Clinical Trials /

Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian

NCT04374630

Description:

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.

Related Conditions:
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal Clear Cell Carcinoma
  • Primary Peritoneal Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study With Afuresertib and Paclitaxel in Platinum Resistant Ovarian
  • 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

Clinical Trial IDs

  • ORG STUDY ID: LAE002INT2001
  • NCT ID: NCT04374630

Conditions

  • Platinum-resistant Ovarian Cancer

Interventions

DrugSynonymsArms
PaclitaxelArm 1
AfuresertibLAE002Arm 1

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalArm 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.
  • Paclitaxel
  • Afuresertib
Arm 2Active ComparatorArm 2 is paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of a 3 week cycle
  • Paclitaxel

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Radiographic imaging will be performed and assessed by investigators

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From date of randomization until date of death, from any cause, assessed up to 1 year.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:o Area under the curve in the inter-dose interval period after first dose (AUCτ)
Measure: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)
Safety Issue:
Description:o Area under the curve in the inter-dose interval period at steady state (AUCτ_SS)
Measure: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)
Safety Issue:
Description:o Maximum concentration after first dose (Cmax)
Measure: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)
Safety Issue:
Description:o Maximum concentration at steady state (Cmax_SS)
Measure: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)
Safety Issue:
Description:o Time to maximum concentration after first dose (Tmax)
Measure: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)
Safety Issue:
Description:o Time to maximum concentration at steady state (Tmax_SS)
Measure: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)
Safety Issue:
Description:o Half-life (T1/2) if data permit
Measure: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)
Safety Issue:
Description:o Trough concentration at steady state (Ctrough_SS)
Measure: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
Safety Issue:
Description:Patients to be queried as to whether they have experienced adverse event
Measure:Vital signs
Time Frame:Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Safety Issue:
Description:Assessment of Blood Pressure
Measure:Vital signs
Time Frame:Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Safety Issue:
Description:Assessment of heart rate
Measure:Vital signs
Time Frame:Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Safety Issue:
Description:Assessment of respiratory rate
Measure:Vital signs
Time Frame:Cycle1Day 1 and Cyle 1 D15, then on Day 1 of subsequent cycles
Safety Issue:
Description:Assessment of body temperature.
Measure:Electrocardiogram (ECG)
Time Frame:Screening and repeated if clinically indicated through study completion, an average of 1 year.
Safety Issue:
Description:ECG QT Interval
Measure:Physical examinations
Time Frame:Assessment to be complete every 2 weeks for first 2 cycles, then once per cycle (each Cycle is 21 days)
Safety Issue:
Description:Assessment of head, eyes, ears, nose, and throat, chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations
Measure: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.
Safety Issue:
Description:Assessment includes Platelet Count, Hemoglobin, WBC Count (absolute), Neutrophils, Lymphocytes, Eosinophils, Monocytes, Basophils
Measure:Clinical Chemistry
Time Frame:Screening and Day1 of each cycle through study completion, an avergae up to 1 year.
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Laekna Limited

Last Updated

August 31, 2020