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

Sex

Female

Minimum age

18 Years

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.

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• BACKGROUNDAndersson 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. PMID 28592618
• BACKGROUNDBaselga 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. PMID 22149875
• BACKGROUNDBurstein 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. PMID 17614302
• BACKGROUNDCortes 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. PMID 23868905
• BACKGROUNDPerez 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.