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

• ClinicalTrials.gov Identifier: NCT06161025
• Recruitment Status: Recruiting
• First Posted: December 7, 2023
• Last Update Posted: April 12, 2024
• Sponsor: Daiichi Sankyo
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Daiichi Sankyo

Study Description

Brief Summary:

This study will evaluate the safety and efficacy of R-DXd therapy in participants with ovarian, peritoneal, or fallopian tube cancer

Condition or disease	Intervention/treatment	Phase
Solid Cancer	Drug: R-DXd; Drug: Gemcitabine; Drug: Paclitaxel; Drug: Topotecan; Drug: PLD	Phase 2; Phase 3

Detailed Description:

This study will focus on R-DXd in participants with platinum-resistant, high-grade ovarian, primary peritoneal, or fallopian tube cancer. R-DXd is an antibody-drug conjugate that specifically binds to CDH6, which is overexpressed in tumor cells. The Phase 2 dose-optimization part of the study (Part A) intends to define the recommended dose based on safety and efficacy, while the Phase 3 (Part B) part of the study will compare R-DXd with Investigator's choice of chemotherapy and further evaluate efficacy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 650 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 27, 2024
• Estimated Primary Completion Date: December 31, 2027
• Estimated Study Completion Date: December 31, 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: R-DXd 4.8mg/kg Q3W; Participants will be randomized to receive intravenous R-DXd administered at a dose of 4.8 mg/kg every 3 weeks (Q3W).	Drug: R-DXd; R-DXd will be administered as an intravenously (IV) infusion; Other Name: DS-6000a
Experimental: Part A: R-DXd 5.6 mg/kg Q3W; Participants will be randomized to receive intravenous R-DXd administered at a dose of 5.6 mg/kg every 3 weeks (Q3W).	Drug: R-DXd; R-DXd will be administered as an intravenously (IV) infusion; Other Name: DS-6000a
Experimental: Part A: R-DXd 6.4 mg/kg Q3W; Participants will be randomized to receive intravenous R-DXd administered at a dose of 6.4 mg/kg every 3 weeks (Q3W).	Drug: R-DXd; R-DXd will be administered as an intravenously (IV) infusion; Other Name: DS-6000a
Experimental: Part B: 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).	Drug: R-DXd; R-DXd will be administered as an intravenously (IV) infusion; Other Name: DS-6000a
Active 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.	Drug: Gemcitabine; Gemcitabine will be administered as an IV infusion; Drug: Paclitaxel; Paclitaxel will be administered as an IV infusion; Drug: Topotecan; Topotecan will be administered as an IV infusion; Drug: PLD; PLD will be administered as an IV infusion; Other Name: Pegylated Liposomal Doxorubicin

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Assessment (Part A) [ Time Frame: From date of randomization to data cut off, up to 18 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 26 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 16 months ]
   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.

Secondary Outcome Measures :

1. Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment [ Time Frame: From date of randomization to data cut off, up to 30 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 40 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 30 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 40 months ]
   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) [ Time Frame: From date of randomization to data cut off, up to 40 months ]
   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) [ Time Frame: From first dose to data cut off, up to 40 months ]
   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 [ Time Frame: From first dose to data cut off, up to 40 months ]
8. Pharmacokinetic (PK) Analysis: Time to Reach Maximum Plasma Drug Concentration (Tmax) of R-DXP [ Time Frame: From first dose to data cut off, up to 40 months ]
9. Pharmacokinetic (PK) Analysis: Area Under the Concentration-Time Curve (AUC) of R-DXd [ Time Frame: From first dose to data cut off, up to 40 months ]
10. Pharmacokinetic (PK) Analysis: Terminal Half-Life (t1/2) of R-DXd [ Time Frame: From first dose to data cut off, up to 40 months ]
11. Percentage of Participants With Treatment Emergent Antidrug Antibody (ADA) [ Time Frame: From baseline to data cut off, up to 40 months ]
12. Percentage of Participants With Cancer Antigen 125 (CA-125) Response Rate [ Time Frame: From baseline to data cut off, up to 40 months ]
    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 (CDH6) protein expression in tumor tissue as determined by immunochemistry assay and correlation with ORR, DoR, PFS and OS [ Time Frame: From baseline to data cut off, up to 40 months ]
    CDH6 protein expression in tumor tissue as determined by immunohistochemistry.
14. Change in Score in the Quality of Life (QoL) Questionnaire [ Time Frame: From baseline to data cut off, up to 40 months ]
15. Time to Next Treatment (TTNT) [ Time Frame: From date of randomization to data cut off, up to 40 months ]
    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 [ Time Frame: From date of randomization to data cut off, up to 40 months ]
    PFS2 is defined as the time from randomization to the second objective disease progression or death due to any cause, whichever comes first.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.
• 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.

• Has received at least 1 but no more than 3 prior systemic lines of anticancer therapy:

  • Neoadjuvant +/-adjuvant considered 1 line of therapy.
  • Maintenance therapy (eg, bevacizumab, poly-ADP ribose polymerase [PARP] inhibitors) will be considered part of the preceding line of therapy.
  • Therapy changed due to toxicity in the absence of progression will be considered part of the same line.
  • Hormonal therapy will be counted as a separate line of therapy, unless it was given as maintenance.
  • At least 1 line of therapy containing bevacizumab, unless the subject is not eligible for treatment with bevacizumab due to precautions/intolerance. Note: Subjects must have progressed radiologically on or after their most recent line of systemic therapy. Biochemical progression will not be considered progression for this study.
• 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.
• 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.
• 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.
• 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.

• Required baseline local laboratory data (within 7 days before start of study drug administration):

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

    • 3.0 × upper limit of normal (ULN) in subjects with no liver metastasis and
    • 5.0 × ULN in subjects with liver metastasis
  • Total bilirubin (TBL) ≤1.5 × ULN (<3 × ULN for subjects with Gilbert's syndrome or liver metastasis at baseline)
  • Absolute neutrophil count ≥1.5 × 109/L (growth factor support allowed up to 14 days before laboratory assessment for eligibility)
  • Platelet count ≥100 × 109/L (transfusion allowed up to 14 days before laboratory assessment for eligibility)
  • Hemoglobin ≥9.0 g/dL (transfusion and/or growth factor support allowed up to 14 days before laboratory assessment for eligibility)
  • Creatinine clearance ≥30 mL/min as calculated using the Cockcroft-Gault equation
  • Serum albumin ≥2.5 g/dL
  • Adequate blood clotting function: International normalized ratio and either activated partial thromboplastin time or partial thromboplastin time ≤1.5 × ULN, unless the subject is receiving anticoagulant therapy as long as activated partial thromboplastin time or partial thromboplastin time is within the therapeutic range of intended use of anticoagulants
• 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.
• 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.
• 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 and must not have received it previously for OVC.

Exclusion Criteria

• Has clear cell, mucinous, or sarcomatous histology, mixed tumors containing any histology, or low-grade/borderline OVC.

• Inadequate washout period before Cycle 1 Day 1, defined as follows:

  • Major surgery <28 days
  • Radiation therapy <28 days (if palliative stereotactic radiation therapy without abdominal radiation, ≤14 days)
  • Systemic anticancer therapy (including antibody-drug therapy, retinoid therapy, and hormonal therapy) <28 days or 5 half-lives, whichever is shorter, before starting study drug
  • Chloroquine/hydroxychloroquine <14 days
  • Exposure to another investigational drug within 28 days prior to start of study treatment or current participation in other therapeutic investigational procedures
• 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.
• Any of the following within the past 6 months prior to randomization: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.

• Uncontrolled or significant cardiovascular disease, including the following:

  • QT interval corrected with Fridericia's formula interval >470 ms (average of triplicate determinations).
  • Diagnosed or suspected long QT syndrome or known family history of long QTsyndrome.
  • History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
  • The participant has bradycardia of less than 50 bpm (as determined by central reading), unless the subject has a pacemaker.
  • History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
  • Myocardial infarction within 6 months prior to screening.
  • Uncontrolled angina pectoris within 6 months prior to screening.
  • New York Heart Association Class 3 or 4 congestive heart failure.
  • Left ventricular ejection fraction <50% or institutional lower limit of normal as measured by echocardiography or multigated acquisition (MUGA) scan.
  • Coronary/peripheral artery bypass graft within 6 months prior to screening
  • Uncontrolled hypertension (resting systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)
  • Complete left or right bundle branch block.
• Has a history of (noninfectious) 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 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.

• Chronic steroid treatment (>10 mg/day), with the exception of the following:

  • Inhaled steroids for asthma or COPD
  • Mineralocorticoids (eg, fludrocortisone) for subjects with orthostatic hypotension
  • Topical steroids for mild skin conditions
  • Low-dose supplemental corticosteroids for adrenocortical insufficiency
  • Premedication for treatment groups and/or premedication in case of any hypersensitivity
  • Intra-articular steroid injections
• 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).

• 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. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for 3 months prior to randomization and managed with SOC treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor, such as the following:

  • Chemotherapy-induced neuropathy
  • Fatigue
  • Endocrinopathies, which may include hypothyroidism, hyperthyroidism, Type 1 diabetes, hyperglycemia, and adrenal insufficiency
  • Skin pigmentation (vitiligo)
• 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).
• 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 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/μL, 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. If an HIV infection meets the above criteria, the subject's viral RNA load and CD4+ cell count should be monitored per local SOC (eg, Q3M).
• 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.

• 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. Subjects are eligible if they meet the following conditions:

  1. Have been curatively treated for hepatitis C virus (HCV) infection as demonstrated by undetectable HCV RNA
  2. Have received hepatitis B virus (HBV) vaccination with only anti-hepatitis B surface antibody (HBs) positivity and no clinical signs of hepatitis
  3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i to iii of criterion "d" below
  4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i to iii below: (i) HBV DNA viral load <2000 IU/mL (ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN that are not attributable to HBV infection (iii) Start or maintain antiviral treatment if clinically indicated as per the Investigator
• 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 subject; 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: Subjects are ineligible if they have a history of any contraindication included in the approved local label for the control group treatment.

Contacts and Locations

Contacts

Contact: Medical Director Contact for Clinical Trial Information; 908-992-6400; CTRinfo@dsi.com

Locations

Japan

National Cancer Center Hospital; Recruiting

Chuo-ku, Japan, 104-0045

Saitama Medical University International Medical Center; Recruiting

Hidaka-shi, Japan, 350-1298

Cancer Institute Hospital of JFCR; Recruiting

Koto-ku, Japan, 135-8550

Sponsors and Collaborators

Daiichi Sankyo

Merck Sharp & Dohme LLC

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

More Information

• Responsible Party: Daiichi Sankyo
• ClinicalTrials.gov Identifier: NCT06161025
• Other Study ID Numbers: DS6000-109; REJOICE-Ovarian01 ( Other Identifier: Daiichi Sankyo ); ENGOT-ov77 ( Other Identifier: ENGOT ); GOG-3096 ( Other Identifier: GOG )
• First Posted: December 7, 2023
• Last Update Posted: April 12, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) 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 Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from 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/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daiichi Sankyo:

Primary pertioneal cancer; Ovarian cancer; Fallopian tube cancer; Raludotatug Deruxtecan (R-DXd); Cadherin 6 (CDH6)

Additional relevant MeSH terms:

Fallopian Tube Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Paclitaxel; Gemcitabine; Doxorubicin; Topotecan; Liposomal doxorubicin; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Topoisomerase I Inhibitors