Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in participants with metastatic castrate-resistant prostate cancer (mCRPC).

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial Testing Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Asymptomatic or Mildly Symptomatic, Previously Untreated, Metastatic Castrate-Resistant Prostate Cancer

Conditions
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Metastatic Prostate Cancer

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Abiraterone
* Drug: Placebo
* Drug: Prednisone/Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Collaborative Oncology Group (ECOG) performance status of 0 or 1 at screening Adequate hematologic and organ function within 28 days before the first study treatment Ability to comply with the study protocol, in the investigator's judgment Willingness and ability of participants to use the electronic device to report selected study outcomes; Caregivers and site staff can assist with patient diary input but patient must be able to independently comprehend and answer the questionnaires Life expectancy of at least 6 months Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm For enrollment into the China extension cohort, residence in the People's Republic of China Disease-specific Inclusion Criteria: Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features Consent to provide a formalin-fixed paraffin-embedded (FFPE) tissue block (preferred) or a minimum of 15 (20 preferred) freshly cut unstained tumor slides from the most recently collected, available tumor tissue accompanied by an associated pathology report (with tumor content information, Gleason score, and disease staging) for PTEN IHC and NGS testing and for other protocol-mandated secondary and exploratory assessments. If only 12-14 slides are available, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor. Cytologic or fine-needle aspiration samples are not acceptable. Tumor tissue from bone metastases is not acceptable A valid PTEN IHC result (testingcentral laboratory tested with results directly sent to IxRS) (e.g., participants with an invalid or failed PTEN IHC result are not permitted to enroll) Metastatic disease documented prior to randomization by clear evidence of bone lesions on bone scan and/or measurable soft tissue disease by computed tomography (CT) and/or magnetic resonance imaging (MRI) (at least one target lesion) according to RECIST v1.1 Asymptomatic or mildly symptomatic form of prostate cancer Progressive disease before initiating study treatment Ongoing androgen deprivation with gonadotropin-releasing hormone (GnRH) analog or bilateral orchiectomy, with serum testosterone <= 50 ng/dL (<= 1.7 nmol/L) within 28 days before randomization Exclusion Criteria: Inability or unwillingness to swallow whole pills History of malabsorption syndrome or other condition that would interfere with enteral absorption Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) Need of more than 10 mg/day of prednisone or an equivalent dose of other anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to treat a chronic disease (e.g., rheumatic disorder) Active infection requiring intravenous (IV) antibiotics within 14 days before Day 1, Cycle 1 Immunocompromised status because of current known active infection with HIV or because of the use of immunosuppressive therapies for other conditions Major surgical procedure or significant traumatic injury within 28 days prior to Day 1, Cycle 1, or anticipation of the need for major surgery during study treatment History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), untreated coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), myocardial infarction or atrial thrombotic events within the past 6 months, severe unstable angina, New York Heart Association Class III and IV heart disease or depressed left ventricular ejection fraction (LVEF; previously documented LVEF < 50% without documentation of recovery), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome History of another malignancy within 5 years prior to randomization, except for either adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta, and low grade T1 tumors), or other malignancies where the patient has undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to have a recurrence rate of <5% at 5 years Any other diseases, cardiovascular, pulmonary, or metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the participants at high risk from treatment complications. Disease-Specific Exclusion Criteria: Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the prostate Any therapy including chemotherapy (e.g., docetaxel) or biological therapy (e.g., vaccine, immunotherapy) for the treatment of castration-resistant prostate cancer. Previous treatment with flutamide, steroidal anti-androgens, androgens, estrogens, bicalutamide, nilutamide, or 5-α reductase inhibitor is permitted. Use of opioid medications for cancer-related pain, including codeine and dextropropoxyphene, currently or any time within 4 weeks of Day 1, Cycle 1 Prior treatment with abiraterone or other known potent CYP17 inhibitors (e.g., ketoconazole, orteronel) or investigational agents that block androgen synthesis. Previous treatment with itraconazole and fluconazole is permitted. Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or experimental (e.g., ARN-509, ODM-201, or galeterone) Prior treatment with flutamide (Eulexin®), steroidal anti-androgens (e.g., cyproterone acetate, chlormadinone acetate), androgens, or estrogens treatment within 4 weeks of Cycle 1, Day 1 Prior treatment with bicalutamide (Casodex®) or nilutamide (Nilandron®) within 6 weeks of Cycle 1, Day 1 Prior treatment with 5-alpha reductase inhibitors within 4 weeks of Cycle 1, Day 1 Prior treatment with systemic radiopharmaceuticals (e.g., radium-223 and strontium-89). Radiopharmaceuticals for the purpose of imaging are permitted. Focal palliative radiation to treat cancer-related pain is permitted provided that the last treatment with radiation is at least 14 days prior to Cycle 1, Day 1. Prior treatment with approved or experimental therapeutic agents with known inhibition of the PI3K pathway, including PI3K inhibitors, AKT inhibitors, and mTOR inhibitors Administration of an investigational therapeutic agent within 28 days of Cycle 1, Day 1 Known untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsant medications or corticosteroids for symptomatic control); a CT or MRI scan of the brain will be performed at screening if required by the local health authority Any chronic therapy or use of food supplements that are strong CYP3A4/5 inducers or inhibitors or sensitive substrates of CYP3A or CYP2D6 with a narrow therapeutic window Abiraterone-Specific Exclusion Criteria: Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg) History of pituitary or adrenal dysfunction Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical therapy Ipatasertib-Specific Exclusion Criteria: Type 1 or Type 2 diabetes mellitus requiring insulin at study entry History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active bowel inflammation (e.g., diverticulitis)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo + Abiraterone<br>Participants received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles. | Drug: Abiraterone<br>* Oral tablets of abiraterone, 1000 mg QD, taken on an empty stomach and swallowed whole with water.<br>Drug: Placebo<br>* Oral tablets (matched to ipatasertib appearance), given QD beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.<br>Drug: Prednisone/Prednisolone<br>* Oral tablets of 5 mg, taken twice daily (BID) until disease progression or intolerable toxicity.<br>|
| Experimental: Ipatasertib + Abiraterone<br>Participants received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles. | Drug: Ipatasertib<br>* Oral tablets, 400 mg, given once daily (QD) beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.<br>Drug: Abiraterone<br>* Oral tablets of abiraterone, 1000 mg QD, taken on an empty stomach and swallowed whole with water.<br>Drug: Prednisone/Prednisolone<br>* Oral tablets of 5 mg, taken twice daily (BID) until disease progression or intolerable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-Assessed Radiographic Progression-Free Survival (rPFS) Per PCWG3 Criteria (PTEN Loss Population) | Radiographic progression-free survival is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first. Disease progression for soft tissue is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the sum of diameters of target lesions; progression of non target lesions; the appearance of one or more new lesions. Disease progression for bone lesions is defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later. rPFS will be analyzed in participants with phosphatase and tensin homolog (PTEN) - loss tumors (using the Ventana PTEN immunohistochemistry (IHC) assay). | Up to approximately 31 months | 
| Investigator-Assessed Radiographic Progression-Free Survival (rPFS) Per PCWG3 Criteria (Intent-To-Treat (ITT) Population) | Radiographic progression-free survival is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first. Disease progression for soft tissue is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the sum of diameters of target lesions; progression of non target lesions; the appearance of one or more new lesions. Disease progression for bone lesions is defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later. rPFS will be analyzed in the Intent-to-Treat (ITT) population. | Up to approximately 31 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) is defined as the time from randomization to death due to any cause. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to Pain Progression | Time to pain progression was defined as the time from randomization to the first occurrence of confirmed clinically meaningful cancer-related pain progression event. Cancer-related pain progression refers to pain onset for participants who are asymptomatic at baseline or pain worsening for those who are mildly symptomatic at baseline. Pain severity will be graded on a 10-point scale, with 0=no pain and 10=severe pain. Pain severity progression is defined as a ≥ 2-point absolute increase from baseline. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to Initiation of Cytotoxic Chemotherapy | Time to initiation of cytotoxic chemotherapy is defined as the time interval from the date of randomization to the date of initiation of cytotoxic chemotherapy (use of antineoplastic agents: docetaxel, cabazitaxel, mitoxantrone, estramustine, cisplatin, carboplatin, cyclophosphamide, doxorubicin, mitomycin, irinotecan, 5-fluorouracil, gemcitabine, or etoposide) for prostate cancer. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to Function Deterioration | Time to function deterioration was defined as the time from the date of randomisation to the date of 10-point or more decrease on either the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) PF (Physical Functioning) or RF (Role Functioning) scale scores (range, 0-100) held for two consecutive assessments, or a 10 point or more score decrease followed by death (any cause) within 28 days, whichever occurs first. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to Prostate-Specific Antigen (PSA) Progression | Time to PSA progression is defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression is defined as a PSA increase that is ≥ 25% and ≥ 2 ng/mL above the baseline or the nadir, which is confirmed by a second value ≥ 3 weeks later. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to First Opioid Use | Time to first opioid use is defined as the documentation of the first opioid prescription for cancer-related pain followed by the participant's record of opioid intake or availability of an Analgesic Quantification Algorithm (AQA) daily score. Participants reporting use of opioid for cancer-related pain at baseline will be excluded from the analysis. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Time to Symptomatic Skeletal Event (SSE) | Time to SSE is defined as the time interval from the date of randomization to the date of an SSE. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Objective Response Rate (ORR) | An objective response is defined as a complete response (CR) or partial response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator using RECIST v1.1 and PCWG3 criteria, in participants with measurable disease at baseline. Participants without a post-baseline tumor assessment will be considered non-responders. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| PSA Response Rate | PSA response rate is defined as the percentage of participants achieving a PSA decline ≥50% from baseline. Participants without a post-baseline PSA assessment will be considered non-responders. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Investigator-Assessed rPFS Per PCWG3 Criteria in Participants With PTEN-Loss Tumors by Next-Generation Sequencing (NGS) | Investigator-assessed rPFS is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first and will be analyzed in participants with PTEN-loss tumors by NGS. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Duration of Response (DOR) | Duration of Response (DOR) is defined as the time from first occurrence of a documented confirmed objective response until the time of documented disease progression as determined by the investigator using RECIST v1.1 and PCWG3 criteria, or death from any cause, whichever occurs first. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Up to approximately 7 years | 
| Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date. | Baseline up until 28 days after the last dose of study drug or initiation of subsequent lines of anti-cancer therapy, whichever occurs first (up to a maximum of 7 years). | 
| Plasma Concentrations of Ipatasertib at Specified Timepoints | Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants. | 1-3 hours post-dose (Cycle 1, Day 1; Cycle 1 Day 15 and Cycle 3 Day 1) and pre-dose at steady state (Cycle 1 Day 15, Cycle 3 Day 1, Cycle 6 Day 1) (each cycle length= 28 days) | 
| Plasma Concentrations of Abiraterone at Specified Timepoints | Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants. | Pre-dose at steady state in Cycle 1, Day 15 and Cycle 3 Day 1 (each cycle length= 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Castrate-Resistant Prostate Cancer