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

NCT04060394 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: LAE201INT2101
• Study Type: interventional
• Target: 49
• Locations: 2 countries
• Sites: 17

Brief 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.

Conditions

Metastatic Castration-resistant Prostate Cancer

Outcome Measures

Primary Outcomes (3)

• Phase II: Radiological progression free survival (rPFS) based on change in tumor per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

  Based on investigator reviewed radiographic tumor assessment.

  At the end of each 28 day treatment cycle and within 15 days of last treatment

• Phase I: Demonstrate safety and tolerability of LAE001/prednisone and afuresertib as combination therapy.

  Frequency and severity of AEs.

  Through study completion for an average of 12 months

• Phase II: Radiological progression free survival (rPFS) based changes per Prostate Cancer Working Group 3 (PCWG3)

  Based on investigator reviewed radiographic tumor assessment.

  At the end of each 28 day treatment cycle and within 15 days of last treatment

Secondary Outcomes (24)

• Phase II: Overall Response Rate (ORR) based tumor changes per RECIST 1.1

  At the end of each 28 day treatment cycle and within 15 days of last treatment

• Phase II: Overall Response Rate (ORR) based tumor changes per PCWG3

  At the end of each 28 day treatment cycle and within 15 days of last treatment

• Phase II: Duration of Response (DOR) based on tumor changes per RECIST 1.1

  At the end of each 28 day treatment cycle and within 15 days of last treatment

• Phase I: Duration of Response (DOR) based on tumor changes per RECIST 1.1

  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

• Phase II: Duration of Response (DOR) based on tumor changes per PCWG3

  At the end of each 28 day treatment cycle and within 15 days of last treatment

Other Outcomes (3)

• Phase I: Relationship between PSA levels and testosterone levels

  Cycle 1 (each cycle is 28 days) Days 1,8,15 and 22 and Day 1 of subsequent cycles

• Phase I: Explore correlation between anti-tumor activity and patient's PTEN status

  At the end of each 28 day treatment cycle and within 15 days of last treatment

• Phase I: Explore correlation between anti-tumor activity and patient's BRCA mutation status

  At the end of each 28 day treatment cycle and within 15 days of last treatment

Study Arms (6)

Phase I Cohort 1

EXPERIMENTAL

LAE001 (capsules) 75mg Twice Daily (BID) + prednisone (tablet) 5mg BID +afuresertib (tablet) 100mg Once Daily (QD) will be administered in Cycles of 28 days.

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Phase I Cohort 2

EXPERIMENTAL

LAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 100mg QD will be administered in Cycles of 28 days.

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Phase I Cohort 3

EXPERIMENTAL

LAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 125mg QD will be administered in Cycles of 28 days.

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Phase I Cohort 4

EXPERIMENTAL

LAE001 (capsules) 100mg BID + prednisone (tablet) 5mg BID +afuresertib (tablet) 150mg QD will be administered in Cycles of 28 days.

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Phase II Cohort 1

EXPERIMENTAL

LAE001 (capsules) + prednisone (tablet) +afuresertib at the Recommended Phase II Dose (RP2D)

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Phase II Cohort 2

EXPERIMENTAL

Docetaxel/prednisone + afuresertib

Drug: Phase I and Phase II: LAE001/prednisone + afuresertib

Interventions

Phase I and Phase II: LAE001/prednisone + afuresertib DRUG

In the Phase I portion of the study will identify the RPD2 of the combined therapy. In the Phase II will evaluate LAE001/prednisone + afuresertib at the RP2D (Cohort 1) and docetaxel/prednisone + afuresertib (Cohort 2).

Also known as: Phase II: Afuresertib

Phase I Cohort 1; Phase I Cohort 2; Phase I Cohort 3; Phase I Cohort 4; Phase II Cohort 1; Phase II Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Prostate cancer
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

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:

Sponsors & Collaborators

• Laekna Limited: lead

Study Sites (17)

Urological Associates of Southern Arizona

Tucson, Arizona, 85741, United States

Location

California Cancer Associates for Researh & Excellence, Inc

Encinitas, California, 92024, United States

Location

Eastern Connnecticut Hematology/Oncology Associates

Norwich, Connecticut, 06360, United States

Location

Piedmont Columbus Regional Research Institute

Columbus, Georgia, 31901, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Cotton-O'Neil Clinical Research Center

Topeka, Kansas, 66606, United States

Location

Associated Medical Professionals of NY

Syracuse, New York, 13215, United States

Location

Oregon Urology Institute

Florence, Oregon, 97439, United States

Location

Greenville Hospital System

Greenville, South Carolina, 29605, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75251, United States

Location

Baylor Scott and White Health

Temple, Texas, 76508, United States

Location

Northwest Medical Specialties, PLLC

Tacoma, Washington, 98405, United States

Location

National Cancer Center

Goyang-si, Gyeonggido, 10408, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyunggido, 13605, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

MeSH Terms

Interventions

Clinical Trials, Phase I as Topic; Prednisone; afuresertib

Intervention Hierarchy (Ancestors)

Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Yong Yue, MD

  Laekna Therapeutics

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase 1 Dose Escalation to determine Recommended Phase II Dose (RP2D) of LAE001/Prednisone plus Afuresertib in m-CRPC patients. Once RP2D is determined, Phase II will evaluate LAE001/Prednisone plus Afuresertib vs and Docetaxel/Prednisone plus Afuresertib in m-CRPC patients.

Study Record Dates

• First Submitted: July 1, 2019
• First Posted: August 19, 2019
• Study Start: September 13, 2019
• Primary Completion: December 27, 2023
• Study Completion: March 30, 2024
• Last Updated: October 10, 2024

Record last verified: 2024-10

Locations

KR (5); US (12)