A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With Human Epidermal Growth Factor-2 (HER2) Positive Locally Advanced or Metastatic Breast Cancer (BC) Who Received Prior Trastuzumab and Taxane Based Therapy (KATE2)

• ClinicalTrials.gov Identifier: NCT02924883
• Recruitment Status: Completed
• First Posted: October 5, 2016
• Results First Posted: February 12, 2019
• Last Update Posted: February 17, 2021
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 21, 2016
• First Posted Date: October 5, 2016
• Results First Submitted Date: December 9, 2018
• Results First Posted Date: February 12, 2019
• Last Update Posted Date: February 17, 2021
• Actual Study Start Date: September 26, 2016
• Actual Primary Completion Date: December 11, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 23, 2019)

• Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) [ Time Frame: Baseline up to approximately 15 months ]
  PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.
• Percentage of Participants With Adverse Events [ Time Frame: Baseline up to study completion, approximately 40 months ]
  An adverse event is 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 adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

• Original Primary Outcome Measures (submitted: October 4, 2016): Progression Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: From Baseline until disease progression or death (up to approximately 28 months) ]

Current Secondary Outcome Measures (submitted: January 28, 2021)

• Overall Survival (OS) [ Time Frame: Baseline up to study completion or death, whichever occurs first, approximately 40 months ]
  OS was defined as the time from randomization to death from any cause.
• Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1 [ Time Frame: Baseline up to approximately 15 months ]
  An OR was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.
• Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1 [ Time Frame: Baseline up to approximately 15 months ]
  Duration of OR was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.
• Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine [ Time Frame: Pre-infusion (0 hour [h]), 30 minutes (min) after end of infusion (EOI) (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days); at any time during study treatment/early discontinuation visit (approx. 40 months) ]
  Average post infusion Trastuzumab Emtansine concentration
• Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1) [ Time Frame: Pre-infusion (0 h) on Day 1 Cycle 1 and 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4 (each cycle = 21 days) ]
  Average post infusion Deacetyl Mercapto 1-Oxopropyl Maytansine concentration of trastuzumab emtansine infusion
• Cmax of Total Trastuzumab [ Time Frame: Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days) ]
• Cmax of Atezolizumab [ Time Frame: Pre-infusion (0 h), 30 min after EOI (over 60 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycles 2, 3, 8, and every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion/early discontinuation (approx. 40 months) ]
  Average post infusion atezolizumab concentration
• Percentage of Participants With Anti-therapeutic Antibodies (ATAs) to Atezolizumab [ Time Frame: Pre-infusion (0 h) on Day 1 Cycles 1, 2, 3, 4, 8, and every 8 cycles thereafter (each cycle = 21 days) up to 120 days after treatment completion or early discontinuation (approximately 40 months) ]
  ATAs are antibodies that inactivate the therapeutic effects of Atezolizumab. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).
• Percentage of Participants With ATAs to Trastuzumab Emtansine [ Time Frame: Pre-infusion (0 h) on Day 1 Cycles 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (approximately 40 months) ]
  ATAs are antibodies that inactivate the therapeutic effects of Trastuzumab Emtansine. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).

Original Secondary Outcome Measures (submitted: October 4, 2016)

• Overall Survival (OS) [ Time Frame: From Baseline until death or end of study (up to approximately 28 months) ]
• Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1 [ Time Frame: From Baseline until disease progression or death (up to approximately 28 months) ]
• Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1 [ Time Frame: From Baseline until disease progression or death (up to approximately 28 months) ]
• Percentage of Participants With Adverse Events [ Time Frame: Up to approximately 28 months ]
• Maximum Serum Concentration of Trastuzumab Emtansine [ Time Frame: Pre-infusion(0 hour [h]),30 min after end of infusion (EOI) (over 90 min) on Day 1 of Cycle 1 and 4; pre-infusion (0 h) on Day 1 of Cycle 2(each cycle=21 days); at any time during study treatment/early discontinuation visit(up to approximately 28 months) ]
• Serum Concentration of Total Trastuzumab [ Time Frame: Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 of Cycle 1 and 4; pre-infusion (0 h) on Day 1 of Cycle 2 (each cycle = 21 days) ]
• Maximum Plasma Concentration of Deacetyl mercapto 1-oxopropyl maytansine (DM1) [ Time Frame: Pre-infusion (0 h) on Day 1 of Cycle 1 and 30 min after EOI (over 90 min) on Day 1 of Cycle 1 and 4 (each cycle = 21 days) ]
• Maximum Serum Concentration of Atezolizumab [ Time Frame: Pre-infusion(0 h),30 min after EOI(over 60 min)on Day 1 of Cycle 1 & 4; pre-infusion(0 h)on Day 1 of Cycles 2,3,8 & every 8 cycles thereafter(each cycle=21 days)up to120 days after treatment completion/early discontinuation(up to approximately 28 months) ]
• Percentage of Participants With Anti-therapeutic Antibodies (ATA) to Atezolizumab [ Time Frame: Pre-infusion (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 & every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion or early discontinuation (up to approximately 28 months) ]
• Percentage of Participants With ATA to Trastuzumab Emtansine [ Time Frame: Pre-infusion (0 h) on Day 1 of Cycle 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (up to approximately 28 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With Human Epidermal Growth Factor-2 (HER2) Positive Locally Advanced or Metastatic Breast Cancer (BC) Who Received Prior Trastuzumab and Taxane Based Therapy
• Official Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab and Taxane Based Therapy
• Brief Summary: This Phase II, double-blind, randomized, placebo-controlled multicenter study will investigate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with HER2-positive locally advanced or metastatic BC who have received prior trastuzumab and taxane based therapy, either alone or in combination, and/or who have progressed within 6 months after completing adjuvant therapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer

Intervention

• Drug: Atezolizumab
  Atezolizumab 1200 mg IV infusion
  Other Name: Tecentriq, RO5541267, MPDL3280A
• Drug: Trastuzumab emtansine
  Trastuzumab emtansine 3.6 mg/kg IV infusion
  Other Name: Kadcyla®, T-DM1, RO5304020
• Other: Placebo
  Placebo matched to atezolizumab

Study Arms

• Experimental: Trastuzumab Emtansine + Atezolizumab
  Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (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 (approximately 29 months)
  Interventions:

  • Drug: Atezolizumab
  • Drug: Trastuzumab emtansine
  • Other: Placebo
• Active Comparator: Trastuzumab Emtansine + Placebo
  Placebo matched to atezolizumab 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 (approximately 29 months)
  Interventions:

  • Drug: Trastuzumab emtansine
  • Other: Placebo

• Publications *: Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, Im SA, Wang Y, Salgado R, Mani A, Shah J, Lambertini C, Liu H, de Haas SL, Patre M, Loi S. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020 Oct;21(10):1283-1295. doi: 10.1016/S1470-2045(20)30465-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 28, 2018): 202
• Original Estimated Enrollment (submitted: October 4, 2016): 200
• Actual Study Completion Date: February 6, 2020
• Actual Primary Completion Date: December 11, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Archival tumor samples must be obtained from primary and/or metastatic sites
• Able to submit tumor tissue that is evaluable for programmed death- ligand 1 (PD-L1) expression
• HER-2 positive BC as defined by an immunohistochemistry score of 3 or gene amplified by in-situ hybridization as defined by a ratio of greater than or equal to (>=) 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies
• Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic BC
• Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic settings; which must include both, a taxane and trastuzumab (alone or in combination with another agent)
• Progression must have occurred during or after most recent treatment for locally advanced/metastatic BC or within 6 months after completing adjuvant therapy
• Participants must have measurable disease that is evaluable as per RECIST v1.1
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and for women less than 12 months after the onset of menopause
• Use of highly effective method of contraception as defined by the protocol

Exclusion Criteria:

• Prior treatment with trastuzumab emtansine, cluster of differentiation 137 agonists, anti-programmed death-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Receipt of any anti-cancer drug/biologic or investigational treatment within 21 days prior to Cycle 1 Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1 Day 1; recovery of treatment related toxicity consistent with other eligibility criteria
• Radiation therapy within 2 weeks prior to Cycle 1, Day 1
• History of exposure to the cumulative doses of anthracyclines
• History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or participants who have undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to be at low risk for recurrence
• Cardiopulmonary dysfunction, symptomatic pleural effusion, pericardial effusion, or ascites
• Participants with severe infection within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Current severe, uncontrolled systemic disease
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
• Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus
• Need for current chronic corticosteroid therapy (>=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids)
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for greater than (>) 2 weeks prior to randomization
• Participants with known central nervous system disease
• Leptomeningeal disease
• History of autoimmune disease
• Prior allogeneic stem cell or solid organ transplantation
• Active tuberculosis
• Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
• Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
• Participants who are breastfeeding, or intending to become pregnant during the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Germany, Italy, Korea, Republic of, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02924883
• Other Study ID Numbers: WO30085; 2015-004189-27 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2021