to evaluate the safety and efficacy of ipatasertib (gdc-0068) in combination with paclitaxel in platinum-resistant recurrent epithelial ovarian cancer

Conditions: Ovarian Neoplasms

Summary: 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.

Eligibility criteria:
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 \ 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

Keywords: platinum-resistant ovarian cancer ipatasertib paclitaxel recurrent