomization.
- Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation therapy).
- Has a history of hemorrhagic disorders, abdominal fistula, gastrointestinal perforation, or active gastrointestinal bleeding within 6 months before randomization.
- Evidence of active or ongoing bowel obstruction.
- Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, pneumonectomy, etc.).
- Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie pulmonary emboli within 3 months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (ie Rheumatoid arthritis, Sjogren's, sarcoidosis etc.), or prior pneumonectomy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 20 Nov 2025 | 12 |
 Belgium | Recruiting | 20 Nov 2025 | 6 |
 Bulgaria | Recruiting | 20 Nov 2025 | 7 |
 Czechia | Recruiting | 20 Nov 2025 | 6 |
 Denmark | Recruiting | 20 Nov 2025 | 4 |
 France | Recruiting | 20 Nov 2025 | 15 |
 Germany | Not Yet Recruiting | 20 Nov 2025 | 32 |
 Greece | Recruiting | 20 Nov 2025 | 6 |
 Hungary | Recruiting | 20 Nov 2025 | 14 |
 Italy | Recruiting | 20 Nov 2025 | 34 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 0.26 | 24 | PRD5308994 |
VEGZELMA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 15 | 12 | PRD9890813 |