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: United States (US) vs China , duration of the
platinum free interval (PFI): 1 3 months vs >3-6 months and number of prior platinum based
therapy treatments (1/2 versus 3 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 PFS follow up). Patients will be
tested at baseline for phosphoinositide 3 kinase (PI3K)/AKT/PTEN pathway alterations, BRCA1/2
mutations 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.
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.
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
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
cancer progression between 1 month and 6 months after completion of prior
platinum-based therapy (at least 4 cycles). Progression is defined by RECIST 1.1
criteria in association with symptoms necessitating treatment (Appendix 3).
6. The OC patients must have received 1 to 3 prior chemotherapies including no more than
one chemotherapy after PROC was diagnosed. No other additional anticancer treatment is
allowed except for PARP inhibitor or bevacizumab. Combination therapy with two or more
drugs will be considered as one treatment, whereas maintenance therapy will be
considered as continuation of the previous therapy. Patients should be appropriate
candidates for treatment with single agent weekly paclitaxel based on investigator's
clinical assessment.
7. Patients must either have received prior treatments with bevacizumab followed by
disease progression, or bevacizumab cannot be used because of a specific
contraindication, as listed (patients not treated with prior bevacizumab because of a
contraindication may represent no more than 10% of the total number enrolled):
- History of GI bleeding, ulceration, or fistula
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
- Proteinuria
- Infusion reaction
- Any radiographic evidence of bowel (gastrointestinal tract) involvement
- Hemorrhage: Grade 3-4 hemorrhage
- Hypertension: hypertensive crisis or hypertensive encephalopathy
- Arterial Thromboembolic Events: severe arterial thromboembolic events
- Venous Thromboembolic Events: Grade 4 thromboembolic events
8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
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 be able to tolerate oral medications and not have any GI illnesses that
would preclude 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 for at least 2 weeks
from Study Day 1.
Exclusion Criteria:
1. Platinum refractory disease (progression during or less than 1 month of receiving
previous platinum containing 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 or 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 Study 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.
