Adavosertib Plus Chemotherapy in Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

You may be eligible if

• Inclusion
• Has read and understands the informed consent form (ICF) and has given written IC prior to any study specific procedures.
• Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• Progressed within 6 months of completing at least 4 cycles of a first-line platinum-containing regimen for Stage III/IV disease. Patients with refractory disease (progression during platinum-containing therapy) are ineligible.
• No more than 2-4 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy.
• Prior doxorubicin (or other anthracycline) at a cumulative dose of ≤ 360 mg/m² or cumulative epirubicin dose of ≤ 720 mg/m² (calculated using doxorubicin equivalent doses: 1 mg of doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin). Subjects without any prior anthracycline exposure can also be included. Applies to Arm D only.
• At least 1 measurable lesion according to RECIST v1.1.
• Any prior palliative radiation therapy must be completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects prior to start of study treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 - 1.
• Baseline Laboratory Values:
• 1. ANC ≥1500/μL
• 2. HgB ≥ 9 g/dL with no blood transfusions in the past 28 days
• 3. Platelets ≥ 100,000/μL
• 4. ALT \& AST ≤3 x ULN or ≤5 x ULN if known hepatic metastases
• 5. Serum bilirubin within normal limits (WNL) or ≤1.5 x the ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert's Syndrome.
• 6. Serum creatinine ≤1.5 x the ULN and a calculated creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method.
• Left ventricular ejection fraction (LVEF) WNL of the institution as determined by multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D only).
• Female patients, ≥18, (not of childbearing potential and fertile female patients of childbearing potential) who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start.
• Predicted life expectancy ≥ 12 weeks
• Exclusion
• Use of a study drug (approved or investigational drug therapy) ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required.
• Major surgical procedures ≤ 28 days of beginning study, or minor surgical procedures ≤ 7 days. No waiting period following port-a-cath placement, or any other central venous access placement.
• Grade \>1 toxicity from prior therapy (except alopecia or anorexia).
• Known malignant CNS disease other than neurologically stable, treated brain metastases, defined as metastasis having no evidence of progression or haemorrhage after treatment for at least 2 weeks (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.
• Patient has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4 which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after last dose of study drug.
• Caution should be exercised when inhibitors or substrates of P-gP, substrates of CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates with a narrow therapeutic range are administered with adavosertib.
• Herbal medications should be discontinued 7 days prior to the first dose of study treatment.
• Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2:
• 1. Unstable angina pectoris
• 2. Congestive heart failure
• 3. Acute myocardial infarction
• 4. Conduction abnormality not controlled with pacemaker or medication
• 5. Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
• Adavosertib should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. Adavosertib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
• Corrected QT interval (QTc) \>470 msec at study entry or congenital long QT syndrome.
• Pregnant or lactating.
• Serious active infection at the time of enrolment, or another serious underlying medical condition that would impair the patient's ability to receive study treatment.
• Presence of other active cancers, or history of treatment for invasive cancer within 3 years. Patients with Stage I cancer who have received definitive local treatment within 3 years, and whom are considered unlikely to recur, are eligible. Patients with previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are patients with prior non-melanoma skin cancers.