MedPath

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

Phase 1
Completed
Conditions
Prostate Cancer
Interventions
Drug: Abiraterone
Drug: Placebo
Drug: Apitolisib
Drug: Ipatasertib
Drug: Prednisone
Drug: Prednisolone
Registration Number
NCT01485861
Lead Sponsor
Genentech, Inc.
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in combination with abiraterone and of apitolisib administrated in combination with abiraterone (this phase is no longer active), a Phase II, 3-arm, double-blind, randomized comparison of ipatasertib with abiraterone and prednisone/prednisolone versus placebo with abiraterone and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.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
Male
Target Recruitment
298
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
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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
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Phase Ib: Apitolisib 30 mg + abirateroneAbirateroneParticipants 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.
Phase Ib: Ipatasertib 400 mg + abirateroneAbirateroneParticipants 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.
Phase II: Ipatasertib 200 mg + abirateronePrednisoneParticipants 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.
Phase II: Placebo + abirateroneAbirateroneParticipants 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.
Phase II: Placebo + abirateronePlaceboParticipants 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.
Safety Cohort: Ipataseritib 400 mg + Abiraterone + PrednisonePrednisoloneParticipants 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.
Phase Ib: Ipatasertib 400 mg + abirateronePrednisoneParticipants 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.
Phase Ib: Ipatasertib 400 mg + abirateronePrednisoloneParticipants 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.
Phase Ib: Apitolisib 30 mg + abirateroneApitolisibParticipants 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.
Phase Ib: Apitolisib 30 mg + abirateronePrednisoloneParticipants 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.
Phase Ib: Apitolisib 30 mg + abirateronePrednisoneParticipants 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.
Phase II: Ipatasertib 400 mg + abirateroneAbirateroneParticipants 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.
Phase II: Ipatasertib 400 mg + abirateroneIpatasertibParticipants 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.
Phase II: Ipatasertib 200 mg + abirateroneAbirateroneParticipants 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.
Phase II: Ipatasertib 400 mg + abirateronePrednisoneParticipants 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.
Phase II: Ipatasertib 400 mg + abirateronePrednisoloneParticipants 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.
Phase II: Ipatasertib 200 mg + abirateroneIpatasertibParticipants 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.
Phase II: Ipatasertib 200 mg + abirateronePrednisoloneParticipants 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.
Phase II: Placebo + abirateronePrednisoloneParticipants 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.
Safety Cohort: Ipataseritib 400 mg + Abiraterone + PrednisoneAbirateroneParticipants 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.
Phase II: Placebo + abirateronePrednisoneParticipants 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.
Safety Cohort: Ipataseritib 400 mg + Abiraterone + PrednisonePrednisoneParticipants 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.
Phase Ib: Ipatasertib 400 mg + abirateroneIpatasertibParticipants 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.
Safety Cohort: Ipataseritib 400 mg + Abiraterone + PrednisoneIpatasertibParticipants 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.
Primary Outcome Measures
NameTimeMethod
Phase Ib: Percentage of Participants With Dose-Limiting Toxicities (DLTs)Days 1 to 28 of Cycle 1 (Cycle length = 28 days)

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.

Phase Ib: Percentage of Participants With Adverse Events (AEs)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).

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.

Phase Ib: Recommended Phase II Dose (RP2D) of Ipatasertib and ApitolisibDays 1 to 28 of Cycle 1 (Cycle length = 28 days)

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.

Phase II: Radiographic Progression Free Survival (rPFS) (Intent-To-Treat [ITT] Population)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)

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).

Phase II: rPFS in Participants With Institute of Cancer Research (ICR) Phosphatase and Tensin Homolog (PTEN) LossScreening 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)

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.

Secondary Outcome Measures
NameTimeMethod
Phase Ib: AUC0-24 of Apitolisib When Co-Administered With AbirateronePre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)
Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With AbirateronePre-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 AbirateronePre-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 AbirateronePre-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 AbirateronePre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 15 of Cycle 1 (cycle length = 28 days)

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.

Phase Ib: Accumulation Ratio of Ipatasertib When Co-Administered With AbirateronePre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Accumulation Ratio was calculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1).

Phase Ib: Cmax of G-037720 (Metabolite of Ipatasertib)Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.

Phase Ib: Tmax of G-037720 (Metabolite of Ipatasertib)Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.

Phase Ib: AUC0-24 of G-037720 (Metabolite of Ipatasertib)Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.

Phase Ib: Accumulation Ratio of G-037720 (Metabolite of Ipatasertib)Pre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

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).

Phase Ib: Cmax of Apitolisib When Co-Administered With AbirateronePre-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 AbirateronePre-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 ApitolisibPre-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 ApitolisibPre-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 ApitolisibPre-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 ApitolisibPre-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 ApitolisibPre-dose (0 hour), 1, 2, 4, 6, 24 hours post dose on Days 1, 15 of Cycle 1 (cycle length = 28 days)

Accumulation Ratio was caculated as AUC0-24 (Cycle 1 Day 15) divided by AUC0-24 (Cycle 1 Day 1).

Phase II: Overall Survival (ITT Population)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)

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.

Phase II: Overall Survival in Participants With ICR IHC PTEN LossScreening 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)

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".

Phase II: Percentage of Participants With PSA Progression (ITT Population)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)

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.

Phase II: Percentage of Participants With PSA Progression in Participants With ICR PTEN LossScreening 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)

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".

Phase II: Time to PSA Progression (ITT Population)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)

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.

Phase II: Time to PSA Progression in Participants With ICR PTEN LossScreening 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)

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".

Phase II: Percentage of Participants With PSA Response (ITT Population)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)

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.

Phase II: Percentage of Participants With PSA Response in Participants With ICR PTEN LossBaseline 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)

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".

Phase II: Percentage of Participants With Objective Response (ITT Population)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)

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.

Phase II: Percentage of Participants With Objective Response in Participants With ICR PTEN LossScreening 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)

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.

Phase II: Duration of Tumor Response (ITT Population)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)

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.

Phase II: Duration of Tumor Response in Participants With ICR PTEN LossScreening 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)

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.

Phase II: Percentage of Participants With Circulating Tumor Cells (CTC) Reduction Response (ITT Population)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)

CTC reduction response was defined as participants with a reduction in CTCs of ≥ 30% compared to baseline.

Phase II: Percentage of Participants With CTC Reduction Response in Participants With ICR PTEN LossBaseline, 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)

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".

Phase II: Percentage of Participants With CTC Conversion (ITT Population)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)

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.

Phase II: Percentage of Participants With CTC Conversion in Participants With ICR PTEN LossBaseline, 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)

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".

Phase II: Percentage of Participants With Pain Progression (ITT Population)Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

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).

Phase II: Percentage of Participants With Pain Progression in Participants With ICR PTEN LossScreening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

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".

Phase II: Time to Pain Progression (ITT Population)Screening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

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).

Phase II: Time to Pain Progression in Participants With ICR PTEN LossScreening, Day 1 of each cycle (cycle length=28 days) up to treatment completion (up to 3.6 years)

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".

Phase II: Percentage of Participants With Adverse Events (AEs)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)

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.

Phase II: Ipatasertib Plasma Concentrations When Co-Administered With AbirateronePhase 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 II: G-037720 (Metabolite of Ipatasertib) Plasma ConcentrationsPhase 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)

G-037220 is N-dealkylated metabolite of ipatasertib and the main metabolite in circulation.

Trial Locations

Locations (59)

HonorHealth Research Institute ? Bisgrove

🇺🇸

Scottsdale, Arizona, United States

Kaiser Permanente Medical Ctr

🇺🇸

Honolulu, Hawaii, United States

Vseobecna fakultni nemocnice v Praze

🇨🇿

Praha 2, Czechia

Fakultni Thomayerova Nemocnice; Revmatologicke Oddeleni

🇨🇿

Praha, Czechia

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

🇨🇿

Hradec Kralove, Czechia

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

🇬🇷

Athens, Greece

Ospedale S. Donato; Divisione Di Reumatologia

🇮🇹

Arezzo, Toscana, Italy

Sf. Constantin Hospital; Oncology

🇷🇴

Brasov, Romania

Prof. Dr. I. Chiricuta Institute of Oncology

🇷🇴

Cluj Napoca, Romania

Sarah Cannon Research Institute

🇬🇧

London, United Kingdom

The Royal Marsden Hospital

🇬🇧

Sutton, United Kingdom

Pacific Hematology Oncology Associates

🇺🇸

San Francisco, California, United States

Florida Cancer Specialists - Fort Myers (New Hampshire Ct)

🇺🇸

Fort Myers, Florida, United States

Florida Cancer Specialists; Sarasota

🇺🇸

Sarasota, Florida, United States

Sarah Cannon Cancer Center - Tennessee Oncology, Pllc

🇺🇸

Nashville, Tennessee, United States

Johns Hopkins Univ; Bunting Blaustein Cancer Center

🇺🇸

Baltimore, Maryland, United States

Karmanos Cancer Institute

🇺🇸

Detroit, Michigan, United States

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

🇫🇷

Lyon, France

Institut Curie; Oncologie Medicale

🇫🇷

Paris, France

Hia Du Val De Grace

🇫🇷

Paris, France

Urology Cancer Center & GU Research Network

🇺🇸

Omaha, Nebraska, United States

New York Cancer and Blood Specialists - Setauket Medical Oncology

🇺🇸

East Setauket, New York, United States

Weill Cornell Medical College

🇺🇸

New York, New York, United States

Masarykuv onkologicky ustav

🇨🇿

Brno, Czechia

Urocentrum Praha s.r.o.

🇨🇿

Praha 2, Czechia

ICO Paul Papin; Oncologie Medicale.

🇫🇷

Angers, France

GH Paris Saint Joseph; Hopital De Jour Oncologie

🇫🇷

Paris, France

Hopital d'Instruction des Armees de Begin

🇫🇷

Saint-Mande, France

Institut Gustave Roussy; Departement Oncologie Medicale

🇫🇷

Villejuif, France

University Hospital of Larissa; Oncology

🇬🇷

Larissa, Greece

Univ General Hosp Heraklion; Medical Oncology

🇬🇷

Heraklion, Greece

University Hospital of Patras Medical Oncology

🇬🇷

Patras, Greece

Irccs Ospedale San Raffaele;Oncologia Medica

🇮🇹

Milano, Lombardia, Italy

Azienda Ospedaliera Istituti Ospitalieri

🇮🇹

Cremona, Lombardia, Italy

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

🇮🇹

Milano, Lombardia, Italy

Metropolitan Hospital; 2Nd Oncology Clinic

🇬🇷

Piraeus, Greece

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

🇮🇹

Meldola, Emilia-Romagna, Italy

Het Nederlands Kanker Inst

🇳🇱

Amsterdam, Netherlands

MC Haaglanden; Oncologie

🇳🇱

Den Haag, Netherlands

Vu Medisch Centrum; Afdeling Longziekten

🇳🇱

Amsterdam, Netherlands

UMC St Radboud

🇳🇱

Nijmegen, Netherlands

Sint Franciscus Gasthuis; Inwendige Geneeskunde

🇳🇱

Rotterdam, Netherlands

Prof. Dr. Th. Burghele Clin Urology Hosp

🇷🇴

Bucharest, Romania

ONCOMED - Medical Centre

🇷🇴

Timisoara, Romania

Hospital General Universitario de Elche; Servicio de Oncologia

🇪🇸

Elche, Alicante, Spain

Municipal Hosp Turdal; Oncology

🇷🇴

Turda, Romania

Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia

🇪🇸

Badalona, Barcelona, Spain

Hospital Univ Vall d'Hebron; Servicio de Oncologia

🇪🇸

Sant Andreu de La Barca, Barcelona, Spain

Corporacio Sanitaria Parc Tauli; Servicio de Oncologia

🇪🇸

Sabadell, Barcelona, Spain

Clinica Universitaria de Navarra

🇪🇸

Pamplona, Navarra, Spain

Hospital General Universitario Gregorio Marañon

🇪🇸

Madrid, Spain

Hospital Universitario 12 de Octubre; Servicio de Oncologia

🇪🇸

Madrid, Spain

Queen Elizabeth Hospital; Centre for Clinical Haematology

🇬🇧

Birmingham, United Kingdom

Hospital Clinico Universitario Virgen de la Victoria

🇪🇸

Malaga, Spain

Hospital Madrid Norte Sanchinarro

🇪🇸

Madrid, Spain

St. James University Hospital; Pharmacy Department

🇬🇧

Leeds, United Kingdom

Gartnavel General Hospital

🇬🇧

Glasgow, United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust

🇬🇧

Liverpool, United Kingdom

Carolina Urologic Research Center

🇺🇸

Myrtle Beach, South Carolina, United States

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