Trial of NP-G2-044 (Prilukae) Combined With PLD for Treatment of Platinum-Resistant Ovarian Cancer (ULTIMUS-1)

This is an open-label, Phase 2/3, multicenter, randomized study of NP-G2-044 in combination with PLD vs. PLD alone in participants with PROC. The Phase 2 component of the study includes a safety lead-in dose escalation of NP-G2-044 monotherapy with twice daily (BID) dosing and a dose escalation phase for NP-G2-044+PLD followed by a randomized dose optimization phase of NP-G2-044+PLD compared with PLD. In the Phase 3 component of the study, participants will be randomized to treatment with NP-G2-044+PLD, at the dose selected from the dose optimization phase, or to PLD alone. Randomized participants will be stratified according to the number of prior lines of therapy, number of prior PLD therapy lines, and region of the world. The study population is women at least 18 years of age with confirmed ovarian high grade serous carcinoma, an Eastern Cooperative Oncology Group (ECOG) status of 0-1, and whose cancer is resistant to platinum-based therapy.

Inclusion criteria

• Participants must have confirmed ovarian high-grade serous carcinoma (histologically or cytologically)

• Participants should have platinum resistance
• No PLD use after developing platinum resistance
• Participants must have had bevacizumab in a prior treatment line or must have been ineligible for bevacizumab therapy.
• ECOG status 0-1
• Measurable disease per RECIST v1.1 as assessed by local site Investigator/radiologists in the Dose Escalation phase, and assessed by BICR in the Dose Optimization phase and Phase 3; lesions situated in previous irradiated areas are considered measurable if progression has been demonstrated in such lesions
• Left ventricular ejection fraction > 50%
• Participants with adequate hematologic function based on following

• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelet count ≥ 100 × 109/L
• Hemoglobin ≥ 9.0 g/dL
• Albumin ≥ 3.0 g/dL
• Adequate coagulation parameters based on the following:

• Prothrombin time-internationalization normal rate (INR)/partial thromboplastin time < 1.5 × upper limit of normal (ULN)
• Partial thromboplastin time or activated partial thromboplastin time < 1.25 × ULN
• Participants must have adequate hepatic and renal function. For hepatic function, total bilirubin should be less than 1.5 times the ULN. For renal function, serum creatinine clearance must be at least 45 mL/min.
• Participants of childbearing potential (defined as sexually mature women who have not undergone surgical sterilization or been postmenopausal for at least 12 months if over 55 years of age) must have a negative pregnancy test within 72 hours before starting treatment. These participants must use highly effective contraception or abstain from heterosexual activity from screening through 120 days after the last dose of study medication.

Exclusion criteria

• Primary platinum-refractory (recurrence within 120 days of first-line platinum-containing therapy or during first-line platinum-containing therapy).
• Recurrence greater than 183 days from the penultimate platinum (platinum-sensitive recurrent ovarian cancer).
• Uncontrolled malignant pleural effusions and/or ascites as defined by a prior needle drainage within 60 days of first dose.
• Major surgery within 4 weeks prior to Screening.
• Prior radiotherapy within 4 weeks of start of study treatment.

• Participants must have recovered from all radiation-related toxicities, not require corticosteroids for their radiation therapy, and have no history of radiation pneumonitis.
• A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
• Anticancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted therapy, or investigational agents prior to administration of the first dose of study treatment.
• Active CNS metastases; participants with leptomeningeal metastases are not eligible.
• Primary CNS malignancy.
• Severe gastrointestinal conditions such as existing bowel obstruction defined as air fluid levels in the small bowel and/or intolerance to oral medications, clinical or radiological evidence of bowel obstruction within 8 weeks prior to study entry requiring hospitalization, current use of nasogastric tube decompression, inability to tolerate solid feedings or vomiting more than once a day.
• Liver metastases involving > 60% of liver parenchyma.
• Known active infection with Human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C virus (HCV)
• Requiring immunosuppressive therapy
• Evidence of ongoing systemic bacterial, fungal, or viral infections at Screening
• Received a live vaccine within 6 weeks of first dose of study drug.
• Received a Coronavirus disease-2019 (COVID-19) vaccine less than 1 week prior to dosing (Cycle 1/Day 1) and/or during the study received a COVID-19 vaccine or booster less than 3 weeks ahead of a tumor assessment.
• Baseline QT interval corrected with Fridericia's method (i.e., QTcF) > 470 ms.
• Female participants who are pregnant or breastfeeding.
• Concurrent active malignancy.
• History of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment.
• History of stroke, unstable angina, myocardial infarction, congestive heart failure (NYHA classification III or IV), clinically significant left ventricular hypertrophy or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening.
• Participants with increased baseline risk of Torsades de Pointe due to:

• Electrolyte imbalance at screening (clinically significant hypokalemia, hypomagnesemia or hypocalcemia per Investigator's determination)
• Known congenital long QT syndrome (LTQS)
• Bradycardia (heart rate < 50 beats per minute)
• Unstable or severe uncontrolled medical condition like unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes or any important medical illness or abnormal laboratory findings
• Grade 3 or 4 toxicity due to PLD in prior treatment.
• Grade 2 or greater neuropathy