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

Genentech, Inc.298 enrolled

Overview

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in combination with abiraterone and of apitolisib administrated in combination with abiraterone (this phase is no longer active), a Phase II, 3-arm, double-blind, randomized comparison of ipatasertib with abiraterone and prednisone/prednisolone versus placebo with abiraterone and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

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

298

Conditions

Prostate Cancer

Interventions

ApitolisibDRUG

Orally once daily

IpatasertibDRUG

Orally once daily

PlaceboDRUG

Orally once daily

PrednisoneDRUG

Orally bid

PrednisoloneDRUG

Orally bid

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (59)

HonorHealth Research Institute ? Bisgrove

Scottsdale, Arizona, United States

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

Kaiser Permanente Medical Ctr

Honolulu, Hawaii, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Secondary Outcomes

Phase Ib: Maximum Plasma Concentration (Cmax) of Ipatasertib When Co-Administered With Abiraterone

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Johns Hopkins Univ; Bunting Blaustein Cancer Center

Baltimore, Maryland, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

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

...and 49 more locations

Time frame: 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.

Time frame: 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).

Time frame: 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 Apitolisib When Co-Administered With Abiraterone

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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).

Time frame: 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.

Time frame: 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".

Time frame: 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.

Time frame: 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".

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.

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".

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.

Time frame: 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".

Time frame: 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.

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.

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.

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

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.

Time frame: 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".

Time frame: 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.

Time frame: 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".

Time frame: 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).

Time frame: 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

Time frame: 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).

Time frame: 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".

Time frame: 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)

Time frame: 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: Ipatasertib Plasma Concentrations When Co-Administered With Abiraterone

Time frame: 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 II: G-037720 (Metabolite of Ipatasertib) Plasma Concentrations

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

Time frame: 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)