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

Completed · Phase 1/Phase 2

Conditions studied: Metastatic Castration-resistant Prostate Cancer

In brief

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.

Key facts

Study ID

NCT04060394

Run by

Laekna Limited

People needed

49

Starts

2019-09-13

Expected to finish

2024-03-30

Last updated by the study team

2024-10-10

Who can join

Age: 18 and older. Sex: male. Healthy volunteers: not accepted.

You may qualify if…

• Patients, males ≥18 years of age, must be able to provide written informed consent.
• Patients must have documented histological or cytological evidence of adenocarcinoma of the prostate (excluding neuroendocrine differentiation or small cell histology).
• Patients must have radiographic evidence of metastatic disease for mCRPC based on the 'Guideline of American Urological Association for Prostate Cancer' before study enrollment. (https://www.auanet.org/guidelines/prostate-cancer-castration-resistant11 guideline)
• For PTEN and PIK3CA/AKT status test:
• Phase I: The PTEN/PIK3CA/AKT status test is optional and the result could be either positive, negative, undetermined or invalid. Phase II: Patients will be allowed to enroll regardless of the biomarker status, medical monitor review is necessary before enrollment. The biomarker status tests will be performed with the following order. The biomarker results of all enrolled patients will be used for retrospective analysis purposes.
• Patients that have a documentation of "PTEN LOSS" and/or PTEN/PIK3CA/AKT alteration from a previous test on either tissue or liquid biopsy (e.g., IHC or next generation sequencing NGS), no further biomarker tests are needed in this study.
• Patients who have PTEN or PI3KPIK3CA/AKT alteration status reported other than "PTEN LOSS", "PIK3CA/AKT alterations" or never completed any PTEN/PIK3CA/AKT test before, could either provide the archival tumor samples collected at any time before study enrollment or do a fresh core tumor biopsy.
• As the last option, patients can perform a liquid biopsy for PTEN LOSS and PTEN/PIK3CA/AKT alteration tests by NGS of cfDNA if they have no archival tissue to provide, no tumor lesion for biopsy or a fresh biopsy is not feasible.
• 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. Note: Patient must have had a prior PSA response, followed by documented PSA progression on prior hormone treatment.
• Patients who have documented disease progression per RECIST 1.1 are eligible independent of PSA.
• Patients with bone only progression according to PCWG3 (i.e., bone scan showing
• appearance of ≥2 new lesions).
• 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.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• 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
• Note: Criteria must be met without growth factors or transfusion within 10 days prior to the screening lab tests. Total serum bilirubin ≤1.5 × ULN within the 28 days before enrollment (in patients with known Gilbert's syndrome, total bilirubin ≤3 × ULN with direct bilirubin ≤1.5 × ULN).
• Aspartate aminotransferase and alanine aminotransferase ≤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.
• Patients must have adequate renal function as evidenced by a serum creatinine of
• ≤1.5 × ULN for the reference laboratory or creatinine clearance ≥30 mL/min within the 28 days before enrollment (calculated from Cockcroft-Gault formula or 24-hour urine collection).
• Serum potassium ≥3.5 mmol/L and < ULN within the 28 days before enrollment.
• Fasting plasma glucose (fasting is defined as no caloric intake for at least 8 hours):

You may not qualify if…

• Major surgery within 28 days before study treatment and/or have not adequately (Grade 1) recovered from the adverse effects of any major surgical procedures before study treatment.
• Patients that received other second-line ADT (including but not limited to ketoconazole and amino glutethimide) within 6 weeks before enrollment.
• Patients who have completed sipuleucel-T (Provenge®) treatment within 6 weeks of enrollment.
• 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.
• Patients who have received Radium Ra 223 dichloride (XOFIGO®) must be off therapy for 7 weeks prior to enrollment or Samarium Sm 153 lexidronam (QUADRAMET®) must be off therapy for at least 2 weeks prior to enrollment.
• Patients that are currently receiving increasing or chronic treatment (>5 days) with corticosteroids or another immunosuppressive agent, other than the following: 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.
• Patients who require potassium-wasting diuretics.
• 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 (whichever is shorter of the two should be preferred).
• Patients who have received palliative and other radiotherapy for the target lesion within 4 weeks of study enrollment.
• 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.
• Patients with a history of hypothalamus, pituitary or adrenal insufficiency.
• Patients with >grade 2 neuropathy at study enrollment.
• History of another primary malignancy that is currently clinically significant or currently requires active intervention.
• 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.
• 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 unsuitable to participate, as determined by the investigator.
• Patients with a Fridericia-corrected QT (QTcF) interval of >470 msec on the screening ECG (using the QTcF formula), has a short/long QT syndrome, or history of QT prolongation/Torsades de Pointes, unless prolonged QTc interval is due to (right or left) bundle branch block and/or pacemaker rhythm. If wide QRS complex is present, cardiology consultation is required to assess the risk for Torsade de Pointes.
• 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.
• Patients who have active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infections.

Where it is running

• Urological Associates of Southern Arizona — Tucson, Arizona, United States
• California Cancer Associates for Researh & Excellence, Inc — Encinitas, California, United States
• Eastern Connnecticut Hematology/Oncology Associates — Norwich, Connecticut, United States
• Piedmont Columbus Regional Research Institute — Columbus, Georgia, United States
• University of Chicago — Chicago, Illinois, United States
• Cotton-O'Neil Clinical Research Center — Topeka, Kansas, United States
• Associated Medical Professionals of NY — Syracuse, New York, United States
• Oregon Urology Institute — Florence, Oregon, United States
• Greenville Hospital System — Greenville, South Carolina, United States
• Mary Crowley Cancer Research Centers — Dallas, Texas, United States
• Baylor Scott and White Health — Temple, Texas, United States
• Northwest Medical Specialties, PLLC — Tacoma, Washington, United States
• National Cancer Center — Goyang-si, Gyeonggido, South Korea
• Seoul National University Bundang Hospital — Seongnam-si, Gyunggido, South Korea
• Seoul National University Hospital — Seoul, South Korea
• Severance Hospital — Seoul, South Korea
• Asan Medical Center — Seoul, South Korea

Full record on ClinicalTrials.gov

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