A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Upifitamab Rilsodotin (XMT-1536) as Post-Platinum Maintenance Therapy for Participants with Recurrent, Platinum-Sensitive Ovarian Cancer (UP-NEXT)

1.Participants must be at least 18 years of age, and female.
2.Participant must have an ECOG performance status 0 or 1
3.Participant must have a histological diagnosis of high grade serous ovarian
cancer, which includes fallopian tube and primary peritoneal cancer, that is
metastatic or recurrent.
4.Participant must be able to understand the study procedures and agree to
participate in the study by providing written informed consent.
5.Participant must have platinum-sensitive recurrent disease, defined as having
achieved either a partial or complete response to 4 or more cycles in their
penultimate platinum- containing regimen and their disease progressing more
than 6 months after completion of the last dose of platinum containing therapy
in the penultimate regimen.
6.Participant must have had 4 to 8 cycles of platinum-based chemotherapy in 2nd
to 4th line setting in their most recent treatment regimen as defined below:
a. Platinum-based chemotherapy regimens allowed immediately preceding
enrollment to the study: carboplatin or cisplatin ±: paclitaxel, docetaxel,
pegylated liposomal doxorubicin or gemcitabine.
b. Participant must receive first study treatment infusion between 4 and 12
weeks after completing final dose of platinum in the most recent platinum-based
regimen.
c. Definitions for prior lines of therapy:
-Adjuvant ± neoadjuvant considered one line of therapy as long as they are
the same regimens (e.g., platinum/taxane for 4 cycles before surgery followed
by platinum/taxane for 4 cycles after surgery)
-Maintenance therapy (e.g., bevacizumab, PARPi, endocrine therapy) will be
considered as part of the preceding line of therapy (i.e., not counted
independently)
- Therapy given for only 1 cycle and discontinued due to toxicity in the
absence of progression will not be counted as a new line of therapy; therapy
given for 2 or more cycles will be counted as a line of therapy. Substitutions
of different platinum agents or taxanes will not be counted as new lines.
-Hormonal therapy (e.g., tamoxifen, letrozole) will be counted as a
separate line of therapy unless given as maintenance.
7. Participant must have had as their best response to last line of treatment
one of the following: No Evidence of Disease (NED); Complete Response (CR);
Partial Response (PR); OR Stable Disease (SD)
8. Participants with NED, CR, or PR as their best response to most recent line
of treatment and who have not received treatment with a prior PARP inhibitor
must have definitive BRCA1 and BRCA2 testing results that demonstrate no
evidence of a deleterious BRCA1 or BRCA2 mutation. Somatic BRCA mutation
testing is required for participants who are classified as not having a
deleterious mutation by germline testing alone.
9. Participant must provide either a tumor tissue block or fresh cut slides for
measurement of NaPi2b expression by a central laboratory. If sufficient
archival tumor tissue is not available, then a tumor tissue block or slides
must be obtained from a fresh biopsy and provided to the central laboratory.
Confirmation of a NaPi2b-H/positive tumor by the central laboratory is required
prior to randomization.
10. Participants with toxicity from prior therapy or surgical procedures must
have recovered to Grade <=1. Participants with alopecia, stable immune-related
toxicity such as hypothyroidism on hormone replacement, adrenal insufficiency
treated with <=10 mg daily prednisone (or equivalent), or chronic Grade 2
peripheral sensory neuropathy after prior taxane therapy is an exception to
this criterion and may qualify for this study.
11. Participants must have cardiac left ventricular ejection fraction (LVEF)
>=50% or >= the institution's lower limit of normal as measured by either Echo or
MUGA scan
12. Participants must have adequate organ function within 14 days prior to
enrollment
13. During the study, female study participants of child-bearing potential
(WOCBP) must a contraceptive method that is highly effective during study
treatment and for at least 6 months after the last dose of study treatment.

1. Participant has received prior treatment with mirvetuximab soravtansine or
another ADC containing an auristatin or maytansinoid payload.
2. Participant has received bevacizumab in combination with last platinum-based
regiment or plans to receive maintenance therapy outside the study intervention.
3. Participant has clinical signs or symptoms of gastrointestinal obstruction
and/or requirement for parenteral hydration or nutrition.
4. Participant has ascites or pleural effusion managed with therapeutic
paracentesis or thoracentesis within 28 days prior to signing the principal
study consent form.
5. Participant has history of cirrhosis, hepatic fibrosis, esophageal or
gastric varices, or other clinically significant liver disease. Testing beyond
laboratory studies otherwise defined in the eligibility criteria, to diagnose
potentially clinically significant liver disease based on risk factors such as
hepatic steatosis or history of excessive alcohol intake, will be based on
clinical judgement of the investigator.
6. Participants cannot receive drugs associated with hepatotoxicity concurrent
with upifitamab rilsodotin administration except as outlined in Appendix 4.
7. Participant currently uses either constant or intermittent supplementary
oxygen therapy.
8. Participant has history of or suspected pneumonitis or interstitial lung
disease.
9. Participant has oxygen saturation on room air <93%.
10. Participant has had major surgery or systemic anti-cancer therapy within 28
days of starting study treatment.
11. Participant has a low-grade, clear cell, endometrioid, mucinous,
carcinosarcoma, germ- cell, mixed histology, or stromal tumor.
12. Participant has untreated CNS metastases (including new and progressive
brain metastases), history of leptomeningeal metastasis, or carcinomatous
meningitis.
- Participants are eligible if CNS metastases are adequately treated and are
neurologically stable for at least 2 weeks prior to enrollment.
- In addition, participants must be either off corticosteroids, or on a
stable/decreasing dose of <= 10 mg daily prednisone (or equivalent).
Anticonvulsants are allowed except for those drugs associated with liver
toxicity.
13. Participant has untreated, known human immunodeficiency virus (HIV),
hepatitis B virus (HBV), or hepatitis C virus (HCV). In addition, negative
serology is required during screening (baseline) for HBV and HCV:
- HBV: Participants with serologic evidence of chronic HBV infection should
have an HBV viral load below the limit of quantification to be eligible.
- HCV: Participants with a history of HCV infection should have completed
curative antiviral treatment and HCV viral load below the limit of
quantification.
- Screening for HIV is not required except if mandated by local regulations or
indicated based on clinical assessment.
14. Participant has current severe, uncontrolled systemic disease (e.g.,
clinically significant cardiovascular, pulmonary, or metabolic disease) or
intercurrent illness that could interfere with per-protocol evaluations.
Further, participants are excluded with the following characteristics:
- A marked baseline prolongation of QTcF interval CTCAE Grade >1: repeated
demonstration of a QTcF interval >480 milliseconds (ms) using Fridericia's
QT correction formula.
- A history of additional risk factors for Torsades de Pointes (e.g., heart
failure, hypokalemia, family history of Long QT Syndrome).
15. Has a diagnosis of additional malignancy that required treatment within 2
years prior to screening, except for adequately treated basal cell or squamous
cell skin cancer, or carcinoma in situ of the breast or of the cervix
16. Participant has clinically significant corneal disease.
17. Participant is unwilling to be transfused with blood components.
18. Participant is receiving concurrent anti-cancer therapy (e.g. chemotherapy,
radiation therapy, biologic therapy, immunotherapy, hormonal therapy,
investigational therapy).
19. Participant is unable or unlikely to comply with dosing schedule and study
evaluations.
20. Participant is using strong CYP450 3A4 inhibitors or inducers that cannot
be discontinued while receiving study treatment (see Appendix 5).
21. Participants who are WOCBP must not be pregnant or nursing. Pregnancy
status must be confirmed with a negative highly sensitive pregnancy test (urine
or serum as required by local regulations) within 72 hours before the first
dose of study treatment.