Raludotatug Deruxtecan (R-DXd) for platinum-resistant high-grade ovarian, fallopian tube, and primary peritoneal cancer

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) 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.
* 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:

  * 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 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.
* If mirvetuximab soravtansine (MIRV) is locally available: Has had prior treatment with MIRV 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.
* Has adequate organ and bone marrow function as assessed by local laboratory (within 14 days before start of 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: Subjects 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.)
* 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 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. Note: If there is a history or suspicion of central nervous system. 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.
  * Diagnosed or suspected long QT syndrome.
  * 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, 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 (HgCTCAE Grade ≥3 hypertension as per NCI-CTCAE version 5.0).
  * 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)
* 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 antibody-drug conjugate 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.
* 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 virus (HBV) or hepatitis C virus (HCV) infection. Hepatitis B and Hepatitis C Screening tests are required.

Subjects are eligible if:

1. Hepatitis B virus surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
2. History of hepatitis C infection: eligible if the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks.
3. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT \<3 × ULN, which are not attributable to HCV infection.

   * 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: Has clinical symptoms or radiographic evidence of intestinal obstruction.
   * For Phase 3 (Part B) only: Has ascites or pleural effusions that require repeated drainage (less than 4 weeks between drainages).