Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian (PROFECTA-II)

• ClinicalTrials.gov Identifier: NCT04374630
• Recruitment Status: Recruiting
• First Posted: May 5, 2020
• Last Update Posted: November 16, 2020
• Sponsor: Laekna Limited
• Information provided by (Responsible Party): Laekna Limited

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Platinum-resistant Ovarian Cancer	Drug: Paclitaxel; Drug: Afuresertib	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 9, 2020
• Estimated Primary Completion Date: July 25, 2022
• Estimated Study Completion Date: January 25, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1; 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; Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.; Drug: Afuresertib; 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); Other Name: LAE002
Active Comparator: Arm 2; 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; Commercially available paclitaxel for IV administration will be obtained by clinical sites in US.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Overall survival (OS) [ Time Frame: From date of randomization until date of death, from any cause, assessed up to 1 year. ]
2. Objective response rate (ORR) according to RECIST 1.1 [ Time Frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average 1 year. ]
3. Duration of response (DOR) according to RECIST 1.1 [ Time Frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. ]
4. Disease control rate (DCR) according to RECIST 1.1 [ Time Frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. ]
5. Best overall response (BOR) according to RECIST 1.1 [ Time Frame: Change form Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. ]
6. Cancer antigen 125 (CA-125) response (Gynecological Cancer Intergroup [GCIG]) [ Time Frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an average of 1 year. ]
7. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
   o Area under the curve in the inter-dose interval period after first dose (AUCτ)
8. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
   o Area under the curve in the inter-dose interval period at steady state (AUCτ_SS)
9. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
   o Maximum concentration after first dose (Cmax)
10. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
    o Maximum concentration at steady state (Cmax_SS)
11. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days) ]
    o Time to maximum concentration after first dose (Tmax)
12. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
    o Time to maximum concentration at steady state (Tmax_SS)
13. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed(a Cycle is 21 days) ]
    o Half-life (T1/2) if data permit
14. 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 [ Time Frame: Samples collected on Cycle1Day1, Cycle2Day1, Cycle3Day1 and Cycle4Day1 will be assessed (a Cycle is 21 days) ]
    o Trough concentration at steady state (Ctrough_SS)
15. 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 [ Time Frame: From date of consent until 30 days following discontinuation of study treatment ]
    Patients to be queried as to whether they have experienced adverse event
16. Vital signs [ Time Frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles ]
    Assessment of Blood Pressure
17. Vital signs [ Time Frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles ]
    Assessment of heart rate
18. Vital signs [ Time Frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles ]
    Assessment of respiratory rate
19. Vital signs [ Time Frame: Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles ]
    Assessment of body temperature.
20. Electrocardiogram (ECG) [ Time Frame: Screening and repeated if clinically indicated through study completion, an average of 1 year. ]
    ECG QT Interval
21. Physical examinations [ Time Frame: Assessment to be complete every 2 weeks for first 2 cycles, then once per cycle (each Cycle is 21 days) ]
    Assessment of head, eyes, ears, nose, and throat, chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations
22. CBC [ Time Frame: Screening then Cycles1 and 2 Day 1, 8,and 15 and D1 of subsequent cycles through study completion, an average up to 1 year. ]
    Assessment includes Platelet Count, Hemoglobin, WBC Count (absolute), Neutrophils, Lymphocytes, Eosinophils, Monocytes, Basophils
23. Clinical Chemistry [ Time Frame: Screening and Day1 of each cycle through study completion, an avergae up to 1 year. ]
    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

Other Outcome Measures:

1. PFS based on RECIST 1.1 [ Time Frame: After C2 (each cycle is 21 days), then every 6 weeks for 30 weeks, then every 8 weeks through study completion, an average up to 1 year. ]
2. OS [ Time Frame: From date of randomization until date of death ]
3. ORR based on RECIST 1.1 [ Time Frame: After C2 (each cycle is 21 days), every 6 weeks x 30 weeks, then every 8 weeks through study completion, an avergae of 1 year. ]
4. BOR based on RECIST 1.1 [ Time Frame: After C2 (each cycle is 21 days), every 6 weeks x 30 weeks, then every 8 weeks through study completion, an avergae of 1 year. ]
5. DOR based on RECIST 1.1 [ Time Frame: After C2 (each cycle is 21 days), every 6 weeks x 30 weeks, then every 8 weeks through study completion, an average of 1 year. ]
6. DCR based on RECIST 1.1 o Alterations of PI3K/AKT/PTEN pathway and BRCA1/2 mutations in tumor samples as assessed by next generation sequencing (NGS) o Levels of phospho AKT in tumor sample as assessed by immunohistochemistry (IHC) [ Time Frame: After C2 (each cycle is 21 days), every 6 weeks x 30 weeks, then every 8 weeks through study completion, an avergae of 1 year. ]
7. CA-125 response (GCIG) [ Time Frame: Change from Baseline every 6 weeks × 30 weeks, then every 8 weeks through study completion, an averge of 1 year. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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 platinum-based regimens before PROC was diagnosed. No other additional anticancer treatment is allowed except for PARP inhibitor or bevacizumab. Combination therapy will be considered as one treatment, 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.

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
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.

Contacts and Locations

Contacts

Contact: Yong Yue, MD; 17328502641; yong.yue@laeknatp.com

Contact: Angela Castagna; 9085076807 ext 9085076807; angela.castagna@laeknatp.com

Locations

United States, Kentucky

University of Kentucky; Recruiting

Lexington, Kentucky, United States, 40536

Principal Investigator: Rachel Miller, MD

United States, Massachusetts

Tufts Medical Center; Recruiting

Boston, Massachusetts, United States, 02111

Principal Investigator: John Schorge, MD

University of Massachusetts; Recruiting

Worcester, Massachusetts, United States, 01605

Principal Investigator: Susan Zweizig, MD

United States, New Jersey

MD Anderson Cooper; Recruiting

Camden, New Jersey, United States, 08103

Principal Investigator: David Warshall, MD

United States, Ohio

University of Cincinnati Medical Center; Recruiting

Cincinnati, Ohio, United States, 45219

Principal Investigator: Thomas Herzog, MD

Sponsors and Collaborators

Laekna Limited

More Information

• Responsible Party: Laekna Limited
• ClinicalTrials.gov Identifier: NCT04374630
• Other Study ID Numbers: LAE002INT2001
• First Posted: May 5, 2020
• Last Update Posted: November 16, 2020
• Last Verified: November 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Paclitaxel; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action