Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian

Study Overview
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Brief Summary
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Afuresertib is an AKT inhibitor, a new class of agents under development that may provide physicians with a new clinical option to control platinum resistant ovarian cancer (PROC) progression. Afuresertib plus chemotherapy has demonstrated anti-tumor efficacy and an acceptable safety profile in patients with PROC in a published Phase I/II study. Therefore, the combination of afuresertib plus weekly paclitaxel could represent a clinically meaningful step forward in the clinical management of these difficult-to-treat patients with PROC.

Detailed Description
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A total of approximately 141 patients with PROC are planned to be enrolled and randomized with a 2:1 ratio in an open label manner to the 2 arms (94 patients in the combination treatment arm and 47 patients in the paclitaxel arm) for efficacy and safety evaluation. The randomization will be stratified by country (the United States vs. China), prior bevacizumab use (yes vs. no), and number of prior platinum based therapy treatments (1-2 vs. 3-5 prior platinum regimens). The study will consist of 3 periods. The first period is the Screening Period (Day -24 to 1) during which patients are screened for eligibility according to the inclusion and exclusion criteria. The second period is a Treatment Evaluation Period with a randomized, open-label, two arm parallel design (from starting study treatment until patients have progressive disease [PD], unacceptable toxicity, death, or withdrawal of consent). The PK study will be applied to both the combination treatment arm and control arm. The third period is a Follow up Period (safety evaluation at 30 days after the last dose of study treatment and OS and/or PFS follow up). Patients will be tested at baseline for phosphoinositide 3 kinase (PI3K)/AKT/PTEN pathway alterations and BRCA1/2 mutations by NGS, and/or level of phospho AKT by IHC; the correlation of the efficacy endpoints and biomarker status will be analyzed retrospectively as an exploratory endpoint.

Official Title
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An Open Label Randomized Active Controlled Phase II Clinical Study to Assess the Efficacy and Safety of Afuresertib Plus Paclitaxel Versus Paclitaxel in Patients With Platinum-Resistant Ovarian Cancer

Conditions
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Platinum-resistant Ovarian Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Afuresertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Female patients at least 18 years of age at the time of signing the informed consent form and capable of giving written informed consent, which includes willingness to comply with the requirements and restrictions listed in the consent form. Must provide informed consent for the procedures and the tests for PI3K/AKT/PTEN pathway alterations, BRCA1/2 mutations, and/or level of phospho-AKT. The archival tumor biopsy sample collected less than 1 year is preferred. If no archival tumor sample is available, fresh biopsy will be recommended. For patients who cannot provide a tumor sample or cannot accept fresh tumor biopsy, the Sponsor should be consulted about their qualification to enter this study. Patients must have histologically or cytologically confirmed high grade serous OC, endometroid OC, or ovarian clear cell carcinoma (including fallopian tube and primary peritoneal cancers). Carcinosarcoma, sarcoma, mucinous OC, or low-grade serous OC or the other histologies must be excluded. Must not have previously received prior AKT or PI3K pathway or mTOR inhibitors. Must have PROC (including fallopian tube and primary peritoneal carcinoma), defined as disease relapsed between 1 to 6 months after the last dose of the first-line platinum-based therapy (at least 3 cycles), or progressed during or relapsed within 6 months of the last dose of platinum-based 2nd-5th line therapies. The OC patients must have received 1 to 5 prior chemotherapies including no more than one chemotherapy after PROC was diagnosed. Combination therapy with two or more drugs will be considered as one therapy, whereas maintenance therapy will be considered as continuation of the previous systemic treatment. Patients should be appropriate candidates for treatment with single agent weekly paclitaxel based on investigator's clinical assessment. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Must meet the following criteria for hematology parameters: Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelets ≥ 100,000/µL Hemoglobin ≥ 9.0 g/dL Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN) (in patients with known Gilbert's syndrome, total bilirubin ≤ 3 × ULN with direct bilirubin ≤ 1.5 × ULN). Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) must be < 2.5 × institutional ULN. For patients with liver metastasis, AST/ALT must be < 5.0 × institutional ULN. Creatinine within 1.5 × ULN or creatinine clearance > 30 mL/min by Cockcroft Gault formula (Appendix 1). Toxicities of prior therapy (except alopecia) should have been resolved to less than or equal to grade 1 as per NCI-CTCAE v5.0. Patients must have GI functions that would allow absorption of afuresertib. Patient must have a life expectancy of greater than 6 months. Must have at least one lesion that meets the definition of measurable disease by RECIST 1.1 criteria (Appendix 3). Patients of childbearing potential must agree to use adequate contraception (barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. Must be off strong inhibitors or inducers of CYP3A4/5 treatment, as showed in Appendix 2, for at least 2 weeks from Study Day 1. Exclusion Criteria: 1. Primary platinum refractory disease, defined as disease progression during or relapsed within 1 month after the last dose of the first-line platinum based therapy. Known or suspected brain metastases. Receiving any other anticancer therapeutic agents other than study medicines. Uncontrolled ascites. Known symptomatic or impending cord compression, except if the patient has received definitive treatment for this and demonstrates evidence of clinically stable disease. Presence of other active cancer within 3 years prior to enrollment (other than basal cell or squamous cell skin cancer, or any other cancer in situ currently in complete remission). History of seizure or condition that may predispose to seizure that needs anti-epileptic medications; brain arteriovenous malformation; or intracranial masses, such as schwannomas and meningiomas that are causing edema or mass effect. Known allergies, hypersensitivity, or intolerance to the excipients of afuresertib (for excipient information, refer to the IB17). Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments. Any medical contraindication to the use of paclitaxel. Prior radiotherapy ≤ 15 days prior to Study Day 1, with the exception of a single fraction of radiotherapy for the purposes of palliation, which is permitted. History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or torsade de pointes). Prolonged corrected QT interval by the Fridericia's correction formula (QTcF) on the screening ECG > 470 msec. Receiving concomitant medications known to prolong QTc, or which are associated with torsade de pointes, and are unable to discontinue use while receiving study drug. History or evidence for any of the following: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks) within 6 months prior to Study Day 1 or New York Heart Association Class III to IV heart disease. Presence of uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg or diastolic BP > 100 mmHg). Patients with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment. Human immunodeficiency virus (HIV)-positive patients with 1 or more of the following: Not receiving highly active antiretroviral therapy Receiving antiretroviral therapy that may interfere with the study drug (consult the Sponsor for review of medication prior to enrollment) CD4 count < 350 based on a test within 3 months of the screening visit An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening Had a major surgery ≤ 30 days prior to first study treatment at Cycle 1 Day 1. Presence of grade > 2 neuropathy. Prior receipt of chemotherapy, PARP inhibitor, bevacizumab, or investigational therapy within 28 days of enrollment or within 5 half lives of the agent, whichever is shorter. Patients who are pregnant or lactating. Patients with high risk of tuberculosis infection, based on investigator's clinical assessment, will be screened by tuberculosis screening test, such as the QuantiFERON® TB Gold In Tube test (QFT-GIT) or the T-SPOT®.TB test (T-Spot). Patients with active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C (positive hepatitis C virus [HCV] antibody test at screening) are not allowed to be enrolled in this study. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antibody [HBcAb] test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Arm 1 is afuresertib 125 mg PO QD + paclitaxel 80 mg/m2 intravenous (IV) infusion over 1 hour on Days 1, 8 and 15 of a 3 week cycle. | Drug: Paclitaxel<br>* Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.<br>Drug: Afuresertib<br>* Each afuresertib 50 mg tablet, intended for oral administration, contains afuresertib (hydrochloride salt) equivalent to 50 mg of afuresertib (free base). Each afuresertib 75 mg tablet, intended for oral administration, contains afuresertib (hydrochloride salt) equivalent to 75 mg of afuresertib (free base)<br>* Other names: LAE002;|
| Active Comparator: Arm 2<br>Arm 2 is paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of a 3 week cycle | Drug: Paclitaxel<br>* Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Radiographic imaging will be performed and assessed by investigators | Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | From date of randomization until date of death, from any cause, assessed up to 1 year. | 
| Objective response rate (ORR) according to RECIST 1.1 |  | Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average 1 year. | 
| Duration of response (DOR) according to RECIST 1.1 |  | Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. | 
| Disease control rate (DCR) according to RECIST 1.1 |  | Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. | 
| Best overall response (BOR) according to RECIST 1.1 |  | Change form Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. | 
| Cancer antigen 125 (CA-125) response (Gynecological Cancer Intergroup [GCIG]) |  | Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Area under the curve in the inter-dose interval period after first dose (AUCτ) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Area under the curve in the inter-dose interval period at steady state (AUCτ_SS) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Maximum concentration after first dose (Cmax) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Maximum concentration at steady state (Cmax_SS) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Time to maximum concentration after first dose (Tmax) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Time to maximum concentration at steady state (Tmax_SS) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Half-life (T1/2) if data permit | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days) | 
| Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state To explore potential effect of coadministration of afuresertib | o Trough concentration at steady state (Ctrough_SS) | Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) | 
| Rate and severity of treatment-emergent adverse events (TEAEs) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Patients to be queried as to whether they have experienced adverse event | From date of consent until 30 days following discontinuation of study treatment | 
| Vital signs | Assessment of Blood Pressure | Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles | 
| Vital signs | Assessment of heart rate | Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles | 
| Vital signs | Assessment of respiratory rate | Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles | 
| Vital signs | Assessment of body temperature. | Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles | 
| Electrocardiogram (ECG) | ECG QT Interval | Screening and repeated if clinically indicated through study completion, an average of 1 year. | 
| Physical examinations | Assessment of head, eyes, ears, nose, and throat, chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations | Assessment to be complete every 2 weeks for first 2 cycles, then once per cycle (each Cycle is 21 days) | 
| CBC | Assessment includes Platelet Count, Hemoglobin, WBC Count (absolute), Neutrophils, Lymphocytes, Eosinophils, Monocytes, Basophils | Screening then Cycles1 and 2 Day 1, 8,and 15 and D1 of subsequent cycles through study completion, an average up to 1 year. | 
| Clinical Chemistry | Assessment includes BUN, Creatinine, Glucose (fasting), Sodium, Total Protein, Magnesium , Potassium, Chloride, Total CO2, Calcium, Albumin, AST (SGOT), ALT (SGPT), Phosphorous, Alkaline phosphatase, Total and direct bilirubin | Screening and Day1 of each cycle through study completion, an avergae up to 1 year. |