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

NCT01485861 | Completed Phase 1 Results

• 2 other identifiers: GO279832011-004126-10
• Study Type: interventional
• Target: 298
• Locations: 9 countries
• Sites: 59

Brief Summary

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in combination with abiraterone and of apitolisib administrated in combination with abiraterone (this phase is no longer active), a Phase II, 3-arm, double-blind, randomized comparison of ipatasertib with abiraterone and prednisone/prednisolone versus placebo with abiraterone and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.

Conditions

Prostate Cancer

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (40)

• 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

  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

  Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Study Arms (6)

Phase Ib: Ipatasertib 400 mg + abiraterone

EXPERIMENTAL

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; Drug: Ipatasertib; Drug: Prednisone; Drug: Prednisolone

Phase Ib: Apitolisib 30 mg + abiraterone

EXPERIMENTAL

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; Drug: Apitolisib; Drug: Prednisone; Drug: Prednisolone

Phase II: Ipatasertib 400 mg + abiraterone

EXPERIMENTAL

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; Drug: Ipatasertib; Drug: Prednisone; Drug: Prednisolone

Phase II: Ipatasertib 200 mg + abiraterone

EXPERIMENTAL

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; Drug: Ipatasertib; Drug: Prednisone; Drug: Prednisolone

Phase II: Placebo + abiraterone

PLACEBO COMPARATOR

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; Drug: Placebo; Drug: Prednisone; Drug: Prednisolone

Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone

EXPERIMENTAL

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; Drug: Ipatasertib; Drug: Prednisone; Drug: Prednisolone

Interventions

Abiraterone DRUG

Orally once daily

Phase II: Ipatasertib 200 mg + abiraterone; Phase II: Ipatasertib 400 mg + abiraterone; Phase II: Placebo + abiraterone; Phase Ib: Apitolisib 30 mg + abiraterone; Phase Ib: Ipatasertib 400 mg + abiraterone; Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone

Apitolisib DRUG

Orally once daily

Phase Ib: Apitolisib 30 mg + abiraterone

Ipatasertib DRUG

Orally once daily

Phase II: Ipatasertib 200 mg + abiraterone; Phase II: Ipatasertib 400 mg + abiraterone; Phase Ib: Ipatasertib 400 mg + abiraterone; Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone

Placebo DRUG

Orally once daily

Phase II: Placebo + abiraterone

Prednisone DRUG

Orally bid

Phase II: Ipatasertib 200 mg + abiraterone; Phase II: Ipatasertib 400 mg + abiraterone; Phase II: Placebo + abiraterone; Phase Ib: Apitolisib 30 mg + abiraterone; Phase Ib: Ipatasertib 400 mg + abiraterone; Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone

Prednisolone DRUG

Orally bid

Phase II: Ipatasertib 200 mg + abiraterone; Phase II: Ipatasertib 400 mg + abiraterone; Phase II: Placebo + abiraterone; Phase Ib: Apitolisib 30 mg + abiraterone; Phase Ib: Ipatasertib 400 mg + abiraterone; Safety Cohort: Ipataseritib 400 mg + Abiraterone + Prednisone

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (59)

HonorHealth Research Institute ? Bisgrove

Scottsdale, Arizona, 85258, United States

Location

Pacific Hematology Oncology Associates

San Francisco, California, 94115, United States

Location

Florida Cancer Specialists - Fort Myers (New Hampshire Ct)

Fort Myers, Florida, 33901-8101, United States

Location

Florida Cancer Specialists; Sarasota

Sarasota, Florida, 34232, United States

Location

Kaiser Permanente Medical Ctr

Honolulu, Hawaii, 96819, United States

Location

Johns Hopkins Univ; Bunting Blaustein Cancer Center

Baltimore, Maryland, 21231, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Urology Cancer Center & GU Research Network

Omaha, Nebraska, 68130, United States

Location

New York Cancer and Blood Specialists - Setauket Medical Oncology

East Setauket, New York, 11733, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Carolina Urologic Research Center

Myrtle Beach, South Carolina, 29572, United States

Location

Sarah Cannon Cancer Center - Tennessee Oncology, Pllc

Nashville, Tennessee, 37203, United States

Location

Masarykuv onkologicky ustav

Brno, 656 53, Czechia

Location

Fakultni nemocnice Hradec Kralove; I. interni klinika,Oddeleni invazivni kardiologie

Hradec Králové, 50012, Czechia

Location

Urocentrum Praha s.r.o.

Prague, 120 00, Czechia

Location

Vseobecna fakultni nemocnice v Praze

Prague, 128 08, Czechia

Location

Fakultni Thomayerova Nemocnice; Revmatologicke Oddeleni

Prague, 140 59, Czechia

Location

ICO Paul Papin; Oncologie Medicale.

Angers, 49055, France

Location

Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes

Lyon, 69008, France

Location

Hia Du Val De Grace

Paris, 75230, France

Location

Institut Curie; Oncologie Medicale

Paris, 75231, France

Location

GH Paris Saint Joseph; Hopital De Jour Oncologie

Paris, 75674, France

Location

Hopital d'Instruction des Armees de Begin

Saint-Mandé, 94160, France

Location

Institut Gustave Roussy; Departement Oncologie Medicale

Villejuif, 94805, France

Location

Alexandras Hospital; Dept. of Clin. Therapeutics, Athens Uni School of Medicine

Athens, 115 28, Greece

Location

Univ General Hosp Heraklion; Medical Oncology

Heraklion, 711 10, Greece

Location

University Hospital of Larissa; Oncology

Larissa, 413 35, Greece

Location

University Hospital of Patras Medical Oncology

Pátrai, 265 04, Greece

Location

Metropolitan Hospital; 2Nd Oncology Clinic

Piraeus, 185 47, Greece

Location

IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica

Meldola, Emilia-Romagna, 47014, Italy

Location

Azienda Ospedaliera Istituti Ospitalieri

Cremona, Lombardy, 26100, Italy

Location

Irccs Ospedale San Raffaele;Oncologia Medica

Milan, Lombardy, 20132, Italy

Location

Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2

Milan, Lombardy, 20133, Italy

Location

Ospedale S. Donato; Divisione Di Reumatologia

Arezzo, Tuscany, 52100, Italy

Location

Het Nederlands Kanker Inst

Amsterdam, 1066 EC, Netherlands

Location

Vu Medisch Centrum; Afdeling Longziekten

Amsterdam, 1081 HV, Netherlands

Location

UMC St Radboud

Nijmegen, 6525 GA, Netherlands

Location

Sint Franciscus Gasthuis; Inwendige Geneeskunde

Rotterdam, 3045 PM, Netherlands

Location

MC Haaglanden; Oncologie

The Hague, 2512 VA, Netherlands

Location

Sf. Constantin Hospital; Oncology

Brasov, 500019, Romania

Location

Prof. Dr. Th. Burghele Clin Urology Hosp

Bucharest, 050659, Romania

Location

Prof. Dr. I. Chiricuta Institute of Oncology

Cluj-Napoca, 400015, Romania

Location

ONCOMED - Medical Centre

Timișoara, 300239, Romania

Location

Municipal Hosp Turdal; Oncology

Turda, 401103, Romania

Location

Hospital General Universitario de Elche; Servicio de Oncologia

Elche, Alicante, 03203, Spain

Location

Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia

Badalona, Barcelona, 08916, Spain

Location

Corporacio Sanitaria Parc Tauli; Servicio de Oncologia

Sabadell, Barcelona, 8208, Spain

Location

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Sant Andreu de la Barca, Barcelona, 08740, Spain

Location

Clinica Universitaria de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital General Universitario Gregorio Marañon

Madrid, 28007, Spain

Location

Hospital Universitario 12 de Octubre; Servicio de Oncologia

Madrid, 28041, Spain

Location

Hospital Madrid Norte Sanchinarro

Madrid, 28050, Spain

Location

Hospital Clinico Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Queen Elizabeth Hospital; Centre for Clinical Haematology

Birmingham, B15 2TH, United Kingdom

Location

Gartnavel General Hospital

Glasgow, G12 0XH, United Kingdom

Location

St. James University Hospital; Pharmacy Department

Leeds, LS9 7TF, United Kingdom

Location

The Clatterbridge Cancer Centre NHS Foundation Trust

Liverpool, L7 8YA, United Kingdom

Location

Sarah Cannon Research Institute

London, W1G 6AD, United Kingdom

Location

The Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

abiraterone; ipatasertib; Prednisone; Prednisolone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: In Phase II participants and investigators were blinded with regard to treatment status (i.e., ipatasertib vs. placebo). Phase Ib and the safety cohort were open-label.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2011
• First Posted: December 6, 2011
• Study Start: January 11, 2012
• Primary Completion: September 1, 2015
• Study Completion: August 31, 2022
• Last Updated: September 14, 2023
• Results First Posted: September 14, 2023

Record last verified: 2023-08

Locations

IT (5); NL (5); US (12); GB (6); ES (9); CZ (5); FR (7); RO (5); GR (5)