A study to investigate the efficacy and safety of luveltamab tazevibulin versus IC chemotherapy in women with ovarian cancer (including fallopian tube or primary peritoneal cancers) expressing FOLR1

Prior treatment

• Subjects with past or current malignancy need to be discussed with the sponsor to determine eligibility. Examples of non exclusionary malignancies include: cervical carcinoma Stage 1A-1B (per Salib et al, 2020; FIGO 2018); non-invasive basal cell and squamous cell skin carcinoma; localized malignant melanoma with a CR of a duration of > 10 years; low risk, in situ breast cancer treated with curative intent; superficial noninvasive bladder cancer treated with curative intent.
• Ongoing immunosuppressive therapy, including systemic corticosteroids. Note: Physiologic replacement and use of topical or inhaled corticosteroids are allowed. Dexamethasone may be used to treat chemotherapy induced nausea per institutional guidelines.
• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral, or psychiatric disease.
• Evidence of clinically significant third spacing (eg, pleural effusions, ascites, anasarca, etc.) that requires therapeutic intervention (paracentesis or pleurocentesis) within 8 weeks prior to the first dose of study drug.
• Active hepatitis B or hepatitis C per Center for Disease Control guidelines and positive serology (unless due to vaccination or passive immunization due to immunoglobulin therapy with the following exceptions: a) Subject has had HCV but has received standard of care direct-acting antiviral treatment and achieved a sustained virologic response 12 weeks after completion of treatment (SVR12), with no detectable viral RNA. b) Subject has had HBV but is HBV surface antigen and viral DNA negative at screening. c) Subject has had HBV but received antiviral treatment and have undetectable viral DNA for 6 months prior to screening.
• Concurrent participation in another therapeutic treatment trial.
• Prior treatment with a FOLR1-targeting ADCs (such as mirvetuximab and MORAB-202; irrespective of warhead type) or with ADCs that contain a tubulin inhibitor (eg, upifitamab rilsodotin, which contains auristatin derivative that inhibits tubulin polymerization).
• Greater than 3 lines of prior treatment.
• Prior anti-cancer therapy (prior to first dose of study drug): • Chemotherapy ≤ 3 weeks, • PARPi ≤ 2 weeks, • Other therapeutic anti-cancer antibodies ≤ 3 weeks, • Radio- or toxin-immunoconjugates (eg, ADCs) ≤ 10 weeks, or • Radiation therapy/major surgery ≤ 2 weeks of first dose of study drug.
• Previous solid organ transplantation.

Other illness

• Residual CTCAE V5.0 ≥ Grade 2 toxicity from prior anticancer therapy, with the exception of Grade 2 alopecia and Grade 2 hypothyroidism due to previous cancer therapy.
• Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, and tuberculosis.
• History of severe COPD or active pneumonitis ≤ 6 months of the first dose of study drug. Subjects with a history of COPD or other lung disease that may limit pulmonary function require a pulmonary function test (PFT) at screening and are excluded with a FEV1 < 50% of predicted.
• History of stroke or significant cerebrovascular disease (ie, transient ischemic attack) ≤ 6 months of initiation of study treatment.
• Females who are pregnant or breastfeeding, and all women of child-bearing potential unwilling to use a contraception method with a failure rate of < 1% while on treatment and for ≥ 6 months after last dose of luveltamab tazevibulin.
• Primary platinum-refractory disease (no response [PR or CR] or disease progression < 3 months of completion of first line platinum-based chemotherapy).
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy or to antibody-related fusion protein treatment.

Lab values

• Clinically significant cardiac disease including unstable angina, acute myocardial infarction ≤ 6 months of first dose of study drug or the following at screening: congestive heart failure (New York Heart Association Grade II or higher), left ventricle ejection fraction (LVEF) < 45% at baseline, and clinically significant arrhythmia. Exceptions which are allowed are asymptomatic stable atrial fibrillation for ≥ 6 months prior to study enrollment with sponsor approval. Extra systoles or minor conduction abnormalities are allowed.

Age

• Pre-existing clinically significant ocular disorders including, but not limited to: active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision, keratitis, symptomatic cataracts with marked decrease in visual acuity (≥ Grade 3), keratitis, glaucoma, retinopathy, uveitis, and Sjogren syndrome. Subjects with myopia, “floaters”, and watering eyes are not excluded.

Other

• Low grade (Grade 1) ovarian carcinoma.
• Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel obstruction ≤ 3 months of initiation of study treatment
• Sensory or motor neuropathy > Grade 1.
• History or clinical signs of meningeal or active central nervous system involvement.
• Clear cell, mucinous, endometrioid, sarcomatous, and mixed histology ovarian carcinomas.
• Known human immunodeficiency virus seropositivity.

• High grade serous epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer with pathology report documentation of tumor type.
• Adequate bone marrow function defined as: a) Absolute neutrophil count (ANC) ≥ 1500/μL – use of growth factors to achieve this level is NOT permitted and must be stable off any growth factor within 3 weeks of first dose of study treatment. b) Hemoglobin ≥ 9 g/dL – use of growth factors or transfusion to achieve this level is NOT permitted and must be stable off any growth factor or post transfusion within 3 weeks of the first dose of study treatment. c) Platelet count ≥ 100 × 103/μL – transfusion to achieve this level is NOT permitted.
• Adequate liver function defined as: a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN). b) Total bilirubin < 1.5 ULN • Subjects with known Gilbert disease: Total bilirubin ≤ 3.0 × ULN
• Adequate renal function defined as: • Creatinine clearance (CrCl) ≥ 30 mL/min
• Serum albumin ≥ 2.5 g/dL
• Calculated QT interval corrected for heart rate using Fridericia correction formula (QTcF), screening ECG and Cycle 1 Day 1 pre-dose ECG must be < 470 msec.
• Ability to comply with treatment, PK, and testing schedules.
• Subjects of childbearing potential must have a negative pregnancy test within 7 days of the first dose of study drug and be willing to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a < 1% failure rate while on treatment. All subjects must agree to avoid pregnancy and breastfeeding/nursing while on treatment and for ≥ 6 months after the last dose of luveltamab tazevibulin. A woman is not of childbearing potential if she has undergone surgical sterilization (total hysterectomy or bilateral oophorectomy or bilateral tubal ligation ≥ 6 weeks before taking study drug) or if she is post-menopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc. for ≥ 12 months, with an appropriate clinical profile, and there is no other cause of amenorrhea (eg, hormonal therapy, prior chemotherapy). (Note: this inclusion criteria may be expanded/modified to ensure country/region specific requirements)
• Age ≥ 18 years at the time of signing the informed consent form (ICF). If country/local age requirements define adulthood with a higher age, only subjects that meet the local age requirements may enroll in that specific country.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
• Life expectancy > 3 months.
• Positive FOLR1 expression per central laboratory testing.
• Relapsed platinum-resistant epithelial ovarian cancer and received a total of 1 to 3 regimens: a) Subjects who have only had 1 line of platinum-based therapy must have had a complete response (CR) or partial response (PR) and then progressed between ≥ 3 and < 6 months after the date of the last dose of platinum. b) Subjects who have received 2 or 3 lines of platinum therapy must have progressed in ≤ 6 months after the date of the last dose of platinum. c) Received ≤ 1 non-platinum regimen for platinum-resistant disease.
• Must be considered candidates for treatment with gemcitabine, paclitaxel, topotecan, or PLD for platinum resistant disease as per institutional standard of care.
• Prior bevacizumab treatment is required a) If labeled and available as standard of care per institutional guidelines b) Unless subject has documented contraindication to receive bevacizumab per bevacizumab label and institutional guidelines (eg, fistula, uncontrolled hypertension; to be discussed with and approved by the sponsor medical monitor or designee prior to enrollment).
• At least 1 radiographically measurable (Target) lesion per RECIST v1.1.