To Evaluate the Safety and Efficacy of Ipatasertib (GDC-0068) in Combination With Paclitaxel in Platinum-resistant Recurrent Epithelial Ovarian Cancer

An Open Label Phase II Study to Evaluate the Safety and Efficacy of Ipatasertib (GDC-0068) in Combination With Paclitaxel in Platinum-resistant Recurrent Epithelial Ovarian Cancer

This is a phase II open label, non-randomized, study to evaluate the safety and efficacy of Ipatasertib (GDC-0068) in combination with paclitaxel in platinum-resistant recurrent epithelial ovarian cancer.

This is a phase II open label, non-randomized, study to evaluate the safety and efficacy of Ipatasertib (GDC-0068) in combination with paclitaxel in platinum-resistant recurrent epithelial ovarian cancer.

The primary objective of the study is to determine - the safety and objective response rate of treatment with ipatasertib (GDC-0068) in combination with paclitaxel in platinum-resistant recurrent epithelial ovarian cancer at week 12 for two cohorts of patients: with PI3K/AKT mutations (altered) and without PI3K/AKT mutations (non-altered)

About 39 patients will participate in the study and the accrual will take place over a course of 30 months Patients will be treated until disease progression and followed for 1 year thereafter.

The two drugs are ipatasertib and paclitaxel.

• Ipatasertib will be given 400mg PO daily: day 1-21 of 28 day cycle
• Paclitaxel will be given 80mg/m2 IV weekly: day 1, 8, 15 of 28 day cycle

The study hypothesis is that the combination of Ipatasertib (GDC-0068) plus paclitaxel will safely induce a tumor response and increase the objective response rate in patients with platinum-resistant recurrent epithelial ovarian cancer, with or without PI3K/AKT mutations.

This trial will enroll patients with platinum-resistant recurrent epithelial ovarian cancer. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates. The benefit-risk ratio for ipatasertib in combination with paclitaxel is expected to be acceptable in this setting.

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses

  o If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study

• Aged at least 18 years at time of signing informed consent

• A pathologic (histology or cytology) confirmed diagnosis of epithelial ovarian cancer, including fallopian or primary peritoneal cancer

  o low grade serous histology is excluded

• Radiographic evidence of recurrent epithelial ovarian cancer (ovarian, fallopian tube, or primary peritoneal cancer) that has become "platinum-resistant," defined as progression of disease within 6 months from the last dose of platinum-based chemotherapy, or platinum refractory

• Not a candidate for cytoreductive surgery

• Measurable disease (at least one lesion that can be accurately assessed repeatedly by CT or MRI) as evidenced on pre-treatment baseline CT of Chest/Abdomen/Pelvis, MRI, or PET/CT, or evaluable disease (defined as anything non-measurable- pleural effusions, lesions <1cm, etc).

• World Health Organization (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

• Up to 3 lines of prior cytotoxic chemotherapy

• Previously received bevacizumab

• Has not received weekly paclitaxel-containing regimen, EXCEPT for in the front-line setting

  o Patients with prior paclitaxel reactions may be enrolled if they have been successfully re-treated with steroid pre-medication in the past

• Patients must use adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing (within 7 days) if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

  • Post-menopausal defined as aged more than 50 years and amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments
  • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 28 days after the last dose of study treatment. Women must refrain from donating eggs during this same period.

Exclusion Criteria:

• Treatment with any of the following:

  • Any investigational agents or study drugs from a previous clinical study within 28 days of the first dose of study treatment
  • Any other chemotherapy, immunotherapy or anticancer agents within 14 days of the first dose of study treatment
  • Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)
  • Any prior exposure to Ipatasertib

• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment

• Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment

• With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment

• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 2 weeks prior to start of study treatment

• Concurrent use of endocrine therapy

• As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.

• Any of the following cardiac criteria:

  • Any clinically important abnormalities in rhythm, known prolonged QTc, conduction or morphology of resting ECG, complete left bundle branch block, third degree heart block
  • Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade 2 or greater
  • Uncontrolled hypotension - Systolic BP <90mmHg and/or diastolic BP <50mmHg
  • Left ventricular ejection fraction (LVEF) below lower limit of normal for site

• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

  • Absolute neutrophil count < 1.5 x 109/L
  • Platelet count < 100 x 109/L
  • Hemoglobin < 9 g/L
  • Alanine aminotransferase > 2.5 times the upper limit of normal (ULN)
  • Aspartate aminotransferase > 2.5 times ULN
  • Total bilirubin > 1.5 times ULN
  • Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN
  • Proteinuria 3+ on dipstick analysis or >500mg/24 hours
  • Sodium or potassium outside normal reference range for site

• Peripheral neuropathy grade 2 or greater

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption Ipatasertib

• History of hypersensitivity to Ipatasertib, or drugs with a similar chemical structure or class to Ipatasertib

• Clinically significant abnormalities of glucose metabolism as defined by any of the following:

  • Diagnosis of type I or type II diabetes mellitus requiring insulin
  • A baseline fasting glucose value of ≥ 200 mg/dL (fasting glucose value to be obtained only if non-fasting glucose >200mg/dL)
  • Glycosylated hemoglobin (HbA1C) >7.5%

• Uncontrolled pleural effusion, pericardial effusion, or ascites

• Other malignancies within the past 3 years, with the exception of adequately resected basal or squamous carcinoma of the skin

• Clinically significant pulmonary symptoms or disease

• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements