A Study Assessing the Safety and Efficacy of Adding Ipatasertib to Paclitaxel Treatment in Participants With Breast Cancer That Has Spread Beyond the Initial Site, and the Cancer Does Not Have Certain Hormonal Receptors
- Conditions
- Breast Neoplasms
- Interventions
- Registration Number
- NCT02162719
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
This multicenter, randomized, double-blind study will estimate the efficacy, safety and tolerability of ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in participants with inoperable locally advanced or metastatic triple-negative breast cancer (mTNBC), as measured by progression-free survival (PFS) in all participants and in participants with phosphatase and tensin homolog (PTEN)-low tumors.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 124
- Histologically documented triple-negative adenocarcinoma of the breast that is inoperable locally advanced or metastatic and is not amenable to resection with curative intent
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen, required prior to randomization
- Measurable disease, according to the RECIST v1.1
- Adequate hematologic and organ function within 14 days before the first study treatment
- For female participants of childbearing potential, agreement (by both participant and partner) to use an effective form of contraception for the duration of the study and for 6 months after last dose of study treatment
- Any previous therapy, including chemotherapy or hormonal or targeted therapy, for inoperable locally advanced or metastatic triple-negative adenocarcinoma of the breast. Participants may have received prior neoadjuvant or adjuvant chemotherapy and/or radiation treatment for locally advanced triple negative adenocarcinoma, provided all treatments were completed greater than or equal to (>/=) 6 months prior to Cycle 1 Day 1. Locally recurrent disease must not be amenable to resection with curative intent
- Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1
- Known Human Epidermal Growth Factor Receptor 2 (HER2) positive, erythrocyte receptor (ER) positive, or progesterone receptor (PR) positive breast cancer
- Previous therapy with Akt, PI3K, and/or mTOR inhibitors
- Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
- Known presence of the brain or spinal cord metastasis, as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or prior radiographic assessments
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Paclitaxel Placebo Participants randomised to receive paclitaxel 80 mg/m\^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. Ipatasertib + Paclitaxel Ipatasertib Participants randomised to receive paclitaxel 80 mg/m\^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. Ipatasertib + Paclitaxel Paclitaxel Participants randomised to receive paclitaxel 80 mg/m\^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. Placebo + Paclitaxel Paclitaxel Participants randomised to receive paclitaxel 80 mg/m\^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
- Primary Outcome Measures
Name Time Method PFS in Participants With Phosphatase and Tensin Homolog (PTEN)-Low Tumors Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (\<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
Progression Free Survival (PFS) Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (\<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
- Secondary Outcome Measures
Name Time Method PFS in Participants With Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 07 June 2016) PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (\<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first.
Overall Survival (OS) Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) OS was defined as the time from the date of randomization to the date of death from any cause.
Duration of Response in Participants With PIK3CA/AKT1/PTEN-altered Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Duration of objective response in participants with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
OS in Participants With PIK3CA/AKT1/PTEN-altered Tumors Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) OS was defined as the time from the date of randomization to the date of death from any cause.
Duration of Response Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
Time to Disease Progression Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
OS in Participants With PTEN-Low Tumors Baseline up to 30 days after the last dose of study drug administration (Clinical Cut Off Date: 31 August 2019) OS was defined as the time from the date of randomization to the date of death from any cause.
ORR in Participants With PIK3CA/AKT1/PTEN-altered Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
ORR in Participants With PTEN-Low Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Patient Reported Outcome (PRO) Measure: Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1 EORTC QLQ-C30 included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1=Not at all to 4=Very much; 2 questions used 7-point scale \[1=very poor to 7=Excellent\]). Scores averaged, transformed to 0-100 scale; a higher score=better level of functioning. For symptom scale scores, higher level=severe level of symptoms. "A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). PRO measures were analyzed from baseline up to cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).
Duration of Response in Participants With PTEN-Low Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1.
Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib Cycle 1 Day 1, Cycle 1 Day 8 PK parameters were not calculated due to sparse PK sampling.
PRO Measure: Percentage of Participants With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30 Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1 Subjects reporting \>/= 10-point increase compared to baseline (Cycle 1 Day 1) were considered "improved", those reporting \<10-point difference were considered "remained stable", and those reporting \>/=10-point decrease were considered "worsened". A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139-44). Patient reported outcome measures were analyzed from baseline up to and including cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of participants remained on treatment beyond cycle 5).
Objective Response Rate (ORR) Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Confirmed tumor ORR in participants with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of participants who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Participants for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time to Disease Progression in Participants With PTEN-Low Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
Time to Disease Progression in Participants With PIK3CA/AKT1/PTEN-altered Tumors Baseline up to every 8 weeks until documented disease progression (Clinical Cut Off Date: 07 June 2016) Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1.
Safety: Percentage of Participants With Adverse Events Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months) An adverse event 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.
Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib Cycle 1 Day 1, Cycle 1 Day 8 PK parameters were not calculated due to sparse PK sampling.
Trial Locations
- Locations (43)
West Virginia University Hospitals Inc
🇺🇸Morgantown, West Virginia, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
St Jude Heritage Medical Group
🇺🇸Fullerton, California, United States
Cancer Care Assoc Med Group
🇺🇸Los Angeles, California, United States
UCLA Medical Center
🇺🇸Santa Monica, California, United States
Holycross Medical Group
🇺🇸Fort Lauderdale, Florida, United States
Hematology Oncology Associates of the Treasure Coast
🇺🇸Port Saint Lucie, Florida, United States
Memorial Healthcare System
🇺🇸Hollywood, Florida, United States
The WEST CLINIC, P.C.
🇺🇸Memphis, Tennessee, United States
Northwest Medical Specialties
🇺🇸Lakewood, Washington, United States
Northern Utah Associates
🇺🇸Ogden, Utah, United States
Sint Augustinus Wilrijk
🇧🇪Wilrijk, Belgium
Institut Bergonié Centre Régional de Lutte Contre Le Cancer de Bordeaux Et Sud Ouest
🇫🇷Bordeaux, France
Centre Francois Baclesse
🇫🇷Caen, France
Istituto Nazionale Tumori Fondazione G. Pascale
🇮🇹Napoli, Campania, Italy
Istituto Nazionale dei Tumori; Divisione Oncologia Chirurgica e Ginecologica
🇮🇹Milano, Lombardia, Italy
Clinique Armoricaine de Radiol
🇫🇷Saint Brieuc, France
Centre Régional de Lutte Contre Le Cancer Val D'aurelle Paul Lamarque
🇫🇷Montpellier, France
Hopital Saint Louis; Oncologie Medicale
🇫🇷Paris, France
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
National Cancer Centre
🇸🇬Singapore, Singapore
HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Farmacia
🇪🇸Madrid, Spain
Complejo Hospitalario de Jaen
🇪🇸Jaen, Spain
Institut Catala d Oncologia Hospital Duran i Reynals
🇪🇸Barcelona, Spain
Hospital Virgen del Rocio
🇪🇸Sevilla, Spain
Chang Gung Medical Foundation - Linkou; Dept of Surgery
🇨🇳Taoyuan, Taiwan
Cancer Center of Kansas
🇺🇸Wichita, Kansas, United States
Chi Mei Medical Center, Yong kang; Endocrinology
🇨🇳Tainan, Taiwan
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Henderson, Nevada, United States
Istituto Oncologico Veneto IRCCS Farmacia Ospedaliera
🇮🇹Padova, Veneto, Italy
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
National University Hospital; National University Cancer Institute, Singapore (NCIS)
🇸🇬Singapore, Singapore
China Medical University Hospital
🇨🇳North Dist., Taiwan
National Cancer Center
🇰🇷Goyang-si, Korea, Republic of
MD Anderson Cancer Center
🇪🇸Madrid, Spain
Carolinas Healthcare System
🇺🇸Charlotte, North Carolina, United States