Phase 2/3 Multicenter Randomized Study of Raludotatug Deruxtecan in Platinum-Resistant High-Grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
- Trial ID
- 2023-507914-28-00
- Protocol
- DS6000-109
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **BICR-assessed ORR** (Best Independent Central Review-assessed Overall Response Rate) at each dose level of **Raludotatug Deruxtecan (R-DXd)** in subjects with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer during Phase 2. In Phase 3, the study aims to compare the BICR-assessed ORR and **PFS** (Progression-Free Survival) of R-DXd treatment with the investigator’s choice of standard chemotherapy options, including paclitaxel, PLD (pegylated liposomal doxorubicin), gemcitabine, or topotecan. These objectives are clinically relevant as they aim to determine the efficacy of R-DXd, a CDH6-directed antibody-drug conjugate, in improving response rates and delaying disease progression in a population with limited treatment options due to platinum resistance.
Participants
The clinical trial involves a total of **423 participants** who are exclusively **female** and have been diagnosed with **platinum-resistant, high-grade serous ovarian cancer**, high-grade endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. The study population is composed of adult women aged **18 years and older**, with an **Eastern Cooperative Oncology Group performance status** of 0 or 1, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their medical history, including having received at least one but no more than three prior systemic lines of anticancer therapy. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with study procedures and restrictions. The trial specifically excludes male subjects and includes a vulnerable population, as defined by the study criteria. Key inclusion criteria require participants to have at least one measurable lesion and a history of prior treatment with specific therapies, such as poly-ADP ribose polymerase inhibitors, if applicable. The trial does not provide information on lifestyle habits or other demographic details beyond those specified.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **Raludotatug Deruxtecan** in subjects with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer. The trial is structured in two phases: Phase 2 and Phase 3. The primary objective of Phase 2 is to assess the objective response rate (ORR) at each dose level of Raludotatug Deruxtecan, while Phase 3 aims to compare the ORR and progression-free survival (PFS) of Raludotatug Deruxtecan treatment with the investigator's choice of chemotherapy, which includes **paclitaxel**, **doxorubicin hydrochloride, liposomal**, **gemcitabine hydrochloride**, or **topotecan**. The trial is expected to conclude by March 2028, with recruitment starting in July 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history. The treatment period will last up to 24 months, during which participants will receive intravenous infusions of the study drug or comparator drugs. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as required. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The study will adhere to strict protocols to ensure the safety and well-being of all participants, with regular assessments conducted to evaluate the efficacy and safety of the treatments administered.
Treatment
The clinical trial involves the administration of several treatments, including the experimental medication **Raludotatug Deruxtecan**. This investigational drug is a **solution for infusion** and is administered via **intravenous infusion**. The active substance, **raludotatug deruxtecan**, is a humanized IgG1 kappa monoclonal antibody against CDH6 conjugated to deruxtecan. The dosing regimen for Raludotatug Deruxtecan is up to 6.4 mg/kg, with a maximum total dose of 153.6 mg/kg over a treatment period of 24 weeks. The drug is provided by DAIICHI SANKYO, INC., and is not a pediatric formulation.
**Doxorubicin Hydrochloride, Liposomal** is used as a comparator treatment in the study. It is also a **solution for infusion** administered intravenously. The maximum daily dose is 40 mg/m², with a total dose not exceeding 960 mg/m² over the 24-week treatment period. This formulation is not specifically designed for pediatric use and involves secondary repackaging and relabeling activities according to Good Manufacturing Practice (GMP).
Another comparator treatment is **Topotecan**, provided as a **powder for concentrate for solution for infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 4 mg/m² and a total dose of 288 mg/m² over the course of 24 weeks. Similar to other comparators, it undergoes secondary repackaging and relabeling as per GMP standards.
**Gemcitabine Hydrochloride** is included as a comparator and is available as a **concentrate for solution for infusion**. Administered intravenously, the maximum daily dose is 1000 mg/m², with a total dose limit of 72000 mg/m² over 24 weeks. This treatment also involves secondary repackaging and relabeling activities according to GMP.
Lastly, **Paclitaxel** serves as a comparator treatment, provided as a **concentrate for solution for infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 80 mg/m² and a total dose of 7680 mg/m² over the 24-week treatment period. As with other comparator treatments, it is subject to secondary repackaging and relabeling in compliance with GMP.
Efficacy
The efficacy of the clinical trial will be assessed through the evaluation of the **Objective Response Rate (ORR)** and **Progression-Free Survival (PFS)**. In Phase 2, the primary endpoint is the ORR as assessed by Blinded Independent Central Review (BICR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In Phase 3, the primary endpoints include both the ORR and PFS, as assessed by BICR based on RECIST version 1.1, or death due to any reason. These assessments will be conducted to compare the efficacy of Raludotatug Deruxtecan (R-DXd) treatment with the investigator’s choice of chemotherapy, which includes paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sign and date the informed consent form prior to the start of any study-specific qualification procedures
- Age ≥18 years or the minimum legal adult age (whichever is greater) at the time the informed consent form is signed
- Participants with histologically or cytologically documented high-grade serous ovarian cancer (OVC), high-grade endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer
- For Phase 2 (Part A): Subjects must have at least 1 lesion, not previously irradiated, amenable to biopsy, and must consent to provide a pretreatment biopsy and on-treatment biopsy tissue sample (on-treatment biopsy sample not required for the Phase 3 part of the study). Fresh pretreatment biopsy may be waived for subjects who consent to provide an archival tumor tissue sample from a lesion not previously irradiated, performed within 6 months of consent, and performed after treatment with their most recent cancer therapy regimen For Phase 3 (Part B): Subjects must be willing and able to provide most recently collected (within 5 years of signing the ICF) archival tumor samples with sufficient quantity and quality of tissue. Alternatively, if an archival tumor tissue sample is not available, a newly obtained tumor tissue biopsy from at least 1 lesion not previously irradiated and amenable to core needle biopsy must be provided. If a biopsy procedure is required, the subject must have a lesion that can be biopsied at an acceptable clinical risk as judged by the investigator to be eligible for this trial
- For Phase 2 (Part A): Has received at least 1 but no more than 3 prior systemic lines of anticancer therapy For Phase 3 (Part B): Has received at least 1 but no more than 4 prior systemic lines of anticancer therapy
- Has platinum-resistant disease. If a subject had only 1 line of platinum therapy, must have received at least 4 cycles of platinum, must have had a best response of not PD, and then progressed between >90 and ≤180 days after the date of the last dose of platinum If a subject had 2 or 4 lines of platinum therapy, must have received at least 2 cycles of platinum and have progressed on or within 180 days after the date of the last dose of platinum Note: Subjects who are primary platinum refractory during front-line treatment (defined as disease that has progressed on or within ≤90 days of the last dose of first line platinum therapy) are excluded.
- Has had prior poly-ADP ribose polymerase (PARP) inhibitors for participants with documented breast cancer gene mutation (germline and/or somatic), unless the participant is not eligible for treatment with a PARP inhibitor (Not applicable to subjects in the Phase 3 part of the study)
- If mirvetuximab soravtansine (MIRV) is locally available: has had prior treatment with MIRV for subjects with documented high folate receptor alpha expression, unless the subject is not eligible for treatment with MIRV
- Has at least 1 measurable lesion evaluated by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per investigator assessment
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Has adequate organ and bone marrow function as assessed by local laboratory within 14 days prior to initiation of study treatment as defined below. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days of initiation of study treatment as appropriate. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to screening laboratory tests.Adequate organ/bone marrow function is defined in inclusion criterion 11 of the protocol.
- If the participant is a female of childbearing potential, she must have a negative serum pregnancy test within 72 hours or urine test within 24 hours before the first dose of study drug and must be willing to use highly effective birth control upon enrollment, during the Treatment Period, and for at least the time required to eliminate each study treatment after the last dose. Male partners of subjects with childbearing potential should use additional barrier methods of contraception for the durationof same period. The length of time required to continue contraception for each study treatment is listed in inclusion criterion 12 of the protocol.
- Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least the time required to eliminate each study treatment after the last dose, as described in the inclusion criterion 12 of the protocol.
- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
- For Phase 3 (Part B) only: Participants must be eligible for one of the treatments included in the Investigator's choice of chemotherapy arm
Exclusion Criteria
- Has clear cell, mucinous, or sarcomatous histology, mixed tumors containing any histology, or low-grade/borderline OVC. (Note for Phase 3 [Part B]: seromucinous, low-grade serous carcinoma or ovarian sarcoma, carcinosarcoma and undifferentiated carcinoma are excluded.)
- For Phase 2 (Part A): Prior exposure to other CDH6-targeted agents or an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan or datopotamab deruxtecan). For Phase 3 (Part B): Prior exposure to other CDH6-targeted agents or an ADC containing a topoisomerase I inhibitor.
- History of hypersensitivity to any excipients in the R-DXd or any known contraindication to treatment with, including hypersensitivity to, the study drug(s)
- Has an active or uncontrolled human immunodeficiency virus (HIV) infection . Participants must be tested for HIV viral load during the Screening Period if acceptable by local regulations or institutional review boards Further details provided in exclusion criterion 13 of the protocol.
- Has any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses or active infection, substance abuse) or other factors that, in the investigator's opinion, makes it undesirable for the participant to participate in the study or which would jeopardize compliance with the protocol
- Has an active or uncontrolled hepatitis B virus (HBV) or hepatitis C infection (HCV). Hepatitis B and Hepatitis C Screening tests are required. Further details provided in exclusion criterion 15 of the protocol.
- Female who is pregnant or breastfeeding or intends to become pregnant during the study
- Psychological, social, familial, or geographical factors that would prevent regular follow-up
- Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participants ; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results
- Has a history of receiving live-attenuated vaccine (messenger RNA [mRNA] and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention
- For Phase 3 (Part B) only: Has clinical symptoms or radiographic evidence of intestinal obstruction for the control group
- Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with untreated and asymptomatic brain metastases or subjects with treated brain metastases who are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy, at the investigator’s discretion. A minimum of 2 weeks must have elapsed between the end of radiotherapy and randomization and there should be no evidence of progression or need for steroid treatment or anticonvulsants for at least 2 weeks prior to randomization.
- Any of the following within the past 6 months prior to randomization: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event (eg, intestinal ischemia).
- Uncontrolled or significant cardiovascular disease as defined in exclusion criterion 5 of the protocol.
- Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- Clinically severe pulmonary compromise (ie, requiring any supplemental oxygen) resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement or prior pneumonectomy
- Chronic steroid treatment (>10 mg/day)
- History of malignancy other than epithelial OVC, primary peritoneal cancer, or fallopian tube cancer within 3 years prior to enrollment
- Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 Grade ≤1 or baseline
- For Phase 3 (Part B) only: Has ascites or pleural effusions that require repeated drainage (less than 4 weeks between drainages).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 01 Jul 2024 | 24 |
 Finland | Not Recruiting | 01 Jul 2024 | 3 |
 France | Not Recruiting | 01 Jul 2024 | 86 |
 Germany | Not Recruiting | 01 Jul 2024 | 31 |
 Greece | Not Recruiting | 01 Jul 2024 | 13 |
 Italy | Not Recruiting | 01 Jul 2024 | 79 |
 Poland | Not Recruiting | 01 Jul 2024 | 17 |
 Portugal | Not Recruiting | 01 Jul 2024 | 13 |
 Spain | Not Recruiting | 01 Jul 2024 | 78 |
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 |
|---|---|---|---|---|---|---|
DOXORUBICIN HYDROCHLORIDE, LIPOSOMAL | Comparator | — | INTRAVENOUS INFUSION | 40 | 24 | SUB126795 |
TOPOTECAN | Comparator | — | INTRAVENOUS INFUSION | 4 | 24 | SUB11191MIG |
PACLITAXEL | Comparator | — | INTRAVENOUS INFUSION | 80 | 24 | SUB09583MIG |
Raludotatug Deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 6.4 | 24 | PRD10768156 |