ONC201 Plus Weekly Paclitaxel in Patients With Platinum Refractory or Resistant Ovarian Cancer

Inclusion Criteria:

• Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritonealcancer.

• Progressed within 6 months of completing at least 1 cycle of last platinumcontaining regimen. Patients with refractory disease (progression duringplatinum-containing therapy) are eligible. This includes both adjuvant therapy andin the recurrent setting.

• No more than 4 prior treatment regimens defined as investigational, chemotherapy,hormonal, biologic, or targeted therapy in the platinum resistant setting and totalof 7 prior regimens in all settings will be allowed. Prior maintenance therapy withbiologic or targeted agent does NOT count as a treatment regimen (e.g. Maintenancebevacizumab, Parpi, or immunotherapy).

• At least one measurable lesion according to RECIST v1.1.

• For the eight patients enrolled for PK/PD. Availability of tissue from carcinoma.For most patients this will be archival tissue. If there is no archival tissueavailable, biopsy of lesion MUST be performed prior to initiation of therapy.Lesions must be available for biopsy as well in these patients.

• Any prior palliative radiation therapy must be completed at least 7 days prior tostart of study treatment and patients must have recovered from any acute adverseeffects prior to start of study treatment.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.

• Female patients who are not of childbearing potential and fertile female patients ofchildbearing potential who agree to use adequate contraceptive measures from 2 weeksprior to the study and until 1 month after study treatment discontinuation, who arenot breastfeeding, and who have a negative serum or urine pregnancy test within 3days prior to start of study treatment.

• Patients must have adequate (at baseline):

1. Bone marrow function: Absolute neutrophil count (ANC) ≥1,500/µL. Platelets ≥100,000/µL and hemoglobin > 8.0 gm/dL, transfusion allowed up to 1 week priorto maintain Hgb >8.

2. Renal function: Calculated creatinine clearance (CrCl) ≥35 mL/min/1.73 mm2

3. Hepatic function: Bilirubin less than or equal to 1.5 x ULN; alkalinephosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT)less than or equal to 3 x ULN. AP, AST and ALT less than or equal to 5 x ULN isacceptable if patient has known hepatic metastasis

Exclusion Criteria:

• Use of a study drug (approved or investigational drug therapy) ≤21 days or 5half-lives (whichever is shorter) prior to the first dose of study treatment. Forstudy drugs for which 5 half-lives is ≤21 days, a minimum of 10 days betweentermination of the study drug and administration of current study treatment isrequired.

• Major surgical procedures ≤21 days of beginning study treatment, or minor surgicalprocedures ≤7 days. No waiting required following port-a-cath placement, ureteralstent placement, percutaneous nephrostomy tube placement.

• No other (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agentis to be permitted while the patient is receiving study medications

• Grade >1 toxicity from prior therapy (except alopecia or anorexia or abovehematologic criteria) unless controlled by medications.

• Inability to swallow oral medication. Note: Patient may not have a percutaneousendoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN)on this trial.

• Known malignant central nervous system disease other than neurologically stable,treated brain metastases - defined as metastasis having no evidence of progressionafter treatment for at least 4 weeks (including brain radiotherapy). Must be off anysystemic corticosteroids for the treatment of brain metastases for at least 14 daysprior to enrollment.

• Patient has had prescription or non-prescription drugs or other products (i.e.grapefruit juice) known to be moderate to strong inhibitors or inducers of CYP3A4,which cannot be discontinued 1 week prior to Day 1 of dosing and withheld throughoutthe study until 1 weeks after the last dose of study drug.

• Any known hypersensitivity or contraindication to the components of study treatment

• Pregnant or lactating

• Serious active infection at the time of enrollment, or another serious underlyingmedical condition at discretion of the enrolling physician that would impair theability of the patient to receive study treatment. HIV or other immunodeficiencydisease that is well controlled and that does not impact baseline lab values (i.e.outside of above noted parameters for inclusion) are NOT considered exclusioncriteria.

• Presence of other active cancers other than ovarian cancer except those that do notrequire active therapy (i.e. on surveillance) and known non-invasive cancers and insitu cancers (e.g. non-melanoma skin cancers).

• Psychological, familial, sociological, or geographical conditions that do not permitcompliance with the protocol.