Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy

A Phase Ib/II Study of Ipatasertib (GDC-0068) or Apitolisib (GDC-0980) With Abiraterone Acetate Versus Abiraterone Acetate in Patients With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy

This multicenter, international, Phase Ib/II trial consists of three stages: a Phase Ib, open-label stage in which the recommended Phase II dose was determined for ipataseritib administrated in combination with abiraterone and of apitolisib administrated in combination with abiraterone (this phase is no longer active), a Phase II, 3-arm, double-blind, randomized comparison of ipatasertib with abiraterone and prednisone/prednisolone versus placebo with abiraterone and prednisone/prednisolone and a safety single-arm, open-label cohort of ipatasertib 400 mg daily alone or in combination with prednisone/prednisolone or prednisone/prednisolone plus abiraterone.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Abiraterone; Drug: Ipatasertib; Drug: Prednisone; Drug: Prednisolone; Drug: Apitolisib; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 298
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia, 656 53
    • Masarykuv onkologicky ustav
  • Hradec Kralove, Czechia, 50012
    • Fakultni nemocnice Hradec Kralove; I. interni klinika,Oddeleni invazivni kardiologie
  • Praha, Czechia, 140 59
    • Fakultni Thomayerova Nemocnice; Revmatologicke Oddeleni
  • Praha 2, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze
  • Praha 2, Czechia, 120 00
    • Urocentrum Praha s.r.o.
• France
  • Angers, France, 49055
    • ICO Paul Papin; Oncologie Medicale.
  • Lyon, France, 69008
    • Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes
  • Paris, France, 75231
    • Institut Curie; Oncologie Medicale
  • Paris, France, 75674
    • GH Paris Saint Joseph; Hopital De Jour Oncologie
  • Paris, France, 75230
    • HIA du Val de Grâce
  • Saint-Mande, France, 94160
    • Hopital d'Instruction des Armées de Bégin
  • Villejuif, France, 94805
    • Institut Gustave Roussy; Departement Oncologie Medicale
• Greece
  • Athens, Greece, 115 28
    • Alexandras Hospital; Dept. of Clin. Therapeutics, Athens Uni School of Medicine
  • Heraklion, Greece, 711 10
    • Univ General Hosp Heraklion; Medical Oncology
  • Larissa, Greece, 413 35
    • University Hospital of Larissa; Oncology
  • Patras, Greece, 265 04
    • University Hospital of Patras Medical Oncology
  • Piraeus, Greece, 185 47
    • Metropolitan Hospital; 2Nd Oncology Clinic
• Italy
  • Emilia-Romagna
    • Meldola, Emilia-Romagna, Italy, 47014
      • IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
  • Lombardia
    • Cremona, Lombardia, Italy, 26100
      • Azienda Ospedaliera Istituti Ospitalieri
    • Milano, Lombardia, Italy, 20133
      • Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2
    • Milano, Lombardia, Italy, 20132
      • Irccs Ospedale San Raffaele;Oncologia Medica
  • Toscana
    • Arezzo, Toscana, Italy, 52100
      • Ospedale S. Donato; Divisione Di Reumatologia
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Vu Medisch Centrum; Afdeling Longziekten
  • Amsterdam, Netherlands, 1066 EC
    • Het Nederlands Kanker Inst
  • Den Haag, Netherlands, 2512 VA
    • MC Haaglanden; Oncologie
  • Nijmegen, Netherlands, 6525 GA
    • UMC St Radboud
  • Rotterdam, Netherlands, 3045 PM
    • Sint Franciscus Gasthuis; Inwendige Geneeskunde
• Romania
  • Brasov, Romania, 500019
    • Sf. Constantin Hospital; Oncology
  • Bucharest, Romania, 050659
    • Prof. Dr. Th. Burghele Clin Urology Hosp
  • Cluj Napoca, Romania, 400015
    • Prof. Dr. I. Chiricuta Institute of Oncology
  • Timisoara, Romania, 300239
    • ONCOMED - Medical Centre
  • Turda, Romania, 401103
    • Municipal Hosp Turdal; Oncology
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Oncologia
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain, 28050
    • Hospital Madrid Norte Sanchinarro
  • Malaga, Spain, 29010
    • Hospital Clinico Universitario Virgen de La Victoria
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche; Servicio de Oncologia
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
    • Sabadell, Barcelona, Spain, 8208
      • Corporacio Sanitaria Parc Tauli; Servicio de Oncologia
    • Sant Andreu de La Barca, Barcelona, Spain, 08740
      • Hospital Univ Vall d'Hebron; Servicio de Oncologia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria De Navarra
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital; Centre for Clinical Haematology
  • Glasgow, United Kingdom, G12 0XH
    • Gartnavel General Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St. James University Hospital; Pharmacy Department
  • Liverpool, United Kingdom, L7 8YA
    • The Clatterbridge Cancer Centre NHS Foundation Trust
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Research Institute ? Bisgrove
  • California
    • San Francisco, California, United States, 94115
      • Pacific Hematology Oncology Associates
  • Florida
    • Fort Myers, Florida, United States, 33901-8101
      • Florida Cancer Specialists - Fort Myers (New Hampshire Ct)
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists; Sarasota
  • Hawaii
    • Honolulu, Hawaii, United States, 96819
      • Kaiser Permanente Medical Ctr
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Univ; Bunting Blaustein Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Urology Cancer Center & GU Research Network
  • New York
    • East Setauket, New York, United States, 11733
      • New York Cancer and Blood Specialists - Setauket Medical Oncology
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center - Tennessee Oncology, Pllc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed metastatic or advanced prostate adenocarcinoma that has been previously treated with docetaxel-based therapy and has progressed during treatment of at least one hormonal therapy(prior docetaxel is not required for the safety cohort)
• Two rising PSA levels greater than or equal to (>/=) 2 ng/mL measured >/= 1 week apart or radiographic evidence of disease progression in soft tissue or bone
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening
• Adequate hematologic and organ function
• Documented willingness to use an effective means of contraception
• Safety cohort only: agreement to use CGM for first cycle of treatment

Exclusion Criteria:

• History of Type I or Type II diabetes mellitus requiring insulin; safety cohort: patients who are receiving any pharmacologic treatment for diabetes are not eligible
• New York Heart Association Class III or IV heart failure or Left ventricular ejection fraction < 50% or ventricular arrhythmia requiring medication
• Significant atherosclerotic disease, as evidenced by: unstable angina, history of myocardial infarction within 6 months prior to Day 1, or cerebrovascular accident within 6 months prior to Day 1
• Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs or active inflammatory disease which requires immunosuppressive therapy
• Clinically significant history of liver disease
• History of adrenal insufficiency or hyperaldosteronism
• Phase II only: Previous therapy for prostate cancer with 17 alpha-hydroxylase/C17,20-lyase inhibitors, including abiraterone
• Phase II only: Previous treatment for prostate cancer with Protein kinase B phosphatidylinositol 3 kinase and/or mammalian target of rapamycin inhibitors
• Need for chronic corticosteroid therapy of >/= 20 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids or immunosuppressant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib: Ipatasertib 400 mg + abiraterone; Participants will receive ipatasertib 400 mg once daily, abiraterone 1000 mg once daily, and prednisone/prednisolone 5 mg twice daily (bid) continuously in 28-day treatment cycles until disease progression or intolerable toxicity.	Drug: Abiraterone; Orally once daily; Drug: Ipatasertib; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid
Experimental: Phase Ib: Apitolisib 30 mg + abiraterone; Participants will receive apitolisib 30 mg once daily, abiraterone 1000 mg once daily, and prednisone/prednisolone 5 mg twice daily (bid) continuously in 28-day treatment cycles until disease progression or intolerable toxicity.	Drug: Abiraterone; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid; Drug: Apitolisib; Orally once daily
Experimental: Phase II: Ipatasertib 400 mg + abiraterone; Participants will receive Ipatasertib 400 mg once daily, abiraterone 1000 mg once daily, and prednisone/prednisolone 5 mg bid continuously in 28-day treatment cycles until disease progression or intolerable toxicity.	Drug: Abiraterone; Orally once daily; Drug: Ipatasertib; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid
Experimental: Phase II: Ipatasertib 200 mg + abiraterone; Participants will receive Ipatasertib 200 mg once daily, abiraterone 1000 mg once daily, and prednisone/prednisolone 5 mg bid continuously in 28-day treatment cycles until disease progression or intolerable toxicity.	Drug: Abiraterone; Orally once daily; Drug: Ipatasertib; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid
Placebo Comparator: Phase II: Placebo + abiraterone; Participants will receive placebo (for Ipatasertib) once daily, abiraterone 1000 mg once daily, and prednisone/prednisolone 5 mg bid continuously in 28-day treatment cycles until disease progression or intolerable toxicity.	Drug: Abiraterone; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid; Drug: Placebo; Orally once daily
Experimental: Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone; Participants will receive ipatasertib 400 mg orally once daily and/or prednisone/prednisolone 5 mg orally once daily or bid and/or abiraterone 1000 mg orally once daily according to the following schedule: ipatasertib in the morning during Cycle 1, Days 1-7; ipatasertib in the morning plus prednisone/prednisolone once at night during Cycle 1, Day 8; ipatasertib in the morning plus prednisone/prednisolone bid (morning and night) during Cycle 1, Days 9-11; ipatasertib in the morning plus prednisone/prednisolone bid (morning and night) and abiraterone in the morning during Cycle 1, Days 12-18; ipatasertib in the evening plus prednisone/prednisolone bid (morning and night) and abiraterone at the same time as ipatasertib during Cycle 1, Days 19-25; Cycle 2 and beyond ipatasertib once daily in the morning or evening, abiraterone at the same time as ipatasertib, and prednisone/prednisolone bid.	Drug: Abiraterone; Orally once daily; Drug: Ipatasertib; Orally once daily; Drug: Prednisone; Orally bid; Drug: Prednisolone; Orally bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: Percentage of Participants With Dose-Limiting Toxicities (DLTs)	DLT: 1 of the following toxicities, at least possibly related to ipatasertib or apitolisib. 1) Grade ≥ 3 non-hematologic, non-hepatic major organ AE; 2) Grade ≥ 3 febrile neutropenia; 3) Grade ≥ 4 neutropenia (absolute neutrophils less than [<] 500 per microliter) lasting greater than (>) 7 days; 4) Grade ≥3 thrombocytopenia associated with acute hemorrhage; 5) Grade ≥4 thrombocytopenia; 6) Grade ≥4 anemia; 7) 1 episode of fasting Grade ≥4 hyperglycemia or 3 episodes of fasting Grade 3 hyperglycemia on separate days within 7 days, as determined by laboratory blood glucose evaluation; 8) Grade ≥3 elevation lasting for > 48 hours for hepatic transaminase or liver-specific alkaline phosphatase or total bilirubin. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0.	Days 1 to 28 of Cycle 1 (Cycle length = 28 days)
Phase Ib: Percentage of Participants With Adverse Events (AEs)	An Adverse Event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately 10 months).
Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and Apitolisib	RP2D is a dose of a drug which would be used in Phase II stage of the study. RP2D was to be determined based on maximum tolerated dose (MTD) in Phase Ib stage of the study. The highest dose level (in 3+3 escalation scheme) with an acceptable safety profile and with a minimum of 6 participants at which fewer than one-third of participants experienced a DLT was declared the MTD and RP2D.	Days 1 to 28 of Cycle 1 (Cycle length = 28 days)
Phase II: Radiographic Progression Free Survival (rPFS) (Intent-To-Treat [ITT] Population)	rPFS: Time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments via CT scan and bone scans, or death on study from any cause, whichever occurred first. Progression was defined as follows: Soft tissue mass (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1): at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Bone: ≥ 2 new bone lesions plus 2 additional at confirmation on a second bone scan ≥ 4 weeks later (< 12 weeks after randomization). ≥ 2 new bone lesions consistent with progression, without need for confirmatory bone scan (≥ 12 weeks after randomization).	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) Loss	rPFS: Time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments via CT scan and bone scans, or death on study from any cause, whichever occurred first. Progression was defined as follows: Soft tissue mass (RECIST 1.1): at least 20% increase in sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Bone: ≥ 2 new bone lesions plus 2 additional at confirmation on 2nd bone scan ≥ 4 weeks later (< 12 weeks after randomization). ≥ 2 new bone lesions consistent with progression, without need for confirmatory bone scan (≥ 12 weeks after randomization). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss". Number of participants analyzed=participants with PTEN loss.	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: Cmax of Apitolisib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: AUC0-24 of Apitolisib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase II: Ipatasertib Plasma Concentrations When Co-Administered With Abiraterone		Phase II: Cycle 1, Day 1: 1, 4 hours postdose; Cycle 1, Day 15: predose, 2, 4 hours postdose; Cycle 2, Day 1: predose, 1-4 hours postdose (cycle length = 28 days)
Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Time to Cmax (Tmax) of Ipatasertib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Area Under The Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Ipatasertib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Total Body Clearance (CL/F) of Ipatasertib When Co-Administered With Abiraterone	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With Abiraterone	Accumulation Ratio was calculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1).	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib)	G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Tmax of G-037720 (Metabolite of Ipatasertib)	G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib)	G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib)	G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation. Accumulation Ratio was calculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1).	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Tmax of Apitolisib When Co-Administered With Abiraterone		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Cmax of Abiraterone When Co-Administered With Ipatasertib or Apitolisib		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Tmax of Abiraterone When Co-Administered With Ipatasertib or Apitolisib		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: AUC0-24 of Abiraterone When Co-Administered With Ipatasertib or Apitolisib		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Plasma Half-Life of Abiraterone When Co-Administered With Ipatasertib or Apitolisib		Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Accumulation Ratio of Abiraterone When Co-Administered With Ipatasertib or Apitolisib	Accumulation Ratio was caculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1).	Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase II: Overall Survival (ITT Population)	Overall survival was defined as the interval between the date of screening and death due to any cause. Overall survival was estimated using Kaplan Meier method.	Screening up to death (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 8.9 years overall]) (cycle length = 28 days)
Phase II: Overall Survival in Participants With ICR IHC PTEN Loss	Overall survival was defined as the interval between the date of randomization and death from any cause. Overall survival was estimated using Kaplan Meier method. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Screening up to death (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 8.9 years overall]) (cycle length = 28 days)
Phase II: Percentage of Participants With PSA Progression (ITT Population)	PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 nanogram per milliliter (ng/mL) from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later.	Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN Loss	PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Time to PSA Progression (ITT Population)	Time to PSA progression: Time from screening to the first occurrence of PSA progression, as determined by investigator. PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later.	Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Time to PSA Progression in Participants With ICR PTEN Loss	Time to PSA progression: Time from screening to the first occurrence of PSA progression, as determined by investigator. PSA progression was defined as per Prostate Cancer Working Group 2 criteria. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the baseline value, or a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the nadir if PSA decreases from baseline after treatment, which was confirmed by a second value obtained ≥ 3 weeks later. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Screening up to PSA progression (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Percentage of Participants With PSA Response (ITT Population)	PSA response was defined as a > 50% decrease in PSA from baseline, which was to be confirmed after ≥ 4 weeks by a confirmatory PSA measurement.	Baseline up to 30 days after last dose (assessed at baseline, Day 1 of every cycle [starting from Cycle 2] till 30 days after last dose [up to overall 3.6 years]) (cycle length = 28 days)
Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN Loss	PSA response was defined as a > 50% decrease in PSA from baseline, which was to be confirmed after ≥ 4 weeks by a confirmatory PSA measurement. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Baseline up to 30 days after last dose (assessed at baseline, Day 1 of every cycle [starting from Cycle 2] till 30 days after last dose [up to overall 3.6 years]) (cycle length = 28 days)
Phase II: Percentage of Participants With Objective Response (ITT Population)	Objective response was defined as having a confirm response (CR) or partial response (PR) according to a RECIST 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions.	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN Loss	Objective response was defined as having a CR or PR according to a RECIST 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss". Number of participants analyzed=participants with PTEN loss and evaluable for this endpoint.	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Duration of Tumor Response (ITT Population)	Duration of tumor response: time period from 1st documentation of objective response (CR/PR) (whichever status was recorded first) to date of 1st occurrence of investigator documented disease progression or death. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least 30% decrease in sum of diameters of target lesions (taking as reference baseline sum diameters), no progression in non-target lesions, and no new lesions. Progression: increase by at least 20% in sum of longest diameters of each target lesion, taking as reference smallest sum of longest diameters or appearance of one or more new lesions. Duration of tumor response was estimated using Kaplan Meier method.	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Duration of Tumor Response in Participants With ICR PTEN Loss	Duration of tumor response: time period from 1st documentation of objective response (CR/PR) (whichever status was recorded first) to date of 1st occurrence of investigator documented disease progression or death. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least 30% decrease in sum of diameters of target lesions (taking as reference baseline sum diameters), no progression in non-target lesions, and no new lesions. Progression: increase by at least 20% in sum of longest diameters of each target lesion, taking as reference smallest sum of longest diameters or appearance of one or more new lesions. Duration of tumor response was estimated using Kaplan Meier method.	Screening up to radiographic progression or death, whichever occurred first (assessed at screening, after Cycles 3, 5, 7, 9, every three cycles [12 weeks] thereafter up to end of treatment [up to 3.6 years overall]) (cycle length = 28 days)
Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response (ITT Population)	CTC reduction response was defined as participants with a reduction in CTCs of ≥ 30% compared to baseline.	Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)
Phase II: Percentage of Participants With CTC Reduction Response in Participants With ICR PTEN Loss	CTC reduction response was defined as participants with a reduction in CTCs of ≥ 30% compared to baseline. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)
Phase II: Percentage of Participants With CTC Conversion (ITT Population)	CTC conversion was defined as a decline to < 5 cells/7.5 milliliter (mL) post baseline among participants with CTC ≥ 5 cells/7.5 mL at baseline.	Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)
Phase II: Percentage of Participants With CTC Conversion in Participants With ICR PTEN Loss	CTC conversion was defined as a decline to < 5 cells/7.5 milliliter (mL) post baseline among participants with CTC ≥ 5 cells/7.5 mL at baseline. PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and at the treatment completion visit (up to overall 3.6 years) (cycle length=28 days)
Phase II: Percentage of Participants With Pain Progression (ITT Population)	Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory - short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10).	Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)
Phase II: Percentage of Participants With Pain Progression in Participants With ICR PTEN Loss	Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory - short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)
Phase II: Time to Pain Progression (ITT Population)	Time to pain progression was defined as the time from screening till first occurrence of pain progression. Pain progression was defined as ≥ 2 point-increase from baseline on the modified Brief Pain Inventory - short form (mBPI-sf). The mBPI-sf consists of four questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10).	Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)
Phase II: Time to Pain Progression in Participants With ICR PTEN Loss	Time to pain progression was defined as the time from screening till first occurrence of pain progression. Pain progression: ≥ 2 point-increase from baseline on the modified Brief Pain Inventory - short form (mBPI-sf). The mBPI-sf consists of 4questions that assess pain intensity (worst, least, average, right now) and seven items within one question that assess the impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each item was assessed on 0-10 scale with 0 being no pain to 10 being worst imaginable pain. Total score was the average of individual item (range 0-10). PTEN status was assessed by RUO IHC assay that was performed at ICR, UK. Samples with 100% of the tumor with no PTEN staining were classified as "ICR PTEN loss".	Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)
Phase II: Percentage of Participants With Adverse Events (AEs)	An Adverse Event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Baseline up until 30 days following the last administration of study treatment or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 8.9 years)
Phase II: G-037720 (Metabolite of Ipatasertib) Plasma Concentrations	G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.	Phase II: Cycle 1, Day 1: 1, 4 hours postdose; Cycle 1, Day 15: predose, 2, 4 hours postdose; Cycle 2, Day 1: predose, 1-4 hours postdose (cycle length = 28 days)

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Investigators: Study Director: Clinical Trials, Genentech, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2012
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: December 2, 2011
• First Submitted That Met QC Criteria: December 2, 2011
• First Posted (Estimated): December 6, 2011

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Prednisolone; Prednisone; Ipatasertib
• Other Study ID Numbers: GO27983; 2011-004126-10 (EudraCT Number)