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A Phase 2/3, Multicenter, Randomized Study of Raludotatug Deruxtecan (R-DXd), a CDH6-directed Antibody-drug Conjugate, in Subjects with Platinum-resistant, High-grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

A Study of Raludotatug Deruxtecan (R-DXd) in Subjects With Platinum-resistant, High Grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Inoguchi Akihiro

Daiichi Sankyo Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

Daiichi Sankyo Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

Not Recruiting

Feb. 01, 2024

Interventional

randomized controlled trial

open(masking not used)

dose comparison control

parallel assignment

treatment purpose

1. Sign and date the informed consent form prior to the start of any studyspecific qualification procedures.
2. Age >=18 years or the minimum legal adult age (whichever is greater) at the time the informed consent form is signed.
3. Participants with histologically or cytologically documented high-grade serous ovarian cancer (OVC), high-grade endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer.
4. Participants 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.
5. Has received at least 1 but no more than 3 prior systemic lines of anticancer therapy.
6. 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 3 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.
7. 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.
8. Has had prior treatment with mirvetuximab soravtansine for participants with documented high-folate receptor alpha expression, unless the participant is not eligible for treatment with mirvetuximab soravtansine due to precautions/intolerance, or if the treatment is not approved or available locally.
9. 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.
10. Eastern Cooperative Oncology Group performance status of 0 or 1.
11. Required baseline local laboratory data (within 7 days before start of study drug administration).
12. If the participant is a female of childbearing potential, she must have a negative serum pregnancy test at 72 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 7 months following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by follicle-stimulating hormone test.
13. 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 7 months after the final study drug administration.
14. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
15. For Phase 3 (Part B) only: Participants must be eligible for one of the treatments included in the Investigator's choice of chemotherapy arm and must not have received it previously for OVC.

1. Has clear cell, mucinous, or sarcomatous histology, mixed tumors containing any histology, or low-grade/borderline OVC.
2. Inadequate washout period before Cycle 1 Day 1.
3. 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. Note: If there is a history or suspicion of central nervous system metastasis, a CT scan of the head or MRI of the brain must be performed at baseline.
4. Any of the following within the past 6 months prior to randomization: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.
5. Uncontrolled or significant cardiovascular disease.
6. 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.
7. 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 study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc) and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc), or prior pneumonectomy.
8. Chronic steroid treatment (>10 mg/day).
9. History of malignancy other than epithelial OVC, primary peritoneal cancer, or fallopian tube cancer within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS rate >90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, ductal carcinoma in situ, or Stage 1 uterine cancer).
10. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Version 5.0, Grade <=1 or baseline.
11. 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).
12. History of hypersensitivity to any excipients in the R-DXd or any known contraindication to treatment with, including hypersensitivity to, the study drug(s).
13. Has a known human immunodeficiency virus (HIV) infection that is not well controlled. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or institutional review boards (IRBs)/ethics committees (ECs). All the following criteria are required to define an HIV infection that is well controlled: undetectable viral ribonucleic acid (RNA) load, CD4+ counts/levels of >350 cells/uL, no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, and stable for at least 3 weeks on the same anti-HIV retroviral medications.
14. 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 subject to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
15. Has an active or uncontrolled hepatitis B and/or hepatitis C infection. Subjects must be tested for hepatitis B (hepatitis B virus surface antigen [HBsAg] and anti-hepatitis B core antigen [HBc]) and hepatitis C virus antibody (HCV Ab) during the Screening Period.
16. Female who is pregnant or breastfeeding or intends to become pregnant during the study.
17. Psychological, social, familial, or geographical factors that would prevent regular follow-up.
18. 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 subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
19. 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.
20. For Phase 3 (Part B) only: Subjects are ineligible if they have a history of any contraindication included in the approved local label for the control group treatment.

Both

Solid Cancer

Phase 2 part: R-DXd 4.8mg/kg Q3W, R-DXd 5.6 mg/kg Q3W, R-DXd 6.4 mg/kg Q3W
Participants will be randomized to receive intravenous R-DXd administered at a dose of 4.8 mg/kg, 5.6 mg/kg, or 6.4 mg/kg every 3 weeks (Q3W).
Phase 3 part: R-DXd RP3D Q3W
Participants will be randomized to receive intravenous R-DXd administered at the Recommended Phase 3 Dose (RP3D) every 3 weeks (Q3W).
Comparator: Part B: Investigator's Choice, Participants will be randomized to receive intravenous treatment with investigator's choice of paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan.

1. Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Assessment (Part A)
The ORR was defined as the percentage of participants who achieved Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), by BICR assessment based on RECIST version 1.1.
2. Progression-free Survival (PFS) Based on BICR Assessment (Part B)
PFS is defined as the time from the date of randomization to the date of disease progression, defined as the first documented radiological progression or death due to any cause
3. Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Assessment (Part B)
The ORR was defined as the percentage of participants who achieved Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), by BICR assessment based on RECIST version 1.1.

1. Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment
The ORR was defined as the percentage of participants who achieved Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), by Investigator assessment based on RECIST version 1.1.
2. Duration of Response (DoR)
DoR is defined as the time from the date of the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of disease progression or death due to any cause, whichever occurs first.
3. Progression-free Survival (PFS) Based on BICR and Investigator Assessment (Part A)
PFS is defined as the time from the date of randomization to the date of disease progression, defined as the first documented radiological progression or death due to any cause.
4. Disease Control Rate (DCR)
DCR is defined as the proportion of participants who achieved a CR, PR, or stable disease maintained for >=12 weeks, as assessed by BICR and investigator based on RECIST version 1.1
5. Overall Survival (OS)
OS is defined as the time from the date of randomization to the date of death due to any cause.
6. Number of participants with Treatment-emergent Adverse Events (TEAEs)
TEAEs are defined as those AEs with a start or worsening date during the on-treatment period (from the first dose date to 40 days after the last dose date of study treatment).
7. Pharmacokinetic (PK) Analysis: Maximum Plasma Drug Concentration (Cmax) of R-DXd
8. Pharmacokinetic (PK) Analysis: Time to Reach Maximum Plasma Drug Concentration (Tmax) of R-DXd
9. Pharmacokinetic (PK) Analysis: Area Under the Concentration-Time Curve (AUC) of R-DXd
10. Pharmacokinetic (PK) Analysis: Terminal Half-Life (t1/2) of R-DXd
11. Percentage of Participants With Treatment Emergent Antidrug Antibody (ADA)
12. Percentage of Participants With Cancer Antigen 125 (CA-125) Response Rate
CA-125 response rate is defined as the percentage of participants with a reduction of 50% in CA-125 levels when compared to levels from a pretreatment sample, as assessed by blood sample based on Gynecological Cancer InterGroup criteria
13. Cadherin-6 (CHD6) protein expression in tumor tissue as determined by immunochemistry assay and correlation with ORR, DoR, PFS and OS
CDH6 protein expression in tumor tissue as determined by immunohistochemistry.
14. Change in Score in the Quality of Life (QoL) Questionnaire
15. Time to Next Treatment (TTNT)
TTNT is defined as the time from randomization to the start date of the next line of therapy
16. Progression-free Survival 2 (PFS2) Based on Investigator Assessment
PFS2 is defined as the time from randomization to the second objective disease progression or death due to any cause, whichever comes first.

+81-3-3520-0111

Jan. 09, 2024

Yes

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Information: -Study Protocol -Statistical Analysis Plan (SAP) -Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

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