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

Primary Purpose

Advanced Breast Cancer, HER2-positive Breast Cancer

Status

Withdrawn

Phase

Phase 3

Locations

Germany

Study Type

Interventional

Intervention

Trastuzumab

Pertuzumab

Vinorelbine

Docetaxel

About this trial

This is an interventional other trial for Advanced Breast Cancer focused on measuring advanced breast cancer, HER2-positive, metastatic, inoperable, female, quality of life

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

iOMEDICO AG

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Kanjinti/Pertuzumab plus Vinorelbine

Kanjinti/Pertuzumab plus Docetaxel

Arm Description

Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine.

Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Overall response rate (ORR)

Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response.

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.

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.

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).

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.

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.

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.

Blood count: Absolute Neutrophil Count

The absolute neutrophil count will be determined as per clinical routine and will be displayed using by-patient listings.

Safety monitoring (coagulation): Coagulation (INR)

Coagulation (INR) as per clinical routine will be displayed using by-patient listings.

Clinical chemistry: Alkaline Phosphatase

Alkaline phosphatase will be measured in U/L as per clinical routine and will be displayed using by-patient listings.

Clinical chemistry: Alanine transaminase (ALT)

ALT will be measured in U/L as per clinical routine and will be displayed using by-patient listings.

Clinical chemistry: Aspartate transaminase (AST)

AST will be measured in U/L as per clinical routine and will be displayed using by-patient listings.

Clinical chemistry: Bilirubin total

Total bilirubin will be measured in mg/dL as per clinical routine and will be displayed using by-patient listings.

Clinical chemistry: Creatinine (Serum)

Serum creatinine will be measured in µmol/L as per clinical routine and will be displayed using by-patient listings.

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.

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.

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.

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

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

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

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

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

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

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.

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

Exploratory endpoint: Treatment costs

Treatment costs (drug costs)

Exploratory endpoints: Duration of hospitalizations

Total duration of hospitalizations (per patients)

Exploratory endpoints: Number of hospitalizations

Number of hospitalizations (in-patient stays)

Exploratory endpoints: Reasons for hospitalizations

Reasons for hospitalizations

Exploratory endpoints: Febrile infections

Incidence of febrile infections

Exploratory endpoints: Employment status

Employment status (kind and duration of sick leaves)

Full Information

NCT ID

NCT03811418

First Posted

December 13, 2018

Last Updated

November 25, 2019

Sponsor

iOMEDICO AG

Collaborators

Arbeitsgemeinschaft fur Internistische Onkologie, Amgen

1. Study Identification

Unique Protocol Identification Number

NCT03811418

Brief Title

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

Acronym

ATTILA

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Withdrawn

Why Stopped

Study approved with treatment regimen based on current guidelines. However, reimbursement of IMP was not feasible.

Study Start Date

January 2019 (Anticipated)

Primary Completion Date

April 2019 (Anticipated)

Study Completion Date

April 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

iOMEDICO AG

Collaborators

Arbeitsgemeinschaft fur Internistische Onkologie, Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Breast Cancer, HER2-positive Breast Cancer

Keywords

advanced breast cancer, HER2-positive, metastatic, inoperable, female, quality of life

7. Study Design

Primary Purpose

Other

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Kanjinti/Pertuzumab plus Vinorelbine

Arm Type

Experimental

Arm Description

Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine.

Arm Title

Kanjinti/Pertuzumab plus Docetaxel

Arm Type

Active Comparator

Arm Description

Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel.

Intervention Type

Drug

Intervention Name(s)

Trastuzumab

Other Intervention Name(s)

Kanjinti®, ABP 980

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pertuzumab

Other Intervention Name(s)

Perjeta®

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Vinorelbine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Docetaxel

Intervention Description

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.

Primary Outcome Measure Information:

Title

Patient-reported health-related quality of life (QoL): FACT-B

Description

Time Frame

Baseline to week 18

Secondary Outcome Measure Information:

Title

Progression-free survival (PFS) assessed by the investigator

Description

Time Frame

Baseline, every 12 weeks after randomization (maximum up to 76 months)

Title

Overall survival (OS)

Description

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 Frame

Time from randomization to date of death (maximum up to approximately 76 months)

Title

Overall response rate (ORR)

Description

Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response.

Time Frame

Baseline, every 12 weeks after randomization (maximum up to 76 months)

Title

Clinical benefit rate (CBR)

Description

CBR is defined as proportion of patients achieving a complete or partial remission or a stable disease lasting at least 24 weeks.

Time Frame

Baseline, every 12 weeks after randomization (maximum up to 76 months)

Title

Time to treatment failure (TTF)

Description

Time Frame

Baseline, every 12 weeks after randomization (maximum up to 56 months)

Title

Incidence of (Serious) Adverse events ((S)AEs)

Description

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).

Time Frame