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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms	Drug: Ipatasertib; Drug: Paclitaxel; Drug: Placebo	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	124 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	A Randomized, Phase II, Multi-Center, Placebo-Controlled Study of Ipatasertib (GDC-0068), an Inhibitor of Akt, in Combination With Paclitaxel as Front-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer
Actual Study Start Date :	September 30, 2014
Actual Primary Completion Date :	June 6, 2016
Estimated Study Completion Date :	August 1, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ipatasertib + Paclitaxel; Participants will receive ipatasertib and paclitaxel in cycles of 28 days (4 weeks) each and study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Drug: Ipatasertib; Participants will receive ipatasertib orally 400 milligrams (mg) daily on Days 1-21 of each 28-day cycle.; Other Name: GDC-0068 Drug: Paclitaxel; Participants will receive paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle.
Placebo Comparator: Placebo + Paclitaxel; Participants will receive placebo and paclitaxel in cycles of 28 days (4 weeks) each and study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.	Drug: Paclitaxel; Participants will receive paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle. Drug: Placebo; Participants will receive oral placebo matched to ipatasertib, daily on Days 1-21 of each 28-day cycle.

Outcome Measures

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Primary Outcome Measures :

1. PFS in All Participants, as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
2. PFS in Participants with PTEN-Low Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]

Secondary Outcome Measures :

1. Percentage of Participants with Adverse Events [ Time Frame: Baseline up to approximately 2.5 years ]
2. Steady State Area Under the Concentration Time Curve from Time Zero to 24 Hours (AUC0-24) of Ipatasertib [ Time Frame: 0.5-2 hours and 4-6 hours post-ipatasertib oral dose on Cycle 1 Day 1 (cycle length=28 days); 0-2 hours and 2-5 hours post-ipatasertib oral dose on Cycle 1 Day 8 ]
3. Overall Survival (OS) in All Participants [ Time Frame: Baseline up to death due to any cause (up to approximately 2.5 years) ]
4. OS in Participants with PTEN-Low Tumors [ Time Frame: Baseline up to death due to any cause (up to approximately 2.5 years) ]
5. OS in Participants with Phosphoinositol 3 Kinase (PI3k)/Protein Kinase B (Akt) Pathway Activated Tumors [ Time Frame: Baseline up to death due to any cause (up to approximately 2.5 years) ]
6. Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib [ Time Frame: 0.5-2 hours and 4-6 hours post-ipatasertib oral dose on Cycle 1 Day 1 (cycle length=28 days); 0-2 hours and 2-5 hours post-ipatasertib oral dose on Cycle 1 Day 8 ]
7. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Score [ Time Frame: Day 1 of each 28-day cycle, at treatment completion/early discontinuation (up to approximately 2.5 years), at tumor follow-up and unscheduled adverse event follow-up (up to approximately 2.5 years overall) ]
8. Percentage of Participants With Protocol Defined Bothersome Treatment-Related Symptoms [ Time Frame: Baseline up to approximately 2.5 years ]
9. Percentage of Participants with Confirmed Objective Tumor Response (Complete Response [CR] or Partial Response [PR]) in All Participants with Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
10. Percentage of Participants with Confirmed Objective Tumor Response (CR or PR) in Participants with Measurable Disease at Baseline and PTEN-Low Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
11. Percentage of Participants with Confirmed Objective Tumor Response (CR or PR) in All Participants with Measurable Disease at Baseline and PI3K/Akt Pathway Activated Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
12. Duration of Confirmed Objective Response in Participants with Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
13. Duration of Confirmed Objective Response in Participants with Measurable Disease at Baseline and PTEN-Low Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
14. Duration of Confirmed Objective Response in Participants with Measurable Disease at Baseline and PI3K/Akt Pathway Activated Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]
15. Time to Disease Progression in Participants with Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression (up to approximately 2.5 years) ]
16. Time to Disease Progression in Participants with Measurable Disease at Baseline and PTEN-Low Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression (up to approximately 2.5 years) ]
17. Time to Disease Progression in Participants with Measurable Disease at Baseline and PI3K/Akt Pathway Activated Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression (up to approximately 2.5 years) ]
18. PFS in All Participants with Measurable Disease at Baseline and PI3K/Akt Pathway Activated Tumors, as Assessed by Investigator Based on RECIST v1.1 [ Time Frame: Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 2.5 years) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Contacts and Locations

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Sponsors and Collaborators

Genentech, Inc.

Investigators

Study Director:	Clinical Trials	Hoffmann-La Roche

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kim SB, Dent R, Im SA, Espié M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Baselga J; LOTUS investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3. Epub 2017 Aug 8.

Responsible Party:	Genentech, Inc.
ClinicalTrials.gov Identifier:	NCT02162719 History of Changes
Other Study ID Numbers:	GO29227; 2014-000469-35 ( EudraCT Number )
First Posted:	June 13, 2014
Last Update Posted:	March 20, 2018
Last Verified:	March 2018

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Albumin-Bound Paclitaxel	Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action