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

Hoffmann-La Roche1,101 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

1,101

Conditions

Metastatic Prostate Cancer

Interventions

IpatasertibDRUG

Oral tablets, 400 mg, given once daily (QD) beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

AbirateroneDRUG

Oral tablets of abiraterone, 1000 mg QD, taken on an empty stomach and swallowed whole with water.

PlaceboDRUG

Oral tablets (matched to ipatasertib appearance), given QD beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity.

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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)

Locations (176)

Outcomes

Primary Outcomes

Investigator-assessed Radiographic Progression-free Survival (rPFS), Per Prostate Cancer Working Group 3 (PCWG3) Criteria in Phosphatase and Tensin Homolog (PTEN) Loss Population

rPFS was defined as time from date of randomization to the first occurrence of documented disease progression (PD), as assessed by the investigator with use of the PCWG3 criteria or death from any cause, whichever occurs first. PD for soft tissue was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 millimeters (mm) in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later according to the PCWG3 criteria. The Kaplan-Meier (KM) estimate was used to determine the median rPFS.

Time frame: Up to approximately 32 months

Investigator-assessed rPFS, Per PCWG3 Criteria in ITT Population

rPFS was defined as time from date of randomization to the first occurrence of documented PD, as assessed by the investigator with use of the PCWG3 criteria or death from any cause, whichever occurs first. PD for soft tissue was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions according to RECIST v1.1 criteria. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later according to the PCWG3 criteria. The KM estimate was used to determine the median rPFS.

Time frame: Up to approximately 32 months

Secondary Outcomes

Overall Survival (OS) in PTEN-loss Population

OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS.

Data from ClinicalTrials.gov

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Oral tablets of 5 mg, taken twice daily (BID) until disease progression or intolerable toxicity.

Ironwood Cancer & Research Centers

Chandler, Arizona, United States

Mayo Clinic Arizona

Scottsdale, Arizona, United States

City of Hope

Duarte, California, United States

USC Norris Cancer Center

Los Angeles, California, United States

UC Irvine Medical Center

Orange, California, United States

Stanford University

Palo Alto, California, United States

Pacific Hematology Oncology Associates

San Francisco, California, United States

University of Colorado Hospital - Anschutz Cancer Pavilion

Aurora, Colorado, United States

Yale Cancer Center

New Haven, Connecticut, United States

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

...and 166 more locations

Time frame: Up to approximately 6.5 years

OS in ITT Population

OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS.

Time frame: Up to approximately 6.5 years

Time to Pain Progression in PTEN-loss Population

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 were asymptomatic at baseline or pain worsening for those who were mildly symptomatic at baseline. Pain severity was graded on a 10-point numeric rating scale \[NRS\], with 0=no pain and 10=severe pain. Pain severity progression was defined as a ≥ 2-point absolute increase from baseline. KM estimates were used to determine the median time to pain progression.