Mo-Rez in First- Line (1L) Maintenance Treatment of Non-Homologous Recombination Deficient Ovarian Cancer (Non-HRd OC) [BEHOLD-Ovarian03]

A Randomized, Open-label, Multicenter, Phase 3 Study to Investigate Mocertatug Rezetecan With or Without Bevacizumab in Comparison to Active Observation With or Without Bevacizumab as Maintenance Treatment in Participants With Newly Diagnosed FIGO Stage III/IV Non-Homologous Recombination Deficient Ovarian Cancer

This study specifically aims to evaluate how well mocertatug rezetecan (Mo-Rez) alone or in combination with bevacizumab works in treating ovarian cancer compared to bevacizumab alone or active observation (AO). The study also assesses whether Mo-Rez is safe and tolerated well by participants in comparison to bevacizumab alone OR AO and will help provide a better understanding of the main side effects of the drugs.

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Is at least 18 years of age and the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the Informed Consent Form (ICF).
• Has newly diagnosed Stage III/IV (2014 FIGO staging) [Berek, 2021] epithelial ovarian, primary peritoneal or fallopian tube cancer with a histologically confirmed diagnosis of high grade serous, high grade endometrioid, clear cell carcinoma, carcinosarcoma or mixed histology.
• Has completed first-line platinum-based chemotherapy cycles. Inclusion of IV regimens at Q3W cycles, consolidation regimens and Intravenous (IV)/ Intraperitoneal (IP) and Hyperthermic intraperitoneal chemotherapy (HIPEC) regimens are acceptable. In the event of history of platinum or paclitaxel allergy, alternative agents are allowed (in consultation with the sponsor). At least cycles of first-line chemotherapy must be completed with or without bevacizumab.
• Has Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) response determined by investigator after the completion of first-line treatment must be Complete response (CR), Partial response (PR), No evidence of disease (NED), or Stable disease (SD).
• Is able to commence C1D1 of study treatment within 9 weeks of the final dose of front-line therapy. Final dose of front-line therapy is defined as the last day that platinum-based chemotherapy with/without bevacizumab was given. Participants may continue bevacizumab dosing if specified cycles of bevacizumab post-chemotherapy are administered prior to randomization.
• If planning to receive bevacizumab: Has received at least specified number of cycles of bevacizumab per label and local approval in combination front-line chemotherapy
• Has provided a sample sufficient for Homologous repair deficiency (HRD) testing (if local testing is not available), and the results available prior to date of randomization.
• Tumor specimen should be obtained from the most recent procedure and from a site not previously irradiated. If a suitable archival sample is not available, a fresh tumor tissue sample must be obtained during Screening. Fine needle aspirates, bone marrow samples, bone specimens, or cell blocks are not acceptable. Additional details regarding acceptable biopsy collections and processing can be found in the Laboratory Manual and other laboratory documentation. Tumor sample may also be used for other biomarker testing.
• Is willing to use adequate contraception. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
• Is a Participant of non-childbearing potential (PONCBP) OR
• Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Protocol, 30 days prior to C1D1 and during the study intervention period and for at least 8 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated) in relationship to the first dose of study intervention.
• A POCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention
• If a urine test cannot be confirmed as negative (e.g., a positive result or an indeterminate result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are provided in Protocol
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy.
• Is capable of giving signed informed consent as described, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
• Has an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 or 1.
• Has adequate organ function.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Has Ovarian cancer (OC) with germline or somatic pathogenic/likely pathogenic Breast cancer gene (BRCA)1/2 mutation or evidence of homologous repair deficiency as per local or central test.

• Has a malignancy (except disease under study) that has progressed or required active treatment within the past 36 months prior to date of randomization except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas (e.g., breast, cervix, bladder) that have been resected with no evidence of metastatic disease, or that is otherwise considered cured by the investigator.

• First-line Poly adenosine diphosphate-ribosylation (ADP) ribose polymerase inhibitor(s) (PARPi) for maintenance is a treatment option for participants, as determined by the Principal Investigator.

• Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.

• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

• Has untreated brain or Central nervous system (CNS) metastases or brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases). Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for ≥14 days prior to the date of C1D1 are not excluded from participation.

• Has any evidence of current Interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis.

• Has ongoing adverse reaction(s) from prior therapy that has (have) not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, excluding alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, Grade 2 neuropathy, or that the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.

• Has any serious and/or unstable medical condition (including infection) or any serious and/or unstable psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant's safety, obtainment of informed consent, or compliance to the study procedures.

• Has clinically significant wound healing complications or incompletely healed wounds.

• Has a history or evidence of Gastrointestinal (GI) perforation, tracheoesophageal fistula, or any Grade 4 fistula; participants with GI fistula, visceral fistula, or abdominal abscess within 6 months prior to the date of C1D1; has osteonecrosis of the jaw.

• Has evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on Computed tomography (CT) scan or clinical symptoms of bowel obstruction.

• Has clinically significant bleeding symptoms, significant bleeding tendency, or bleeding tumors within 30 days prior to the date of C1D1.

• Has congenital bleeding diathesis, acquired coagulopathy, recent pulmonary hemorrhage/hemoptysis (>2.5 mL of red blood or a half teaspoon) within the last 3 months prior to the date of C1D1.

• Has had any major surgery within 28 days prior to date of C1D1 or received focal radiotherapy within 21 days prior to date of C1D1.

• Has received treatment with any cytotoxic chemotherapy drugs or other antitumor drugs within 30 days or 5 half-lives, whichever is shorter, prior to date of C1D1 (or need to continue these drugs during study participation) other than maintenance bevacizumab. Cytotoxic chemotherapy drugs or other antitumor drugs include endocrine therapy, molecular targeted therapy, immunotherapy, or biotherapy.

• Has received treatment with an investigational agent within 30 days of the date of C1D1.

• Has ever received prior therapy

• Has received treatment with inhibitors of P-glycoprotein (P-gp), Breast cancer gene (BCRP), or Organic anion transporting polypeptides (OATP) 1B1/1B3 transporters within 7 days prior to the date of C1D1. Has received treatment with inducers of P-gp within 14 days prior to date of C1D1.

• Has received any live vaccine within 30 days of C1D1. mRNA and adenoviral based Coronavirus disease 2019 (COVID-19) vaccines are considered non-live.

• Has received any transfusion of blood products (including platelets or RBCs) or administration of colony-stimulating factors (including Granulocyte colony stimulating factor (G-CSF), Granulocyte macrophage colony-stimulating factor (GM-CSF), or recombinant Erythropoietin (EPO)s) within 14 days prior to date of C1D1.

• Has a known Human immunodeficiency virus (HIV) infection AND meets at least 1 of the following criteria:

  • Has documented evidence of plasma HIV-1 Ribonucleic acid (RNA) ≥50 c/mL within 3 months prior to or at screening. In the 3 months to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥50 c/mL occurred in the 3 months to 12 months prior to screening, the participant is not eligible for enrollment unless, per the investigator's assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR
  • Has not had Cluster of differentiation (CD)4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at screening); OR
  • Has had any CD4 cell count values ≤350 cells/mm3 in the past 12 months; OR
  • Has had 1 or more changes in their combination antiretroviral therapy regimen (except for switches as allowed per details provided in the protocol) or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR
  • Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to screening; OR
  • Has received treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening.

Participants with history of Centers for Disease Control and Prevention (CDC) Stage III disease (also known as AIDS defining disease [CDC, 2014] are eligible (provided all other applicable criteria are met) if the Acquired immunodeficiency syndrome (AIDS)-defining disease has been treated and cured or is stable for at least 3 months prior to screening. Cutaneous Kaposi's Sarcoma not requiring systemic therapy is not exclusionary.

• Has an Alanine aminotransferase (ALT) value >2.5 × Upper limit of normal (ULN) and/or, for participants with documented liver metastases/tumor infiltration, has an ALT value >5 × ULN.
• Has a total bilirubin value >1.5 × ULN. Participants with Gilbert's syndrome can be included with a total bilirubin value >1.5 × ULN, provided direct bilirubin is ≤1.5 × ULN and participant otherwise meets entry criteria.
• Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. Participants who exhibit these signs or symptoms as a result of the malignancy under investigation and whose conditions are deemed adequately controlled by the investigator may be eligible for inclusion. Stable noncirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones), hepatobiliary involvement of malignancy, or chronic stable Hepatitis B virus (HBV) infection (in a participant for whom Hepatitis D virus (HDV) infection has been excluded) or chronic Hepatitis C virus (HCV) infection is acceptable if the participant otherwise meets entry criteria.
• Has documented positive Hepatitis B surface antigen (HBsAg) at screening, unless they meet all of the following criteria:
• Are receiving effective antiviral therapy (i.e., with nucleos(t)ide analogs with a high barrier to viral resistance [tenofovir or entecavir]) for at least 7 days prior to first dose of study intervention and are willing to continue for at least 6 months after the last dose of study intervention or longer at the discretion of the treating hepatologist;
• Have undetectable HBV DNA, per institutional or local guidelines, at screening;
• Have documented negative HDV antibody testing at screening.
• Has documented positive Hepatitis B surface antibody (HBcAb) at screening unless they meet all of the following criteria:
• Have undetectable HBV DNA, per institutional or local guidelines, at screening;
• Have negative HBsAg at screening.
• Has a positive HCV antibody test result at screening unless HCV RNA is negative, indicating past resolved HCV infection, including participants who have undergone curative treatment. The HCV RNA test is optional, and participants with a negative HCV antibody test are not required to undergo HCV RNA testing as well. Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled if a confirmatory negative HCV RNA test is obtained and the participant otherwise meets entry criteria.
• Has QTcF >470 msec.
• Has a history within 12 months prior to screening of clinically significant or uncontrolled cardiac disease, acute MI, New York Heart Association Class III or IV congestive heart failure ], or clinically significant arrhythmia not controlled by standard of care therapy.
• Has baseline Left ventricular ejection fraction (LVEF) <50% or less than institutional Lower limit of normal (LLN)
• Has clinically significant abnormal BP according to investigator assessment, or inadequately treated and uncontrolled hypertension including history of hypertensive crisis; hypertensive encephalopathy; or adjustment of antihypertensive medications due to poor blood pressure control within 14 days prior to the C1D1.
• Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition that could affect the participant's safety). Successfully managed renal obstruction is permitted.
• Has a history of nephrotic syndrome or Grade 3 proteinuria.
• Meets the following criteria for proteinuria during screening assessments: ≥2+ proteinuria on urine dipstick and 24-hour urine collection demonstrating ≥1g of urine in 24 hours. Only participants with ≥2+ proteinuria on dipstick at screening will undergo a 24-hour urine collection. Participants with ≥2+ proteinuria on dipstick but <1g of protein in 24 hours are eligible.