Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian

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.

• Paclitaxel (Drug): Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.
• Afuresertib (Drug), also known as LAE002: Afuresertib tablet, intended for daily oral administration.

Primary outcomes

• Progression-free Survival(PFS ) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [From first dose, evaluate every 6 weeks × 30 weeks, then change to every 8 weeks until study completion, assessed up to 40 months. Progress-free survival (PFS) is defined as from randomization to disease progression or death due to any reason]: Radiographic imaging will be performed and assessed by investigators to evaluate the duration of progress-free survival(PFS) based on RECIST 1.1

Secondary outcomes

• Objective Response Rate (ORR) According to RECIST 1.1 [The percentage of objective response achieved, objective response is from randomization to either complete response (CR) or partial response (PR) . Evaluate every 6 weeks × 30 weeks, then change to every 8 weeks, up to 40 months]: To further evaluate the clinical efficacy via objective response rate
• Duration of Response (DOR) According to RECIST 1.1 [Evaluate every 6 weeks × 30 weeks, change to every 8 weeks, up to 40 months. DOR is from first observation of response (complete response (CR) or partial response( PR)) until first observation of disease progression or death, whichever occurs first.]: To further evaluate the clinical efficacy via duration of response
• Disease Control Rate (DCR) According to RECIST 1.1 [the percentage of participant who have achieved complete response(CR), partial response (PR) or stable disease(SD) from first study treatment to discontinued study treatment. Evaluate every 6 weeks × 30 weeks, change to every 8 weeks, up to 40 months.]: To further evaluate the clinical efficacy via Disease control rate
• Overall Survival (OS) [OS is defined from date of randomization until death date for any cause. Evaluated from randomization to study completion which is 105 events, up to 40 months.]: To further evaluate the clinical efficacy via OS collection
• Cancer Antigen 125 (CA-125) Response (Gynecological Cancer Intergroup [GCIG]) [every 6 weeks × 30 weeks from Baseline , then every 8 weeks through study completion of 105 PFS events achievement, up to 40 months]: To further evaluate the clinical efficacy via cancer antigen 125 (CA125) response rate
• Area Under the Curve in the Inter-dose Interval Period After First Dose (AUCτ) [Samples collected on Cycle1Day1 (a Cycle is 21 days) of pre-dose and at 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel at steady-state via AUCτ
• Area Under the Curve in the Inter-dose Interval Period at Steady State (AUCτ_SS) [sample collection on cycle2 Day 1 (21days in 1 cycle) of pre-dose and at 0.5h, 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via AUCτ_SS
• Maximum Concentration After First Dose (Cmax) [Samples collected on Cycle1Day1 (a Cycle is 21 days) of pre-dose and at 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel at steady-state via Cmax
• Maximum Concentration at Steady State (Cmax_SS) [sample collection on cycle2 Day 1 (21days in 1 cycle) of pre-dose and at 0.5h, 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Cmax_SS
• Time to Maximum Concentration After First Dose (Tmax) To Explore Potential Effect of Coadministration of Afuresertib [Samples collected on Cycle1Day1 (a Cycle is 21 days) of pre-dose and at 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib in patients with PROC under combination therapy of afuresertib plus paclitaxel at steady-state via Tmax
• Time to Maximum Concentration at Steady State (Tmax_SS) [sample collection on cycle2 Day 1 (21days in 1 cycle) of pre-dose and at 0.5h, 1h (at the end of paclitaxel infusion), 2h, 3h, 4h, 8h and 24 hours post-dose]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady-state via Tmax_SS
• Trough Concentration at Steady State (Ctrough_SS) [Samples collected on Cycle2Day1was assessed (a Cycle is 21 days)]: To Characterize Pharmacokinetics (PK) of afuresertib and paclitaxel in patients with PROC under combination therapy of afuresertib plus paclitaxel, or paclitaxel alone at steady state via Ctrough_SS

Other outcomes

• Progress-free Survival (PFS) Based on RECIST 1.1 [After C2 (each cycle is 21 days), then every 6 weeks for 30 weeks, then every 8 weeks through study completion, assessed up to 40 months.]: explore the PFS of the combination treatment arm versus paclitaxel arm in association with the biomarkers: o Levels of phospho-AKT in tumor sample as assessed by immunohistochemistry (IHC)
• OS [From date of randomization until date of death for any cause, assessed up to 40 months.]: explore the OS of the combination treatment arm versus paclitaxel arm in association with the biomarkers: o Levels of phospho-AKT in tumor sample as assessed by immunohistochemistry (IHC)

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1. 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.
2. 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.
3. 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.
4. Must not have previously received prior AKT or PI3K pathway or mTOR inhibitors.
5. 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.
6. 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.
7. Patients should be appropriate candidates for treatment with single agent weekly paclitaxel based on investigator's clinical assessment.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
9. Must meet the following criteria for hematology parameters:

   * Absolute neutrophil count (ANC) ≥ 1,500/mm3
   * Platelets ≥ 100,000/µL
   * Hemoglobin ≥ 9.0 g/dL
10. 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).
11. 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.
12. Creatinine within 1.5 × ULN or creatinine clearance > 30 mL/min by Cockcroft Gault formula (Appendix 1).
13. Toxicities of prior therapy (except alopecia) should have been resolved to less than or equal to grade 1 as per NCI-CTCAE v5.0.
14. Patients must have GI functions that would allow absorption of afuresertib.
15. Patient must have a life expectancy of greater than 6 months.
16. Must have at least one lesion that meets the definition of measurable disease by RECIST 1.1 criteria (Appendix 3).
17. 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.
18. 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. 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".
2. Known or suspected brain metastases.
3. Receiving any other anticancer therapeutic agents other than study medicines.
4. Uncontrolled ascites.
5. Known symptomatic or impending cord compression, except if the patient has received definitive treatment for this and demonstrates evidence of clinically stable disease.
6. 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).
7. 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.
8. Known allergies, hypersensitivity, or intolerance to the excipients of afuresertib (for excipient information, refer to the IB17).
9. 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.
10. Any medical contraindication to the use of paclitaxel.
11. 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.
12. History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or torsade de pointes).
13. 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.
14. 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.
15. 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.
16. Human immunodeficiency virus (HIV)-positive patients with 1 or more of the following:

    1. Not receiving highly active antiretroviral therapy
    2. Receiving antiretroviral therapy that may interfere with the study drug (consult the Sponsor for review of medication prior to enrollment)
    3. CD4 count < 350 based on a test within 3 months of the screening visit
    4. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening
17. Had a major surgery ≤ 30 days prior to first study treatment at Cycle 1 Day 1.
18. Presence of grade > 2 neuropathy.
19. 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.
20. Patients who are pregnant or lactating.
21. 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).
22. 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.

Participant flow

Outcome results

• Progression-free Survival(PFS ) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Primary), Median, month: Afuresertib and Paclitaxel 4.3 (3.58 to 5.62); Paclitaxel Only 4.1 (2.63 to 5.36)
• Objective Response Rate (ORR) According to RECIST 1.1 (Secondary), Number, Participants: Afuresertib and Paclitaxel 25 (17.06% to 34.98%); Paclitaxel Only 9 (8.4% to 30.87%)
• Duration of Response (DOR) According to RECIST 1.1 (Secondary), Median, months: Afuresertib and Paclitaxel 6.8 (4.14 to 14.69); Paclitaxel Only 3.7 (2.56 to 7.2)
• Disease Control Rate (DCR) According to RECIST 1.1 (Secondary), Number, Participants: Afuresertib and Paclitaxel 67; Paclitaxel Only 29
• Overall Survival (OS) (Secondary), Median, month: Afuresertib and Paclitaxel 11.2 (8.38 to 13.77); Paclitaxel Only 13.1 (7.75 to 18.00)
• Cancer Antigen 125 (CA-125) Response (Gynecological Cancer Intergroup [GCIG]) (Secondary), Number, Participants: Afuresertib and Paclitaxel 19; Paclitaxel Only 9
• Area Under the Curve in the Inter-dose Interval Period After First Dose (AUCτ) (Secondary), Geometric mean, h*ng/ml: Afuresertib and Paclitaxel 3370 +/- 47.9; Paclitaxel Only
• Area Under the Curve in the Inter-dose Interval Period at Steady State (AUCτ_SS) (Secondary), Geometric mean, h*ng/ml: Afuresertib and Paclitaxel 5100 +/- 2.51; Paclitaxel Only 4450 +/- 1.33
• Maximum Concentration After First Dose (Cmax) (Secondary), Geometric mean, ng/ml: Afuresertib and Paclitaxel 264.68 +/- 53; Paclitaxel Only
• Maximum Concentration at Steady State (Cmax_SS) (Secondary), Geometric mean, ng/ml: Afuresertib and Paclitaxel 625.7 +/- 1.76; Paclitaxel Only 2342.7 +/- 1.71
• Time to Maximum Concentration After First Dose (Tmax) To Explore Potential Effect of Coadministration of Afuresertib (Secondary), Median, h: Afuresertib and Paclitaxel 3 (1.15 to 24); Paclitaxel Only
• Time to Maximum Concentration at Steady State (Tmax_SS) (Secondary), Median, h: Afuresertib and Paclitaxel 3.05 (0.5 to 8.12); Paclitaxel Only 1.05 (0.5 to 1.82)
• Progress-free Survival (PFS) Based on RECIST 1.1 (Other pre specified), Median, months: Afuresertib and Paclitaxel 5.4 (3.4 to 6.4); Paclitaxel Only 2.9 (1.3 to NA)
• OS (Other pre specified), Median, months: Afuresertib and Paclitaxel 9.5 (6.1 to 12.0); Paclitaxel Only 9.0 (3.1 to 15.3)
• Trough Concentration at Steady State (Ctrough_SS) (Secondary), Mean, ng/ml: Afuresertib and Paclitaxel 329.49 +/- 215.824; Paclitaxel Only 0 +/- 0

Adverse events

Time frame: AEs were collected from first participant first visit until 30 days following discontinuation of study treatment, up to 40 months.

Serious adverse events by term

Other adverse events by term

14 more terms not shown.

• Study Protocol (PDF, 2023-01-23)
• Statistical Analysis Plan (PDF, 2023-12-19)

• Herzog Thomas, Professor, Principal investigator, University of Cincinnati Medical Center/USA/1010