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 (LOTUS)
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| ClinicalTrials.gov Identifier: NCT02162719 |
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Recruitment Status :
Completed
First Posted : June 13, 2014
Results First Posted : January 11, 2021
Last Update Posted : March 10, 2021
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Sponsor:
Genentech, Inc.
Information provided by (Responsible Party):
Genentech, Inc.
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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 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 : | August 19, 2014 |
| Actual Primary Completion Date : | June 7, 2016 |
| Actual Study Completion Date : | August 31, 2019 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Breast cancer
MedlinePlus related topics:
Breast Cancer
Drug Information
available for:
Paclitaxel
| Arm | Intervention/treatment |
|---|---|
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Experimental: Ipatasertib + 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.
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Drug: Ipatasertib
Participants received ipatasertib orally 400 milligrams (mg) daily on Days 1-21 of each 28-day cycle.
Other Name: GDC-0068 Drug: Paclitaxel Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle. |
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Placebo Comparator: Placebo + 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.
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Drug: Paclitaxel
Participants received paclitaxel 80 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1, 8, and 15 of each cycle. Drug: Placebo Participants received oral placebo matched to ipatasertib, daily on Days 1-21 of each 28-day cycle. |
Primary Outcome Measures :
- Progression Free Survival (PFS) [ Time Frame: 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.
- PFS in Participants With Phosphatase and Tensin Homolog (PTEN)-Low Tumors [ Time Frame: 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 :
- PFS in Participants With Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors [ Time Frame: 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) [ Time Frame: 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.
- OS in Participants With PTEN-Low Tumors [ Time Frame: 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.
- OS in Participants With PIK3CA/AKT1/PTEN-altered Tumors [ Time Frame: 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.
- Objective Response Rate (ORR) [ Time Frame: 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.
- ORR in Participants With PTEN-Low Tumors [ Time Frame: 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.
- ORR in Participants With PIK3CA/AKT1/PTEN-altered Tumors [ Time Frame: 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.
- Duration of Response [ Time Frame: 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.
- Duration of Response in Participants With PTEN-Low Tumors [ Time Frame: 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.
- Duration of Response in Participants With PIK3CA/AKT1/PTEN-altered Tumors [ Time Frame: 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.
- Time to Disease Progression [ Time Frame: 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 PTEN-Low Tumors [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 8 ]PK parameters were not calculated due to sparse PK sampling.
- Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 8 ]PK parameters were not calculated due to sparse PK sampling.
- 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 [ Time Frame: 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).
- 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 [ Time Frame: 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).
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02162719
Locations
Show 44 study locations
Sponsors and Collaborators
Genentech, Inc.
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Genentech, Inc. |
| ClinicalTrials.gov Identifier: | NCT02162719 |
| Other Study ID Numbers: |
GO29227 2014-000469-35 ( EudraCT Number ) |
| First Posted: | June 13, 2014 Key Record Dates |
| Results First Posted: | January 11, 2021 |
| Last Update Posted: | March 10, 2021 |
| Last Verified: | February 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm). |
Additional relevant MeSH terms:
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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Paclitaxel Ipatasertib Antineoplastic Agents, Phytogenic |
Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Protein Kinase Inhibitors Enzyme Inhibitors |