Clinical trial NCT06161025: A Study of Raludotatug Deruxtecan (R-DXd) in Subjects With Platinum-resistant, High-grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Solid Cancer
Keywords: Primary pertioneal cancer
Ovarian cancer
Fallopian tube cancer
Raludotatug Deruxtecan (R-DXd)
Cadherin 6 (CDH6)
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-12-07
Enrollment: 650
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Assessment (Part A)
timeFrame: From date of randomization to data cut off, up to 18 months
measure: Progression-free Survival (PFS) Based on BICR Assessment (Part B)
timeFrame: From date of randomization to data cut off, up to 26 months
measure: Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Assessment (Part B)
timeFrame: From date of randomization to data cut off, up to 16 months
Secondary outcomes:
measure: Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment
timeFrame: From date of randomization to data cut off, up to 30 months
measure: Duration of Response (DOR)
timeFrame: From date of randomization to data cut off, up to 40 months
measure: Progression-free Survival (PFS) Based on BICR and Investigator Assessment (Part A)
timeFrame: From date of randomization to data cut off, up to 30 months
measure: Disease Control Rate (DCR)
timeFrame: From date of randomization to data cut off, up to 40 months
measure: Overall Survival (OS)
timeFrame: From date of randomization to data cut off, up to 40 months
measure: Number of participants with Treatment-emergent Adverse Events (TEAEs)
timeFrame: From first dose to data cut off, up to 40 months
measure: Pharmacokinetic (PK) Analysis: Maximum Plasma Drug Concentration (Cmax) of R-DXd
timeFrame: From first dose to data cut off, up to 40 months
measure: Pharmacokinetic (PK) Analysis: Time to Reach Maximum Plasma Drug Concentration (Tmax) of R-DXP
timeFrame: From first dose to data cut off, up to 40 months
measure: Pharmacokinetic (PK) Analysis: Area Under the Concentration-Time Curve (AUC) of R-DXd
timeFrame: From first dose to data cut off, up to 40 months
measure: Pharmacokinetic (PK) Analysis: Terminal Half-Life (t1/2) of R-DXd
timeFrame: From first dose to data cut off, up to 40 months
measure: Percentage of Participants With Treatment Emergent Antidrug Antibody (ADA)
timeFrame: From baseline to data cut off, up to 40 months
measure: Percentage of Participants With Cancer Antigen 125 (CA-125) Response Rate
timeFrame: From baseline to data cut off, up to 40 months
measure: Cadherin-6 (CDH6) protein expression in tumor tissue as determined by immunochemistry assay and correlation with ORR, DoR, PFS and OS
timeFrame: From baseline to data cut off, up to 40 months
measure: Change in Score in the Quality of Life (QoL) Questionnaire
timeFrame: From baseline to data cut off, up to 40 months
measure: Time to Next Treatment (TTNT)
timeFrame: From date of randomization to data cut off, up to 40 months
measure: Progression-free Survival 2 (PFS2) Based on Investigator Assessment
timeFrame: From date of randomization to data cut off, up to 40 months
Other outcomes:
Locations:
city: Miami Beach
country: United States
facility: 'Mount Sinai Comprehensive Cancer Center
state: Florida
city: Mineola
country: United States
facility: Perlmutter Cancer Center at NYU Langone Hospital- Long Island
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute
state: Oklahoma
city: South Australia
country: Australia
facility: GenesisCare St Andrews Hospital
city: St Leonards
country: Australia
facility: GenesisCare North Shore (Oncology)
city: Montreal
country: Canada
facility: McGill University Health Centre/Glen Site / Royal Victoria Hospital
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret Cancer Centre
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Chongqing
country: China
facility: Chongqing Cancer Hospital
city: Fuzhou
country: China
facility: Fujian Provincial Cancer Hospital
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
city: Jinan
country: China
facility: Shandong Cancer Hospital
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
city: Nanning
country: China
facility: Guangxi Medical University Cancer Hospital
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
city: Tainan
country: China
facility: National Cheng Kung University Hospital
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
city: Wuhan
country: China
facility: Hubei Cancer Hospital
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
city: Hradec Kralove -Novy Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Praha
country: Czechia
facility: Fakultni nemocnice Bulovka
city: Caen Cedex 05
country: France
facility: Centre Francois Baclesse
city: Dijon cedex
country: France
facility: Centre Georges François Leclerc
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille cedex
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier
city: Nantes cedex 2
country: France
facility: Hôpital Privé du Confluent
city: Paris cedex 12
country: France
facility: Groupe Hospitalier Diaconesses - Hôpital De La Croix Saint Simon
city: Plérin
country: France
facility: CARIO - Centre Armoricain de Radiothérapie, Imagerie médicale et Oncologie
city: Saint Cloud
country: France
facility: Institut Curie
city: Vandoeuvre les Nancy
country: France
facility: ICL Alexis Vautrin
city: Mannheim
country: Germany
facility: Universitaetsklinikum Mannheim
city: Aviano
country: Italy
facility: IRCCS Centro di Riferimento Oncologico
city: Catania
country: Italy
facility: Azienda Ospedaliera Per Lemergenza Cannizzaro
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: Humanitas San Pio X
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Torino
country: Italy
facility: Ospedale Mauriziano Umberto I
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Fukuoka-shi
country: Japan
facility: NHO Kyushu Cancer Center
city: Hidaka-shi
country: Japan
facility: Saitama Medical University International Medical Center
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital of JFCR
city: Minato-ku
country: Japan
facility: Jikei University Hospital
city: Nagoya-shi
country: Japan
facility: Aichi Cancer Center Hospital
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
city: Osaka-shi
country: Japan
facility: Osaka International Cancer Institute
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
city: Shiwa-gun
country: Japan
facility: Iwate Medical University Hospital
city: Sunto-gun
country: Japan
facility: Shizuoka Cancer Center
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seoul
country: Korea, Republic of
facility: National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Siedlce
country: Poland
facility: Mazowiecki Szpital Wojewodzki w Siedlcach Sp z o o
city: Amadora
country: Portugal
facility: Hospital Professor Doutor Fernando Fonseca, E.P.E.
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Jaén
country: Spain
facility: Hospital Universitario Ciudad de Jaen
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra (MAD)
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Valencia
country: Spain
facility: Hospital Clínico Universitario Valencia
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Koo Foundation Sun Yat-Sen Cancer Center
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital,Linkou
city: Bath
country: United Kingdom
facility: Royal United Hospital
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: