A Study to Compare Pertuzumab + Trastuzumab + Vinorelbine vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (ATTILA)

Phase III Study to Compare Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Vinorelbine With Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Docetaxel as First-line Treatment for HER2-positive Advanced Breast Cancer

This is a randomized, open-label, two-arm, phase III trial in Germany to investigate whether vinorelbine-based triple combination presents a less toxic treatment option than docetaxel-based triple combination in patients with HER2-positive advanced breast cancer who have not previously received any systemic treatment in the metastatic setting.

The primary objective of the study is to compare patient-reported quality of life in the two treatment arms. Patients will be followed-up for survival until death or end of study after at least 79 deaths occured in each arm, whatever comes first.

Study Overview

• Status: Withdrawn
• Conditions: Advanced Breast Cancer; HER2-positive Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Pertuzumab; Drug: Vinorelbine; Drug: Docetaxel

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • iOMEDICO AG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Signed and dated written informed consent prior to beginning of protocol-specific procedures.
• Histologically or cytologically confirmed adenocarcinoma of the breast. Locally advanced and inoperable or metastatic disease.
• HER2-positive disease, defined as IHC status HER2+++ or CISH/FISH status positive.
• Female patients aged ≥ 18 years.
• In case of adjuvant treatment, disease-free interval of at least 12 months after completion of adjuvant treatment (excluding hormonal therapy).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Left Ventricular Ejection Fraction (LVEF) ≥ 50%.

• For women with childbearing potential, defined as physiologically capable of becoming pregnant:

  • Negative pregnancy test.
  • Agreement to use an effective form of contraception during study treatment and for 7 months after the last dose of study treatment.
• Life expectancy of at least 12 weeks.
• Adequate organ and bone marrow function
• Fluent in spoken and written German and willing to answer the questionnaires

Exclusion Criteria:

• Previous systemic treatment in palliative intention (chemotherapy, hormonal therapy and / or biological therapy)
• Persistent peripheral sensory or motor neuropathy grade 2 or higher (NCI CTCAE v5.0)
• Evidence of central nervous system metastases. CT or MRI of the brain is only mandatory in case of clinical suspicion of brain metastases
• Current uncontrolled hypertension (systolic > 150 mmHg and / or diastolic > 100 mmHg) or clinically significant cardiovascular disease
• History of LVEF < 50% during or after prior (neo)adjuvant therapy with trastuzumab
• Current severe, uncontrolled systemic disease (e.g. cardiovascular, pulmonary, or metabolic disease, wound healing disorder, ulcers, or bone fractures, or severe fungal, bacterial or viral infection)
• Major surgery within 28 days prior to start of study medication, or anticipation of the need for major surgery during the course of study treatment
• Current known infection with HIV, HBV, or HCV (testing not required)
• Dyspnea at rest due to complications of advanced malignancy, or other diseases requiring continuous oxygen therapy.
• Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies.
• Participation in investigational studies within 30 days or five half-lives of the respective IMP, whichever is longer, prior randomization.
• Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Kanjinti/Pertuzumab plus Vinorelbine; Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine.	Drug: Trastuzumab; administered as combined therapy with pertuzumab and vinorelbine or docetaxel. Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.; Other Names: ABP 980; Kanjinti®; Drug: Pertuzumab; administered as combined therapy with Kanjinti® and vinorelbine or docetaxel. Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.; Other Names: Perjeta®; Drug: Vinorelbine; administered as combined therapy with Kanjinti® and pertuzumab. Vinorelbine will be administered as an IV dose of 25 milligrams per kilogram (mg/kg) on days 1 and 8 of cycle 1 (1 cycle length = 21 days), and 25mg/kg up to 30 mg/kg (as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.
ACTIVE_COMPARATOR: Kanjinti/Pertuzumab plus Docetaxel; Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel.	Drug: Trastuzumab; administered as combined therapy with pertuzumab and vinorelbine or docetaxel. Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.; Other Names: ABP 980; Kanjinti®; Drug: Pertuzumab; administered as combined therapy with Kanjinti® and vinorelbine or docetaxel. Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.; Other Names: Perjeta®; Drug: Docetaxel; administered as combined therapy with Kanjinti® and pertuzumab. Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) on day 1 of cycle 1 (1 cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-reported health-related quality of life (QoL): FACT-B	Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 18 weeks (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life. To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.	Baseline to week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) assessed by the investigator	PFS is defined as time from randomization to date of progressive disease or death, whichever comes first. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive without progressive disease at database lock. If subsequent treatment was started prior to progressive disease, then data will be censored at the onset of this treatment.	Baseline, every 12 weeks after randomization (maximum up to 76 months)
Overall survival (OS)	OS is defined as time from randomization to date of death. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive at database cut/lock.	Time from randomization to date of death (maximum up to approximately 76 months)
Overall response rate (ORR)	Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response.	Baseline, every 12 weeks after randomization (maximum up to 76 months)
Clinical benefit rate (CBR)	CBR is defined as proportion of patients achieving a complete or partial remission or a stable disease lasting at least 24 weeks.	Baseline, every 12 weeks after randomization (maximum up to 76 months)
Time to treatment failure (TTF)	TTF is defined as time from randomization to discontinuation of all study medications. Date of discontinuation is the earliest end of last cycle (= 20 days after first administration of a study drug in the last cycle) OR progressive disease after last administration of any study drug OR death OR start of a subsequent treatment.	Baseline, every 12 weeks after randomization (maximum up to 56 months)
Incidence of (Serious) Adverse events ((S)AEs)	Type, frequency and severity of adverse events (including those from the pre- and post-treatment periods) will be listed according to Common Toxicity Criteria for Adverse Events (CTCAE).	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Blood count: Hemoglobin	The amount of hemoglobin in the blood will be measured in g/dL as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Blood count: Platelet Count	The number of platelets in the blood will be counted as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Blood count: Leukocytes	The number of leukocytes in the blood will be counted as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Blood count: Absolute Neutrophil Count	The absolute neutrophil count will be determined as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Safety monitoring (coagulation): Coagulation (INR)	Coagulation (INR) as per clinical routine will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Clinical chemistry: Alkaline Phosphatase	Alkaline phosphatase will be measured in U/L as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Clinical chemistry: Alanine transaminase (ALT)	ALT will be measured in U/L as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Clinical chemistry: Aspartate transaminase (AST)	AST will be measured in U/L as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Clinical chemistry: Bilirubin total	Total bilirubin will be measured in mg/dL as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Clinical chemistry: Creatinine (Serum)	Serum creatinine will be measured in µmol/L as per clinical routine and will be displayed using by-patient listings.	From date of informed consent to +30 days from last application of study medication (maximum up to 57 months)
Left Ventricular Ejection Fraction (LVEF) monitoring	Incidence of clinically relevant LVEF levels. Change from baseline at each assessment time point, worst-on-treatment will be displayed using descriptive statistics.	LVEF at baseline, every three months thereafter until end of treatment, then every six months for 24 months thereafter (maximum up to 76 months)
Patient-reported health-related quality of life (QoL): Trial Outcome Index-Physical/Functional/Breast (TOI-PFB)	AUC in TOI-PFB at 12, 18, 24 and 36 months. Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 12, 18, 24 and 36 months (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life. To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life.	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B TOI-PFB	Time to decline by 5 points in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB). To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; decline of scale indicates worsening quality of life.	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B total score	Change from baseline in the FACT-B total score for all questionnaire timepoints. To calculate FACT-B total score patient ratings from 0 (not at all) - 4 (very much) to each of the 37 questionnaire statement are summed up. Total score range: 0 - 148. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B subscale physical well-being (PWB)	Change from baseline in the FACT-B subscale PWB for all questionnaire timepoints. PWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B subscale social/family well-being (SWB)	Change from baseline in the FACT-B subscale SWB for all questionnaire timepoints. SWB subscale consists of 8 statements leading to a scale range of 0-32. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B subscale emotional well-being (EWB)	Change from baseline in the FACT-B subscale EWB for all questionnaire timepoints. EWB subscale consists of 6 statements leading to a scale range of 0-24. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B subscale functional well-being (FWB)	Change from baseline in the FACT-B subscale FWB for all questionnaire timepoints. FWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS)	Change from baseline in the FACT-B BCS score for all questionnaire timepoints. BCS consists of 10 statements leading to a score range of 0-40. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS) score decline	Time to decline by 2 points in the FACT-B BCS score. BCS consists of 10 statements leading to a score range of 0-40. BCS score decline indicates worsening quality of life.	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Patient-reported health-related quality of life (QoL): FACT/GOG-Ntx4 subscale	Change from baseline in the FACT/GOG-Ntx4 subscale for all questionnaire timepoints. FACT/GOG-Ntx4 subscale consists of 11 statements leading to a scale range of 0-44. Higher values indicate better quality of life	Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months).
Exploratory endpoint: Treatment costs	Treatment costs (drug costs)	From randomization until end of treatment (maximum up to 56 months).
Exploratory endpoints: Duration of hospitalizations	Total duration of hospitalizations (per patients)	From randomization until end of treatment (maximum up to 57 months).
Exploratory endpoints: Number of hospitalizations	Number of hospitalizations (in-patient stays)	From randomization until end of treatment (maximum up to 57 months).
Exploratory endpoints: Reasons for hospitalizations	Reasons for hospitalizations	From randomization until end of treatment (maximum up to 57 months).
Exploratory endpoints: Febrile infections	Incidence of febrile infections	From randomization until end of treatment (maximum up to 57 months).
Exploratory endpoints: Employment status	Employment status (kind and duration of sick leaves)	From randomization until end of treatment (maximum up to 56 months).

Collaborators and Investigators

• Sponsor: iOMEDICO AG
• Collaborators: Amgen; Arbeitsgemeinschaft fur Internistische Onkologie
• Investigators: Principal Investigator: Anja Welt, Dr., Essen University Hospital

Publications and helpful links

General Publications

• Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sorensen PG, Moller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. doi: 10.1200/JCO.2010.30.8213. Epub 2010 Dec 13.
• Andersson M, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Perez EA. Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results. Oncologist. 2017 Oct;22(10):1160-1168. doi: 10.1634/theoncologist.2017-0079. Epub 2017 Jun 7.
• Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.
• Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. doi: 10.1002/cncr.22885.
• Cortes J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. doi: 10.1093/annonc/mdt274. Epub 2013 Jul 17.
• Perez EA, Lopez-Vega JM, Petit T, Zamagni C, Easton V, Kamber J, Restuccia E, Andersson M. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res. 2016 Dec 13;18(1):126. doi: 10.1186/s13058-016-0773-6.
• Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 1, 2019
• Primary Completion (ANTICIPATED): April 1, 2019
• Study Completion (ANTICIPATED): April 1, 2019

Study Registration Dates

• First Submitted: December 13, 2018
• First Submitted That Met QC Criteria: January 17, 2019
• First Posted (ACTUAL): January 22, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 26, 2019
• Last Update Submitted That Met QC Criteria: November 25, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: quality of life; inoperable; metastatic; female; advanced breast cancer; HER2-positive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Docetaxel; Trastuzumab; Vinorelbine; Pertuzumab
• Other Study ID Numbers: iOM-110383; 2017-004749-25 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No