A Phase II, Open-label, Multi-cohort Study to Assess the Efficacy and Safety of ASP5541 in Participants With Advanced Prostate Cancer

Study Identifier:
5541-CL-0201
CT.gov Identifier:
NCT07005154
EudraCT Identifier:
202452000000
EU Trial (CTIS) Number:
N/A
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

To sssess the efficacy and safety of ASP5541 in participants with advanced prostate cancer.

Primary Objectives: ● To evaluate the efficacy of ASP5541 in combination with Prednisone/ Prednisone versus Acetate Abiraterone in mCRPC participants who Prednisone Prednisone Prednisone Prednisone Acetate Abiraterone Prednisone Prednisone. ● To evaluate the safety of ASP5541 with or without Prednisone/ Prednisone versus Acetate acetate versus Abiraterone / Prednisone. ● To evaluate the pharmacodynamic characteristics of ASP5541 with or without Prednisone/ Prednisone versus Acetate Abiraterone versus Prednisone/ Prednisone . ● To evaluate post-treatment pain progression of ASP5541 with or without Prednisone/ Prednisone versus Acetate Abiraterone versus PrednisonePrednisone.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Prostate
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    II
    Sex
    Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Cohort 1 (mCRPC) Group A
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    Inclusion criteria
    • Inclusion Criteria:
    • Participant is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
    • Participant has ECOG performance status of 0 or 1, or ECOG performance status of 2 if due to bone pain.
    • Participant must have an estimated life expectancy of ≥ 12 months with mHSPC or ≥ 6 months with mCRPC.
    • Participant is able to understand and comply with all study requirements and procedures.
    • Participant has been diagnosed with mCRPC or mHSPC documented by metastatic lesions on a bone scan, computed tomography (CT), magnetic resonance imaging (MRI) or prostate-specific membrane antigen positron emission tomography (PSMA-PET).
    • Participant is receiving ongoing ADT with a gonadotropin-releasing hormone (GnRH) analogue or has a history of bilateral orchiectomy (i.e., surgical or medical castration). Participant with mHSPC must have started castration therapy (medical or surgical) at least 14 days prior to Cycle 1 Day 1 (C1D1).
    • Note: Participant who has not had a bilateral orchiectomy must have a plan to maintain effective GnRH analogue therapy for the duration of the study.
    • If the participant has mCRPC, participant has evidence of disease progression defined as 1 or more of the following criteria at study entry:
    • Evidence of radiographic progression of disease prior to first dose and following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 or on a bone scan per PCWG3.
    • PSA progression defined as an increase in PSA of at least 25% and ≥ 1 ng/mL above the nadir, confirmed by a second value 1 week later, and with at least 1 of the measurements within 90 days prior to screening. PSA nadir is defined as the lowest PSA during or after the most recent treatment.
    • If the participant has mCRPC, participant has a serum testosterone level < 1.73 nmol/L (< 50 ng/dL) at the Screening visit.
    • Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period and for 7 months after final ASP5541 administration.
    • Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the investigational period and for 7 months after final ASP5541 administration.
    • Male participant must not donate sperm during the treatment period and for 7 months after final ASP5541 administration.
    • Participant agrees not to participate in another interventional study while receiving ASP5541 in the present study.
    • Participant should have normal serum potassium (within the local laboratory normal range) at screening without supplementation.
    • Male participants who were 18 years of age or older when signing the informed consent form.
    • Participants were diagnosed with prostate adenocarcinoma by histological or cytological examination, without neuroendocrine differentiation or small cell carcinoma characteristics.
    • Participants' ECOG fitness score is 0 or 1, or 2 if bone pain is present.
    • The estimated life expectancy of mHSPC participants must be ≥12 months, and the estimated life expectancy of mCRPC participants must be >6 months.
    • The researchers assessed that the participants were able to understand and comply with all research requirements and procedures, including completing the PRO questionnaire.
    • Male participants: ● Male participants whose partners are women of reproductive age (including those whose partners are breastfeeding) must agree to use the prescribed form of contraception during treatment and for 7 months after the last dose of the study intervention ASP5541 or 3 months after the last dose of Abiraterone . ● Male participants whose partners are pregnant must agree to abstain from sexual intercourse or use condoms during their partner's pregnancy and for 7 months after the last dose of the study intervention ASP5541 or 3 months after the last dose of Abiraterone . ● Sperm donation is prohibited during treatment and for 7 months after the last dose of the study intervention ASP5541 or 3 months after the last dose of Abiraterone Acetate .
    • Participants have provided informed consent, including consent to comply with the requirements and restrictions listed in the ICF and the program.
    • The participants had sufficient muscle mass in their gluteus medius muscles to be able to receive intramuscular injections.
    • Participants agreed not to participate in other interventional studies while receiving ASP5541 treatment in this study.
    • Participants should have normal serum potassium levels (within the normal range as determined by local laboratory tests) at the time of screening, and no potassium supplementation is required.
    • Participants were diagnosed with mCRPC and had evidence of metastatic lesions on bone scans, CT, MRI, or PSMA-PET.
    • Evidence of disease progression in participants was defined as meeting at least one of the following criteria at the time of enrollment in the study: ● Imaging evidence of disease progression, as assessed by the investigator, following the participant's most recent prostate cancer treatment and prior to the first administration of the study drug, defined as PD shown on CT/MRI (as determined according to RECIST v1.1) or PD shown on bone scan (as determined according to PCWG3 criteria). ● PSA progression was defined as at least two measurements (at least one week apart, with at least one measurement performed within 90 days prior to screening) confirming an increase in PSA of ≥25% from the lowest value and an absolute increase of ≥1 ng/mL. The lowest PSA value was defined as the lowest PSA level during or after the most recent treatment.
    • Participants must be currently using a GnRH analog for ADT treatment or have a history of bilateral orchiectomy (i.e., surgical or medical castration). Note: If a participant has not undergone bilateral orchiectomy, there must be a plan to continue treatment with an effective GnRH analog during the study period.
    • Participants' serum testosterone levels at the screening visit were <1.73 nmol/L (<50 ng/dL).
    • Participants were able to swallow Acetate Abiraterone.
    Exclusion criteria
    • Exclusion Criteria:
    • Participant has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.
    • Participant has known active central nervous system (CNS) metastases. Note: Participant with CNS metastases who has been treated with surgery and/or radiation therapy, who is off pharmacologic doses of glucocorticoids and who is neurologically stable is eligible.
    • Participant has a known additional malignancy beyond prostate cancer that requires active treatment with the exception of any of the following:
    • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ carcinoma of any type
    • Adequately treated Stage I cancer from which the participant is currently in remission and has been in remission for ≥ 2 years
    • Any other cancer from which the participant has been disease-free for ≥5 years
    • Participant has clinically significant cardiac disease, defined as any of the following:
    • Clinically significant cardiac arrhythmias including bradyarrhythmia which are poorly controlled. Rate-controlled atrial fibrillation is permitted.
    • Congenital long QT syndrome.
    • QT interval corrected by Fridericia's formula (QTcF) ≥450 msec at Screening. If the QT interval corrected for heart rate intervals (QTc) is prolonged in a participant with a pacemaker or bundle branch block, the participant may be enrolled in the study if confirmed by the medical monitor.
    • History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II or left ventricular ejection fraction measurement of < 50% at baseline.
    • Cohorts 1 and 3: Participant must not have unstable angina (symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
    • Cohort 2: Participants must not have symptomatic heart failure, unstable or new-onset angina or myocardial infarction within the past 12 months.
    • Cohorts 1 and 3: Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg that has been confirmed by 2 successive measurements despite optimal medical management.
    • Cohort 2: Uncontrolled hypertension, defined as systolic BP > 140 mmHg or diastolic BP > 90 mmHg that has been confirmed by 2 successive measurements despite optimal medical management. Participants may be receiving a maximum of 2 antihypertensives that were initiated at least 3 months prior to Cycle 1 Day 1.
    • Cohort 1 and 3: Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter related venous thrombosis occurring > 1 month before Cycle 1 Day 1).
    • Cohort 2: Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within the last 12 months.
    • Participant has any unresolved National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 5.0) Grade > 2 toxicity at the Screening visit. Note: Participant receiving ongoing hormone replacement therapy for endocrine immune-related AEs without clinical symptoms will not be excluded.
    • Participant has had major surgery (e.g., requiring general anesthesia) within 30 days before screening, or has not fully recovered from surgery, or has major surgery planned during the time the participant is expected to participate in the study.
    • Participant has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 28 days prior to day 1.
    • Participant received a blood transfusion within 1 month of the first dose of study intervention.
    • Participant has a history of impaired pituitary or adrenal gland function (e.g., Addison's disease, Cushing's syndrome).
    • Participant has hemoglobin A1c (HbA1c) > 10% (if diabetes mellitus was previously diagnosed) or HbA1c > 8% (if diabetes mellitus was previously undiagnosed). (Excluded participant may be rescreened after referral and evidence of improved control of their condition.)
    • Participant has jaundice or known current active liver disease from any cause, including hepatitis A (hepatitis A virus IgM positive, but testing for hepatitis A in screening is not required), hepatitis B (hepatitis B virus surface antigen positive, confirmed by hepatitis B virus DNA), or hepatitis C (hepatitis C virus antibody positive, confirmed by hepatitis C virus RNA).
    • Participant has moderate or severe hepatic impairment (Child-Pugh Class B or C).
    • Participant has a known history of human immunodeficiency virus (HIV) infection (HIV antibody positive).
    • Participant has a body mass index > 40 kg/m2.
    • Participant has a history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria within 2 years before screening.
    • Participant received treatment with glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to C1D1. The use of topical, intraocular, inhalational, intranasal or intra-articular glucocorticoids is permitted.
    • Participant received treatment with herbal medications with known anti-cancer properties or known effects on prostate physiology within 4 weeks prior to Cycle 1 Day 1 (e.g., saw palmetto, St. John's wort, turmeric/curcumin). Participants must agree not to use herbal products during study participation.
    • Participant is receiving current treatment with systemic ketoconazole, abiraterone acetate (AA) or any other cytochrome P450 17A1 (CYP17) inhibitor. Participant who has received systemic ketoconazole, AA or any other CYP17 inhibitor must have discontinued these agents ≥ 4 weeks prior to the first dose of study intervention.
    • Participant received prior systemic treatment with a strong inducer or inhibitor of cytochrome p450 3A4 (CYP3A4) within 4 weeks of first dose of study intervention. Concomitant use of strong inducers or inhibitors of CYP3A4 are not permitted on study.
    • Participant requires use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg. Note: Participant who switches from a high dose to a dose of 30 μg/day or less prior to first dose of study drug is eligible for study entry.
    • Participant is required to use any prohibited medication on the List of Excluded Concomitant Medications.
    • For mCRPC participants only: Participant has been treated with any of the following for prostate cancer, during the indicated time frame prior to enrollment:
    • Hormonal therapy (e.g., androgen receptor blockers [AR] antagonists, second-generation androgen receptor pathway inhibitors [including enzalutamide, apalutamide, darolutamide, rezvilutamide and AA], 5-alpha reductase inhibitors, estrogens, cyproterone acetate) within 4 weeks of C1D1. Note: Participant has been treated with bicalutamide within 6 weeks prior to enrollment is not permitted. Participant has been treated with all other GnRH analogues or antagonists is permitted.
    • Chemotherapy within 2 weeks or 5 half-lives of C1D1 (whichever is longer)
    • Biologic therapy within 4 weeks of C1D1
    • Immunotherapy within 4 weeks of C1D1
    • Radiation therapy (includes radioligands) within 4 weeks of C1D1
    • For mHSPC participants only: Participant has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (the following exceptions are permitted):
    • Up to 4 months of ADT with GnRH agonists or antagonists or orchiectomy (within 3 months prior to C1D1) with or without concurrent antiandrogens.
    • Participant may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to C1D1.
    • Up to 6 cycles of docetaxel therapy, with the last dose of docetaxel ≤ 2 months prior to C1D1. A participant who has received docetaxel should have maintained a response to docetaxel of stable disease or better, by imaging and PSA, prior to C1D1.
    • Up to 6 months of ADT with GnRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to C1D1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to C1D1.
    • Participant has received any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to C1D1.
    • Participant has received ASP5541 previously.
    • Participant has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin < 9 g/dL (6.2 mmol/L) or international normalized ratio (INR) ≥ 1.5 (unless participant is taking oral anticoagulants in which case INR ≤ 2.0 is permitted) at Screening. Note: Participant may not have received any growth factors within 7 days or blood transfusions within 28 days prior to the hematology values obtained at Screening.
    • Participant has serum total bilirubin > 1.5 x upper limit of normal (ULN) (or > 3 x ULN for participants with documented Gilbert's disease), or serum alanine aminotransferase or aspartate aminotransferase > 2.5 x ULN at Screening.
    • Participant does not have adequate renal function defined as a calculated creatinine clearance < 30 mL/min as determined by a validated algorithm for calculating creatinine clearance.
    • Participant has serum albumin < 3.0 g/dL (30 g/L) at Screening.
    • Participant has a known or suspected hypersensitivity to ASP5541, prednisone, or any components of the formulations used.
    • Participant has a gastrointestinal disorder affecting absorption.
    • The presence of complications, infections, or comorbidities in participants may affect their participation in the study, and researchers may believe that such conditions pose unnecessary risks to participants or increase the difficulty of data interpretation.
    • Participants had known active central nervous system metastases. Note: Participants with central nervous system metastases who had undergone surgery and/or radiation therapy, discontinued pharmacological doses of Glucocorticoid , and had stable neurological conditions were eligible to participate in the study.
    • Participants must have other malignancies requiring active treatment (excluding prostate cancer), except for: ● Well-treated basal cell carcinoma, squamous cell carcinoma of the skin, or any type of carcinoma in situ. ● Well-treated stage I cancer, and the participant is currently in remission for ≥2 years. ● Any other cancer, and the participant has a disease-free survival of ≥5 years.
    • Participants with any unrecovered grade >2 toxicities as assessed by NCI-CTCAE (version 5.0) at the screening visit were excluded. Note: Participants currently receiving hormone replacement therapy for endocrine system immune-related adverse events (AEs) and who are asymptomatic will not be excluded.
    • Participants who have undergone major surgery (e.g., requiring general anesthesia) within 90 days prior to screening, or who will not fully recover from surgery, or who plan to undergo major surgery during the period when the participant is expected to participate in the study.
    • Participants had a febrile illness or a symptomatic viral, bacterial (including upper respiratory tract infection) or fungal (non-skin) infection within 28 days prior to Day 1 of Cycle 1.
    • Participants had received blood transfusions within one month prior to Day 1 of Cycle 1.
    • Participants had a history of pituitary or adrenal dysfunction (e.g., Addison's disease and Cushing's syndrome).
    • Participants with HbA1c > 10% and a prior diagnosis of diabetes. Participants with HbA1c > 8% and no prior diagnosis of diabetes (excluded participants may be re-screened upon referral and evidence of disease control).
    • Participants must have jaundice or be currently suffering from active liver disease of any cause, including hepatitis A (positive hepatitis A virus IgM, but hepatitis A testing is not required at screening), hepatitis B (positive HBsAg; or if HBsAg negative/anti-HBc positive, then HBV DNA positive), or hepatitis C (positive HCV antibody, confirmed by HCV RNA).
    • Participants had moderate or severe liver dysfunction (Child-Pugh grade B or C).
    • Participants had a known history of HIV infection. HIV testing was not required unless mandated by local health regulatory authorities. (China only: Participants tested positive for HIV antibodies.)
    • Participants had a body mass index (BMI) > 40 kg/m2.
    • According to the DSM-5 criteria, participants had a history of drug or alcohol abuse within 2 years prior to screening.
    • Participants received treatment with a Prednisone/ Prednisone equivalent dose of Glucocorticoid >10 mg/day for the four weeks preceding Day 1 of Cycle 1. Topical, intraocular, inhaled, intranasal, or intra-articular administration of Glucocorticoid was permitted.
    • Participants must have received treatment with herbal products (China only: and traditional Chinese medicine products) (e.g., saw palmetto) within 4 weeks prior to Day 1 of Cycle 1. Participants must agree not to use herbal products (China only: and traditional Chinese medicine products) during the study period.
    • Participants are currently receiving systemic ketoconazole or any of its CYP17 inhibitors. If a participant has received systemic ketoconazole or any other CYP17 inhibitor, such medication must be discontinued ≥4 weeks before day 1 of cycle 1.
    • Participants are receiving a narrow therapeutic index of CYP2D6 substrate.
    • Participants had received systemic therapy with a potent CYP3A4 inducer or inhibitor within the four weeks prior to Day 1 of Cycle 1. Concomitant use of potent CYP3A4 inducers or inhibitors was not permitted during the study.
    • Participants are required to use biotin (i.e., vitamin B7) or a biotin-containing supplement at a dose higher than the recommended daily intake of 30 μg. Note: Participants who switched from a high dose to a dose ≤30 μg/day before Day 1 of Cycle 1 are eligible to enroll in the study.
    • 20
    • :
    • twenty one Participants received a live attenuated vaccine within 30 days prior to the planned start of the study treatment. Examples of live attenuated vaccines include, but are not limited to: measles, mumps, rubella, varicella/shingles (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Injectable seasonal influenza vaccines are usually inactivated virus vaccines and are permitted; however, intranasal influenza vaccines (such as FluMist®) are live attenuated vaccines and are not permitted.
    • 21
    • :
    • twenty two Participants are required to use any of the prohibited medications listed in the prohibited combination medications list in the protocol.
    • 22
    • :
    • twenty three Participants must have received any experimental treatment within the four weeks prior to Day 1 of Cycle 1 or be within five half-lives of the treatment on Day 1 of Cycle 1 (whichever is longer).
    • 23
    • :
    • twenty four Participants had previously received ASP5541 (PRL-02) treatment.
    • Participants at screening must have an absolute neutrophil count <1500/μL, a platelet count <100,000/μL, a hemoglobin level <9 g/dL (6.2 mmol/L), or an INR ≥1.5 (unless the participant is using an oral anticoagulant, in which case an INR ≤2.0 is permissible). Note: Participants must not have used any growth factors within 7 days prior to the measurement of hematological parameters at screening, and must not have received a blood transfusion within the preceding 28 days.
    • Participants were screened with serum TBL > 1.5 × ULN (except for participants with Gilbert syndrome) or serum ALT/AST > 2.5 × ULN.
    • Participants who did not have adequate renal function at the time of screening were defined as having a creatinine clearance rate <30 mL/min calculated using a validated creatinine clearance method.
    • Participants had serum albumin levels <3.0 g/dL (30 g/L) at the time of screening.
    • Participants were known or suspected of having hypersensitivity to any component of ASP5541, Abiraterone , Prednisone/ Prednisone , or the formulation used in the study.
    • The participants suffered from gastrointestinal diseases that affected absorption.
    • Prior treatment with a second-generation ARPI (e.g., Abiraterone , Enzalutamide, Apalutamide, or Darolutamide). Note: Limited second-generation ARPI treatment may be permitted in the context of neoadjuvant, adjuvant, or non-metastatic biochemical relapse, provided there is no evidence of disease progression at least 6 months after the last dose.
    • Received any of the following prostate cancer treatments within the specified time frame prior to enrollment: ● Hormone therapy (e.g., AR antagonists, 5α-reductase inhibitors, estrogen, Acetate acetate) within 4 weeks prior to Day 1 of Cycle 1. Note: Bicalutamide treatment within 6 weeks prior to enrollment is not permitted. GnRH agonist or antagonist therapy is permitted. ● Chemotherapy within 2 weeks prior to Day 1 of Cycle 1 or still within 5 half-lives of chemotherapy on Day 1 of Cycle 1 (whichever is longer) ● Biotherapy within 4 weeks prior to Day 1 of Cycle 1 ● Immunotherapy within 4 weeks prior to Day 1 of Cycle 1 ● Radiation therapy (including radioligand therapy) within 4 weeks prior to Day 1 of Cycle 1.
    • Participants known to carry BRCA mutations should be excluded unless they have previously received PARPi or are ineligible for PARPi or PARPi is unavailable.
    • Participants must have clinically significant cardiac disease, defined as one of the following: ● Clinically significant arrhythmia, including poorly controlled bradycardia. Controllable atrial fibrillation is acceptable. ● Congenital long QT syndrome. ● QTcF ≥ 450 ms at screening. For participants with implanted pacemakers or bundle branch block, QTc prolongation may be admitted to the study upon confirmation by a medical monitor. ● History of clinically significant cardiac disease or NYHA class II or higher congestive heart failure, or a left ventricular ejection fraction < 50% at baseline. Participants must not have experienced unstable angina (symptoms present at rest) or new-onset angina within the past 3 months, or a myocardial infarction within the past 6 months. ● Confirmed uncontrolled hypertension, defined as two consecutive measurements confirming systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg with optimal medical care. ● An arterial or venous thrombotic or embolic event, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism, occurred within 3 months prior to the start of the study drug treatment (except for catheter-related venous thrombosis that has been adequately treated >1 month before day 1 of cycle 1).

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Carolinas
    Myrtle Beach, SC, United States, 29572
    Investigator
    Neal Shore
    Status
    Recruiting
    Condition(s) Treated at Site
    Prostate