A Study of Trastuzumab Emtansine in Combination With Atezolizumab or Placebo as a Treatment for Participants With Human Epidermal Growth Factor 2 (HER2)-Positive and Programmed Death-ligand 1 (PD-L1)-Positive Locally Advanced (LABC) or Metastatic Breast Cancer (MBC)

Phase 3

Terminated

Conditions: Metastatic Breast Cancer

Interventions: Drug: Trastuzumab Emtansine
Other: Placebo
Drug: Atezolizumab

Registration Number: NCT04740918

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This study will evaluate the efficacy, safety and patient-reported outcomes of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo in participants with HER2-positive and PD-L1-positive LABC or MBC.Participants must have progressed either during or after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC; or during (or within 6 months after completing) trastuzumab- (+/-pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 96

Inclusion Criteria

HER2+ and PD-L1+ locally advanced (LABC) or metastatic breast cancer (MBC)
Progression must have occurred during most recent treatment for LABC/MBC or during, or within 6 months after completing, neoadjuvant and/or adjuvant therapy
Prior treatment with trastuzumab (+/- pertuzumab) and taxane in the neoadjuvant and/or adjuvant, locally advanced, or metastatic setting
No more than two prior lines of therapy in the metastatic setting
Measurable disease per RESIST version 1.1
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Life expectancy >= 6 months
Adequate hematologic and end-organ function
For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs
For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria

Prior treatment with trastuzumab emtansine in metastatic setting
History of exposure to cumulative doses of anthracyclines
Symptomatic or actively progressing central nervous system (CNS) metastases; asymptomatic CNS lesions ≤ 2cm without clinical requirement for local intervention or asymptomatic patients with treated CNS lesions are eligible
Current Grade >= 3 peripheral neuropathy
Cardiopulmonary dysfunction
History of malignancy within 5 years prior to initiation of study treatment, with the exception of the cancer under investigation and malignancies with a negligible risk of metastasis or death
History of leptomeningeal disease
Active or history of autoimmune disease or immune deficiency
Active hepatitis B, hepatitis C and/or tuberculosis
Prior allogeneic stem cell or solid organ transplantation
Receipt of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, during treatment, or within 5 months following the last dose of study treatment
Pregnancy or lactation

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: Trastuzumab Emtansine and Placebo	Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor.
Arm A: Trastuzumab Emtansine and Placebo	Trastuzumab Emtansine	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor.
Arm B: Trastuzumab Emtansine and Atezolizumab	Trastuzumab Emtansine	Atezolizumab 1200 mg IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.
Arm B: Trastuzumab Emtansine and Atezolizumab	Atezolizumab	Atezolizumab 1200 mg IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	Up to 28 months	PFS was defined as the time from randomization to the first occurrence of documented disease progression (PD), as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Median PFS was calculated using the Kaplan-Meier (KM) methodology. Data for participants without PD or death from any cause as of the data cut-off date were censored at the time of the last tumor assessment.
Overall Survival (OS)	Up to 28 months	OS was defined as the time from the first dose of study treatment to the time of death from any cause. Participants who are alive as of the data cut-off date of the analysis were censored at the last known date they were alive. Participants with no post-baseline information were censored at the date of randomization plus 1 day. Median OS was calculated using the KM methodology.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to 28 months	ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) on two consecutive assessments, at least 28 days apart, as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. Only participants with measurable disease at baseline were analyzed for this outcome measure. Participants without a post-baseline tumor assessment were considered non-responders. An estimate of the ORR and its 95% CI (Wilson score confidence interval) were calculated for each treatment arm.
Duration of Response (DOR)	Up to 28 months	DOR was calculated for participants who had a best OR of CR/PR. DOR was defined as time from first occurrence of a documented OR until the time of documented PD or death from any cause, whichever occurs first as determined by investigator assessment using RECIST v1.1. CR=the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR=at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Median DOR was calculated using the KM methodology.
PFS in Participants With Baseline Brain Metastases as Determined by Investigator Assessment Using RECIST v1.1	Up to 28 months	PFS was defined as the time from randomization to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Median PFS was calculated using the KM methodology.
OS in Participants With Baseline Brain Metastases	Up to 28 months	OS is defined as the time from the first dose of study treatment to the time of death from any cause. Median OS was calculated using the KM methodology.
Central Nervous System (CNS) PFS as Determined by Investigator Using RECIST v1.1 in Participants With Baseline CNS Metastases	Up to 28 months	CNS PFS was defined as the time from randomization to the first occurrence of documented CNS PD, or first occurrence of symptomatic CNS disease as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Median PFS was calculated using the KM methodology. Participants who experienced non-CNS PD at the time of analysis were censored at the date of this progression. Participants who experienced no PD and were alive at the time of analysis were censored at date of their last post-baseline tumor assessment or, if they had no post-baseline tumor assessment, on the date of randomization + 1 day.
CNS PFS as Determined by Investigator Using RECIST v1.1 in Participants Without Baseline CNS Metastases	Up to 28 months	CNS PFS was defined as the time from randomization to the first occurrence of documented CNS PD, or first occurrence of symptomatic CNS disease as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Median PFS was calculated using the KM methodology. Participants who experienced non-CNS PD at the time of analysis were censored at the date of this progression. Participants who experienced no PD and were alive at the time of analysis were censored at date of their last post-baseline tumor assessment or, if they had no post-baseline tumor assessment, on the date of randomization + 1 day.
Percentage of Participants With Adverse Events (AEs)	Up to 28 months	An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.

Trial Locations

Locations (51): Emad Ibrahim, Md, Inc
🇺🇸
Redlands, California, United States
Peter MacCallum Cancer Center
🇦🇺
Melbourne, Victoria, Australia
Hospital Sao Rafael - HSR
🇧🇷
Salvador, Bahia, Brazil
Hospital do Cancer de Pernambuco - HCP
🇧🇷
Recife, Pernambuco, Brazil
Oncosite - Centro de Pesquisa Clinica Em Oncologia Ltda
🇧🇷
Ijui, Rio Grande Do Sul, Brazil
Hospital de Base de Sao Jose do Rio Preto
🇧🇷
Sao Jose do Rio Preto, São Paulo, Brazil
Núcleo de Pesquisa São Camilo
🇧🇷
Sao Paulo, São Paulo, Brazil
Royal Victoria Hospital
🇨🇦
Barrie, Ontario, Canada
Centre Hospitalier de l?Université de Montréal (CHUM)
🇨🇦
Montreal, Quebec, Canada
Peking University People's Hospital
🇨🇳
Beijing, China
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Emad Ibrahim, Md, Inc
🇺🇸Redlands, California, United States