Inclusion Criteria - Registration:

• Age ≥ 18 years.
  • NOTE: Because no dosing or adverse event data are currently available on the use of PLX038 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Histological confirmed high grade serous ovarian cancer consistent with ovarian, fallopian tube, or primary peritoneal carcinoma (NOTE: Any of these diseases are referred to in this protocol as “ovarian cancer”).
• Recurrent high grade serous ovarian cancer that was initially platinum sensitive (i.e., had at least one platinum-free interval of at least 6 months before progression) is now platinum resistant.
• No more than one prior line of therapy for platinum resistant disease.
  • NOTE: Prior PARP inhibitor therapy is allowed.
• Measurable disease per RECIST 1.1.
• Disease that is amenable to two biopsies.
• Life expectancy greater ≥ 12 weeks.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤ 28 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.

Exclusion Criteria - Registration:

Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential who are unwilling to employ adequate contraception.
• Histology other than high grade serous carcinoma.
• Prior treatment restrictions.
• Chemotherapy ≤ 4 weeks prior to registration.
• Immunotherapy ≤ 4 weeks prior to registration.
• Radiotherapy ≤ 4 weeks prior to registration.
• Any other investigational therapy ≤ 4 weeks prior to registration.
• History of prior or concurrent malignancy ≤ 2 years prior to registration.
  • Exceptions: If natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.
• Uncontrolled intercurrent illness including, but not limited to:
  • Myocardial infarction within 6 months of study entry;
  • NYHA class III or IV heart failure;
  • Uncontrolled dysrhythmias or poorly controlled angina;
  • History of serious ventricular arrhythmia (VT or VF) and/or factors that predispose to arrhythmia (e.g., heart failure, hypokalemia, family history of Long QT syndrome).
• Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents.
  • Exception: Patients should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better.
• Known HIV.
  • Exception: Patients on effective anti-retroviral therapy with undetectable viral load ≤ 6 months prior to registration are eligible for this trial.
• Known hepatitis.
  • Exception: For patients with evidence of chronic hepatitis B virus infection the HepB viral load must be undetectable on suppressive therapy, if indicated, to be eligible.
  • Exception: Patients with a history of hepatitis C virus infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Receiving any other investigational agent.
• History of clinically significant gastrointestinal bleeding, colitis, or gastrointestinal perforation.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Requirement for anticoagulation treatment that increases INR or APTT above the normal range.
  • Exceptions: low dose DVT or line prophylaxis allowed.
• Known CNS disease.
  • Exception: Patients with treated brain metastases are eligible if follow-up brain imaging after CNS directed therapy shows no evidence of progression.
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determined that immediate CNS specific treatment is not required and is unlikely to be required during the 1st cycle of therapy.
• Known Gilbert's syndrome or homozygous for the UGT1A1*28 variant allele or other relevant alleles with severely reduced UGT1A1 activity.
• Patients who require treatment with UGT1A1 inhibitors during the planned period of investigational treatment with PLX038.