MC# 19-16 - A Phase I/II Dose-Escalation and Efficacy Study of LAE001/Prednisone Plus Afuresertib or Docetaxel/Prednisone Plus Afuresertib in Patients with Metastatic Castration Resistant Prostate Cancer Following Standard of Care Treatment
Agent(s): LAE001 / Afuresertib
Disease Type(s): Prostate
Phase(s): I, II
Drug Classification(s): Targeted Therapy, Small Molecule
Molecular Target(s): AKT, CYP17, CYP11B
Mechanism of Action
LAE001 is a non-steroid, potent reversible dual inhibitor of Cytochrome P450 (CYP) 17 and CYP11B2.
Afuresertib is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B). Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis.
In this study, the sponsor and investigators want to learn:
- How much of LAE001 and Afuresertib can be given with an acceptable level of side effects
- The effects of LAE001 and Afuresertib (good and bad) when given in combination or when only Afuresertib is given
- How much of LAE001 and Afuresertib are absorbed into the blood and how fast they are removed
- If research tests can be used in the future to predict who will benefit from LAE001 and Afuresertib
- Males ≥18 years of age
- 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-resistant-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, invalid or failed
- Phase II: The PTEN/PIK3CA/AKT status test is mandatory.
- Patients that have a documentation of “PTEN LOSS” and/or PTEN/PI3KCA/AKT alteration from a previous test (e.g. next generation sequencing NGS, or IHC) are allowed to be enrolled in this study.
- Patients who have PTEN status test reported other than “PTEN LOSS” or never completed any PTEN test before could either provide the archival tumor samples collected within 12 months before study enrollment or do a fresh core tumor biopsy.
- Alternatively, patients with confirmed PTEN LOSS and/or PIK3CA/AKT/PTEN alteration by NGS of cfDNA testing of peripheral blood could also be permitted for enrollment after getting the permission from the sponsor.
- 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 (ie, bone scan showing appearance of ≥2 new lesions)
- Must have castration levels of testosterone (<50 ng/dL or 1.7 nmol/L). 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.
- Must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- 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
- 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
- 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
- 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):
- ≤120 mg/dL for those patients without a pre-existing diagnosis of Type 2 diabetes mellitus
- ≤167 mg/dL for those patients with a pre-existing diagnosis of Type 2 diabetes mellitus AND glycosylated haemoglobin (HbA1C) ≤8%
- Phase I: Patients who have mCRPC progressed or are intolerant after receiving at least 1 prior treatments of any anti-androgen (such as abiraterone, enzalutamide, apalutamide, or any other AR antagonists that are approved later), and/or chemotherapy. 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.
- Phase II: Patients who have mCRPC progressed or are intolerant after receiving 1-3 prior standard treatments for mCSPC, or nmCRPC, or mCRPC, including at least one second-generation antiandrogen treatment (i.e., abiraterone, enzalutamide, apalutamide, or darolutamide), and no more than one chemotherapy. Patients must have at least 3 weeks of treatment of any antiandrogen and/or completed at least 3 Cycles of docetaxel or cabazitaxel treatment and/or at least 3 injections of R223 and/or at least 2 injections of sipuleucel-T to be counted as one prior therapy. Patient’s current diagnosis at screening must be mCRPC.
- 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, biologics, antiandrogens, R223, etc.) before enrollment, starting from the day the therapies were stopped.
- 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
- Patient should be suitable for oral medication and should not have any known gastrointestinal diseases that may interfere with drug absorption
- Life expectancy of at least 6 months
- 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
- Received other second-line ADT (including but not limited to ketoconazole and amino glutethimide) within 6 weeks before enrollment
- Completed sipuleucel-T (Provenge®) treatment within 3 months of enrollment
- 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 on 5-alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®), or dutasteride (AVODART®) must stop medication at least 3 months prior to enrollment
- Received Radium Ra 223 dichloride (XOFIGO®) or Samarium Sm 153 lexidronam (QUADRAMET®) must be off therapy for at least 3 months prior to enrollment
- 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
- Require potassium-wasting diuretics
- 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
- Received palliative and other radiotherapy within 4 weeks of study enrollment
- Symptomatic or known central nervous system metastases from prostate cancer or who are at high risk for spinal cord compression, per investigator’s judgment
- 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
- 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
- Fridericia-corrected QT (QTcF) interval of >450 msec on the screening ECG (using the QTcF formula), has a short/long QT syndrome, or history of QT prolongation/Torsades 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
- 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.
- 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.
- Other medical, psychiatric, or social condition, including substance abuse, which in the opinion of the investigator, would preclude participation in the study
- History of upper gastrointestinal bleeding or peptic disease in the previous 6 months
- Previously received AKT or PI3 kinase pathway or mTOR inhibitors
- Dallas, TX - Mary Crowley Cancer Research - Medical City