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

  • STATUS
    Recruiting
  • End date
    Oct 4, 2022
  • participants needed
    74
  • sponsor
    Laekna Limited
Updated on 4 June 2022
platelet count
renal function
prednisone
fasting
AKT
endocrine therapy
gilbert's syndrome
testosterone
metastasis
progressive disease
neutrophil count
hormone therapy
docetaxel
antiandrogen therapy
androgen suppression
bone scan
bicalutamide
antiandrogens
abiraterone
orchiectomy
enzalutamide
luteinizing hormone
cabazitaxel
apalutamide
gonadotropin releasing hormone
hormone releasing
androgen
bisphosphonate
other therapies

Summary

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.

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 docetaxel/prednisone plus afuresertib will be assessed in mCRPC patients with PTEN loss and/or PIK3CA/AKT/PTEN alteration who have progressed on, or who are intolerant of, 1-3 prior standard treatments for mCSPC, or nmCRPC, or mCRPC, including at least one antiandrogen treatment and no more than one chemotherapy. Participants will be assigned to one of the two study cohorts, based on the investigator's clinical judgement. Cohort 1 will receive LAE001/prednisone plus afuresertib using RP2D established in the Phase I study. Cohort 2 will receive docetaxel/prednisone plus afuresertib, with a safety run-in period during the first cycle in the first 6 patients. These study results will provide preliminary efficacy and safety information of the combination of LAE001/prednisone plus afuresertib and docetaxel/prednisone plus afuresertib as requested in the Food and Drug Administration (FDA) combined therapy guideline. Whether to move one or both combination therapies to the pivotal study will be based on the PFS improvements of the combination therapy versus historical controls of abiraterone or docetaxel monotherapies in mCRPC patients who failed 1-3 lines of standard of care therapies.

Details
Condition Metastatic Castration-resistant Prostate Cancer
Treatment Phase I and Phase II: LAE001/prednisone + afuresertib
Clinical Study IdentifierNCT04060394
SponsorLaekna Limited
Last Modified on4 June 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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-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
Patients who have documented disease progression per RECIST 1.1 are eligible independent of PSA
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
progression on prior hormone treatment
in this study
• Patients who have PTEN status test reported other than "PTEN LOSS" or never
samples collected within 12 months before study enrollment or do a fresh core
completed any PTEN test before, could either provide the archival tumor
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
Please consult sponsor for participants with an "invalid" or "failed
PTEN/PIK3CA/AKT alteration results
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
Patients with bone only progression according to PCWG3 (ie, 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
Phase II: Patients who have mCRPC progressed or are intolerant after receiving
Absolute neutrophil count ≥1,500/μL
-3 prior standard treatments for mCSPC, or nmCRPC, or mCRPC, including at
Platelet count ≥75,000/μL
least one second-generation antiandrogen treatment (i.e., abiraterone
Hemoglobin ≥9 g/dL
enzalutamide, apalutamide, or darolutamide), and no more than one
Total serum bilirubin ≤1.5 × ULN within the 28 days before enrollment (in patients
chemotherapy. Patients must have at least 3 weeks of treatment of any
with known Gilbert's syndrome, total bilirubin ≤3 × ULN with direct bilirubin
antiandrogen and/or completed at least 3 Cycles of docetaxel or cabazitaxel
≤1.5 × ULN)
treatment and/or at least 3 injections of R223 and/or at least 2 injections of
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
sipuleucel-T to be counted as one prior therapy. Patient's current diagnosis
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
at screening must be mCRPC
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
prior treatments of any anti-androgen (such as abiraterone, enzalutamide
apalutamide, or any other AR antagonists that are approved later), and/or
antiandrogen and/or completed at least 4 Cycles of docetaxel or cabazitaxel
treatment before their screening visit
chemotherapy. Patients must have at least 3 weeks of treatment of any
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

Exclusion Criteria

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
1. 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. 2. Patients that received other second-line 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 6 weeks 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 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. 6. 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. 7. Patients who require potassium-wasting diuretics. 8. 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). 9. Patients who have received palliative and other radiotherapy for the target lesion within 4 weeks of study enrollment. 10. 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. 11. Patients with a history of hypothalamus, pituitary or adrenal insufficiency. 12. Patients with >grade 2 neuropathy at study enrollment. 13. History of another primary malignancy that is currently clinically significant or currently requires active intervention. 14. 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. 15. Patients with active cardiac disease or a history of cardiac dysfunction including any of the following
History of clinically significant cardiac arrhythmias unsuitable to participate, as determined by the investigator. 16. Patients with a 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. 17. 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. 18. Patients who have active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infections. 19. 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. 20. 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. 21. 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. 22. Patients with a history of upper gastrointestinal bleeding or uncontrolled peptic disease in the previous 3 months which in Investigator's opinion may impact patient's participation in the trial. 23. Patients have previously received AKT or PI3 kinase pathway or mTOR inhibitors
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