Clinical Trials /

Dose-Escalation and Efficacy Study of LAE001/Prednisone Plus Afuresertib Patients With m-CRPC

NCT04060394

Description:

The combination treatment of protein kinase B (AKT) inhibitor, afuresertib, with androgen synthesis enzyme inhibitor, LAE001, may provide an effective treatment for metastatic castration resistant prostate cancer (m-CRPC) patients who have progressed/drug resistant following prior standard care treatments of any anti-androgen. This study intends to identify the most appropriate combined doses of LAE001/prednisone and afuresertib in m-CRPC patients who have progressive disease or are intolerant of 2 prior standard treatments of any anti-androgen or anti-androgen treatment plus chemotherapy.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose-Escalation and Efficacy Study of LAE001/Prednisone Plus Afuresertib Patients With m-CRPC
  • Official Title: A Phase I/II Dose-Escalation and Efficacy Study of LAE001/Prednisone Plus Afuresertib in Patients With Metastatic Castration-resistant Prostate Cancer Following Standard of Care Treatment

Clinical Trial IDs

  • ORG STUDY ID: LAE201INT2101
  • NCT ID: NCT04060394

Conditions

  • Metastatic Castration-resistant Prostate Cancer

Interventions

DrugSynonymsArms
Phase I and Phase II: LAE001/prednisone + afuresertibPhase II: AfuresertibPhase I Cohort 1

Purpose

The combination treatment of protein kinase B (AKT) inhibitor, afuresertib, with androgen synthesis enzyme inhibitor, LAE001, may provide an effective treatment for metastatic castration resistant prostate cancer (m-CRPC) patients who have progressed/drug resistant following prior standard care treatments of any anti-androgen. This study intends to identify the most appropriate combined doses of LAE001/prednisone and afuresertib in m-CRPC patients who have progressive disease or are intolerant of 2 prior standard treatments of any anti-androgen or anti-androgen treatment plus chemotherapy.

Detailed Description

      The Phase I part of this study will perform a dose-escalation to identify the recommended
      Phase II dose of LAE001/prednisone plus afuresertib in m-CRPC patients.

      In the Phase II part of this study, the anti-tumor efficacy of LAE001/prednisone plus
      afuresertib and of afuresertib alone will be assessed in m-CRPC patients with Phosphatase and
      tensin homolog (PTEN) loss who have progressed on, or who are intolerant of, 2 prior standard
      treatments of any anti-androgen or one anti-androgen treatment plus one of the chemotherapy
      from docetaxel or cabazitaxel. These study results will provide preliminary efficacy and
      safety information of the combination of LAE001/prednisone plus afuresertib and afuresertib
      alone.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I Cohort 1ExperimentalLAE001 (capsules) 75mg Twice Daily (BID) + prednisone (tablet) 5mg BID +afuresertib (tablet) 100mg Once Daily (QD) will be administered in Cycles of 28 days.
  • Phase I and Phase II: LAE001/prednisone + afuresertib
Phase I Cohort 2ExperimentalLAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 100mg QD will be administered in Cycles of 28 days.
  • Phase I and Phase II: LAE001/prednisone + afuresertib
Phase I Cohort 3ExperimentalLAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 125mg QD will be administered in Cycles of 28 days.
  • Phase I and Phase II: LAE001/prednisone + afuresertib
Phase I Cohort 4ExperimentalLAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 150mg QD will be administered in Cycles of 28 days.
  • Phase I and Phase II: LAE001/prednisone + afuresertib
Phase II Arm 1ExperimentalLAE001 (capsules) + prednisone (tablet) +afuresertib at the Recommended Phase II Dose (RP2D)
  • Phase I and Phase II: LAE001/prednisone + afuresertib
Phase II Arm 2ExperimentalAfuresertib 150 mg
  • Phase I and Phase II: LAE001/prednisone + afuresertib

Eligibility Criteria

        Inclusion Criteria:

          1. Patients, males ≥18 years of age, must be able to provide written informed consent.

          2. Patients must have documented histological or cytological evidence of adenocarcinoma
             of the prostate (excluding neuroendocrine differentiation or small cell histology).

          3. Patients must have radiographic evidence of metastatic disease based on RECIST 1.1
             within the 28 days before enrollment.

          4. Patients are able to provide tumor biopsy samples for PTEN immunohistochemical (IHC)
             staining. A valid PTEN IHC result must be collected within 4 months of screening visit
             or from a fresh biopsy sample during screening visit. The PTEN ICH results should be
             either performed or confirmed, if there is a previous PTEN ICH result, by central
             laboratory testing (participants with an "invalid" or "failed" PTEN IHC result are not
             permitted to be enrolled in Phase II study but allowed to participate in Phase I
             study).

          5. Patients must have progressive disease based on the PCWG3 criteria:

               -  Patients who progressed based solely on total PSA rising, should have had a
                  sequence of rising values on 3 consecutive occasions of at least 1-week intervals
                  (if the third measurement is not greater than the second measurement, a fourth
                  measurement at least a week apart must be taken and must be greater than the
                  second measurement) and should have 2.0 ng/mL minimum level for entry.

               -  Patients who have documented disease progression per RECIST 1.1 are eligible
                  independent of PSA.

               -  Patients with bone only progression according to PCWG3 (ie, bone scan showing
                  appearance of ≥2 new lesions).

             Note: Patients must have had a prior PSA response, followed by documented PSA
             progression on prior hormone treatment.

          6. Patients must have castration levels of testosterone (<50 ng/dL or 1.7 nmol/L). Note:
             Patients must have undergone androgen deprivation therapy (ADT), such as orchiectomy,
             or have been on Luteinizing Hormone Releasing Hormone (LHRH) agonists or antagonists,
             for at least 3 months prior to study enrollment. Patients on LHRH agonists/antagonists
             must remain on these agents for the duration of the study.

          7. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             ≤1.

          8. Patients must have adequate hematopoietic function by local laboratory within the 28
             days before enrollment, as evidenced by:

               -  Absolute neutrophil count ≥1,500/μL

               -  Platelet count ≥75,000/μL

               -  Hemoglobin ≥9 g/dL

          9. Total serum bilirubin ≤1.5 × Upper Limit of Normal (ULN) within the 28 days before
             enrollment (in patients with known Gilbert's syndrome, total bilirubin ≤3 × ULN with
             direct bilirubin ≤1.5 × ULN).

         10. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN except
             for patients with tumor involvement of the liver who must have AST and ALT ≤5 × ULN
             within the 28 days before enrollment.

         11. Patients must have adequate renal function as evidenced by a serum creatinine of ≤1.5
             × the ULN for the reference laboratory or creatinine clearance ≥50 mL/min within the
             28 days before enrollment (calculated from Cockcroft-Gault formula or 24-hour urine
             collection).

         12. Serum potassium ≥3.5 mmol/L and < ULN within the 28 days before enrollment.

         13. Fasting glucose ≤120 mg/dL or ≤6.7 mmol/L; glycosylated hemoglobin ≤8% within the 28
             days before enrollment.

         14. Patients who have mCRPC progressed or are intolerant after receiving 2 prior
             treatments of any anti-androgen (such as abiraterone, enzalutamide, apalutamide, or
             any other Adrenergic Agonist (AR) antagonists that are approved later), or one of the
             above anti-androgen treatments plus one of the chemotherapies from docetaxel or
             cabazitaxel. Patients must have at least 3 weeks of treatment of any antiandrogen
             and/or completed at least 4 Cycles of docetaxel or cabazitaxel treatment before their
             screening visit.

         15. Concomitant use of bisphosphonates and other bone supportive agents is allowed if the
             dose and renal function have been stable for at least 12 weeks before enrollment and
             no related ≥Grade 2 side effects are present for at least 4 weeks prior to study drug
             treatment.

             The minimum washout period is 4 weeks for prostate cancer therapy (cytotoxic,
             biologic, other therapies), and 6 weeks for antiandrogens bicalutamide and MDV3100
             before enrollment, starting from the day the therapies were stopped.

         16. Patients with a female partner of childbearing potential must agree to use condoms
             plus an additional contraceptive method to avoid conception until the end of relevant
             systemic exposure plus 90 days following the Clinical Trial Facilitation Group
             contraception guideline from September 2014.

         17. Patient should be able to swallow and retain oral medication and should not have any
             known gastrointestinal diseases that may interfere with drug absorption.

         18. Life expectancy of at least 6 months.

        Exclusion Criteria:

          -  1. Major surgery within 28 days before study treatment and/or have not recovered fully
             from the adverse effects of any major surgical procedures before study treatment.

             2. Patients that received other second-line Androgen Deprivation Therapy (ADT)
             (including but not limited to ketoconazole and amino glutethimide) within 6 weeks
             before enrollment.

             3. Patients who have completed sipuleucel-T (Provenge®) treatment within 3 months of
             enrollment.

             4. Patients who have received antiandrogens such as flutamide (EULEXIN®), bicalutamide
             (CASODEX®), or nilutamide (NILANDRON®) for >3 months must be off treatment for 6 weeks
             prior to enrollment and should demonstrate a continued rise in PSA after withdrawal.

             5. Patients on 5-alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®),
             or dutasteride (AVODART®) must stop medication at least 3 months prior to enrollment.

             6. Patients who have received Radium Ra 223 dichloride (XOFIGO®) or Samarium Sm 153
             lexidronam (QUADRAMET®) must be off therapy for at least 3 months prior to enrollment.

             7. Patients that are currently receiving increasing or chronic treatment (>5 days)
             with corticosteroids or another immunosuppressive agent, other than daily use of up to
             10 mg prednisone (or equivalent) or low-dose steroid for the control of nausea and
             vomiting, topical steroid, or inhaled steroid use.

             8. Patients who require potassium-wasting diuretics. 9. Patients who have received any
             investigational agent beyond those indicated for the treatment of prostate cancer
             within 5 half-lives of the agent; if the half-life of the agent is not known, the
             patients must be off investigational therapy for 4 weeks prior to enrollment.

             10. Patients who have received palliative and other radiotherapy within 4 weeks of
             study enrollment.

             11. Patients with symptomatic or known central nervous system metastases from prostate
             cancer or who are at high risk for spinal cord compression, per investigator's
             judgment.

             12. Patients with a history of hypothalamus, pituitary or adrenal insufficiency.

             13. Patients with diabetes mellitus that require insulin at study enrollment. 14.
             History of another primary malignancy that is currently clinically significant or
             currently requires active intervention.

             15. Inadequately controlled hypertension (eg, systolic blood pressure ≥160 mmHg or
             diastolic blood pressure ≥95 mmHg) or hypotension (eg, systolic blood pressure ≤80
             mmHg or diastolic blood pressure ≤50 mmHg) after up to 3 measurements with at least 5
             minutes apart during 28 days before study enrollment.

             16. Patients with active cardiac disease or a history of cardiac dysfunction including
             any of the following:

          -  Severe or unstable angina pectoris or acute coronary syndrome or stroke within 6
             months prior to study enrollment.

          -  Symptomatic pericarditis.

          -  Documented myocardial infarction or arterial thrombotic events within 6 months prior
             to study enrollment.

          -  History of documented congestive heart failure (New York Health Association functional
             classification III to IV).

          -  Documented history of cardiomyopathy.

          -  Known left ventricular ejection fraction <50% as determined by multiple gated
             acquisition scan or echocardiogram within 28 days prior to enrollment.

          -  History of clinically significant cardiac arrhythmias, as determined by the
             investigator.

             17. Patients with a Fridericia-corrected QT (QTcF) interval of >450 msec on the
             screening electrocardiogram (ECG) (using the QTcF formula), has a short/long QT
             syndrome, or history of QT prolongation/Torsades de Pointes.

             18. Patients with a history of an active infection (viral, bacterial, or fungal)
             requiring systemic therapy within 10 days before enrollment, including but not limited
             to tuberculosis.

             19. Patients who have active human immunodeficiency virus (HIV), hepatitis B, or
             hepatitis C infections.

             20. Patients that are currently receiving treatment with drugs known to be moderate or
             strong inhibitors or inducers of isoenzyme CYP1A (including but not limited:
             α-Naphthoflavone, Furafylline, Omeprazole, Lansoprazole) and isoenzyme CYP3A
             (including but not limited: Itraconazole, Ketoconazole, Azamulin, Troleandomycin,
             Verapamil, Rifampicin). The patients must have discontinued moderate or strong
             inducers for at least 2 weeks prior to study enrollment and must have discontinued
             moderate or strong inhibitors for at least 1 week before study enrollment.
             Spironolactone, Strong bile salt export pump (BSEP) inhibitors, grapefruit juice,
             herbal medicines such as St. John's wort, Kava, ephedra, gingko biloba,
             dehydroepiandrosterone, yohimbe, saw palmetto and ginseng should be discontinued.

             21. Sexually active males not willing to use a condom during the whole course of the
             study and for 16 weeks after stopping treatment. Male patients must not father a child
             in this period. A condom is required to be used also by vasectomized men as well as
             during intercourse with a male partner in order to prevent delivery of the drug via
             seminal fluid.

             22. Patients with any other medical, psychiatric, or social condition, including
             substance abuse, which in the opinion of the investigator, would preclude
             participation in the study.

             23. Patients with a history of upper gastrointestinal bleeding or peptic disease in
             the previous 6 months.

             24. Patients have previously received AKT or PI3 kinase pathway or mTOR inhibitors.

             25. Any condition that in the assessment of the investigator renders the patient not
             suitable for participation in this clinical study protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase II: Radiological progression free survival (rPFS) based on change in tumor per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment.

Secondary Outcome Measures

Measure:Phase II: Overall Response Rate (ORR) based tumor changes per RECIST 1.1
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessments and death from any cause.
Measure:Phase II: Overall Response Rate (ORR) based tumor changes per PCWG3
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessments and death from any cause.
Measure:Phase II: Duration of Response (DOR) based on tumor changes per RECIST 1.1
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase I: Duration of Response (DOR) based on tumor changes per RECIST 1.1
Time Frame:At the end of the 28 day treatment cycle for cycles 2,4 and 6 and then every 3 cycles after cycle 6 and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase II: Duration of Response (DOR) based on tumor changes per PCWG3
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase I: Duration of Response (DOR) based on tumor changes per PCWG3
Time Frame:At the end of the 28 day treatment cycle for cycles 2,4 and 6 and then every 3 cycles after cycle 6 and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase II: Disease Control Rate (DCR) based on tumor changes per RECIST 1.1
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase II: Disease Control Rate (DCR) based on tumor changes per PCWG3
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase II: Overall Survival (OS)
Time Frame:At the end of each 28 day treatment cycle and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment and death.
Measure:Phase II: Changes in Prostate Specific Antigen (PSA) levels
Time Frame:End of Treatment as compared to baseline
Safety Issue:
Description:Analysis of blood samples to be drawn at baseline and end of treatment
Measure:Phase I: Changes in Prostate Specific Antigen (PSA) levels
Time Frame:Day 1 Cycle 2 (each cycle is 28 days) and all subsequent cycle and End of Treatment for an avergae of 12 months as compared to baseline
Safety Issue:
Description:Analysis of blood samples to be drawn at baseline and end of treatment
Measure:Phase II: PSA response
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:A >/=50% reduction in PSA from baseline
Measure:Phase I: PSA response
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:A >/=50% reduction in PSA from baseline
Measure:Phase II: Secondary PSA response
Time Frame:Baseline to>/=12 weeks after study treatment; confirmed 4 weeks later
Safety Issue:
Description:A >/=30% reduction
Measure:Phase I: Secondary PSA response
Time Frame:Baseline to>/=12 weeks after study treatment; confirmed 4 weeks later
Safety Issue:
Description:A >/=30% reduction
Measure:Phase II: Best PSA response
Time Frame:Through study completion for an avergae of 12 months
Safety Issue:
Description:According to PCWG3
Measure:Phase I: Best PSA response
Time Frame:Through study completion for an average of 12 months
Safety Issue:
Description:According to PCWG3
Measure:Phase II: Time to PSA progression
Time Frame:Through study completion for an average of 12 months
Safety Issue:
Description:According to PCWG3
Measure:Phase I: Time to PSA progression
Time Frame:Through study completion for an average of 12 months
Safety Issue:
Description:According to PCWG3
Measure:Phase II: % patients with PSA progression or death from any cause
Time Frame:At 12 weeks from start of study treatment
Safety Issue:
Description:Patients with PSA progression or have died 12 weeks after treatment
Measure:Phase II: Frequency and severity of AEs
Time Frame:Through study completion for an average of 12 months
Safety Issue:
Description:Findings on physical examination, ECGs, vital signs and laboratory results based on CTCAE v5.0
Measure:Phase I: Evaluate PK characteristics of study drug in combination treatment
Time Frame:Cycle 1 (each cycle is 28 days) Day 1 and Cycle 1 Day 15
Safety Issue:
Description:Assess PK parameters as various timepoints
Measure:Phase I: Describe pharmacodynamics of study drugs
Time Frame:Cycle 1 (each cycle is 28 days) Days 1,8,15 and 22 and Day 1 of subsequent cycles
Safety Issue:
Description:Based on changes in blood levels on adrenal hormone and testosterone levels
Measure:Phase I: Radiographic tumor response based on Prostate Cancer Working Group 3 (PCWG3)
Time Frame:At the end of each 28 day treatment cycle for cycles 2,4 and 6 and then every 3 cycles after cycle 6 and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment.
Measure:Phase I: Radiographic tumor response based on RECIST 1.1
Time Frame:At the end of each 28 day treatment cycle for cycles 2,4 and 6 and then every 3 cycles after cycle 6 and within 15 days of last treatment
Safety Issue:
Description:Based on investigator reviewed radiographic tumor assessment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Laekna Limited

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