Trastuzumab & Pertuzumab Followed by T-DM1 in MBC

NCT ID: NCT01835236

Last Updated: 2021-03-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 208 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-03
• Study Completion Date: 2020-05-26

Brief Summary

In HER2-positive metastatic breast cancer, trastuzumab based treatment is the standard of care as long as there are no contraindications to trastuzumab. Frequently, trastuzumab is being combined with taxanes in the first-line setting. However, since therapy with trastuzumab is active even in the absence of chemotherapy in HER2-positive MBC, the optimal treatment strategy either in combination or in sequence with chemotherapy is still under debate. This randomized phase II trial is studying a new strategy for the treatment of metastatic breast cancer with HER2-positive. First-line treatment consists of trastuzumab and pertuzumab, a treatment without chemotherapy. In case of disease progression, chemotherapy with T-DM1 is then performed as second-line treatment. Third-line and further line therapies are performed according to the physician's discretion. If this new therapeutic strategy is as effective and better tolerated than the conventional strategy, this would mean a serious breakthrough in the treatment of HER2-positive metastatic breast cancer.

Detailed Description

OBJECTIVES:

Primary

-To evaluate the efficacy in terms of overall survival (OS) at 24 months of a chemotherapy-free dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer.

Secondary

• To evaluate other efficacy parameter
• To evaluate the safety and tolerability profile of the two treatment strategies
• To evaluate the Quality of Life (QoL)
• To learn how patients are treated after trial treatment

OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (positive vs negative), prior trastuzumab (never or >12 months vs ≤12 months after last infusion), visceral metastases (present vs absent) and site. Patients are randomized to 1 of 2 treatment arms.

Conditions

Metastatic Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Trastuzumab, Pertuzumab, T-DM1

First line therapy: Trastuzumab, Pertuzumab Second line therapy: T-DM1

Group Type: ACTIVE_COMPARATOR

Trastuzumab

Intervention Type: DRUG

First administration (loading dose) 8 mg/kg i.v. infusion over 90 min.

• then every 3 weeks until progression 6 mg/kg i.v. infusion over 30 to 90 min.

Pertuzumab

Intervention Type: DRUG

First administration (loading dose) 840 mg i.v. infusion over 60 min.

• then every 3 weeks until progression 420 mg i.v. infusion over 30 to 60 min.

T-DM1

Intervention Type: DRUG

Every 3 weeks until unacceptable toxicity or progressive disease is observed 3.6 mg/kg i.v. infusion First dose: over 90 min (± 10 min.) Subsequent doses: over 30 min. (± 10 min.)

Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine plus T-DM1

First line therapy: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine Second line therapy: T-DM1

Group Type: ACTIVE_COMPARATOR

Trastuzumab

Intervention Type: DRUG

First administration (loading dose) 8 mg/kg i.v. infusion over 90 min.

• then every 3 weeks until progression 6 mg/kg i.v. infusion over 30 to 90 min.

Pertuzumab

Intervention Type: DRUG

First administration (loading dose) 840 mg i.v. infusion over 60 min.

• then every 3 weeks until progression 420 mg i.v. infusion over 30 to 60 min.

Paclitaxel

Intervention Type: DRUG

Day 1, 8 and 15; every 4 weeks for ≥4 months 90 mg/m2 i.v. infusion

Vinorelbine

Intervention Type: DRUG

First administration: Day 1 and 8 25 mg/m2 i.v. infusion

• then day 1 and 8, every 3 weeks for ≥4 months 30 mg/m2 i.v. infusion

T-DM1

Intervention Type: DRUG

Every 3 weeks until unacceptable toxicity or progressive disease is observed 3.6 mg/kg i.v. infusion First dose: over 90 min (± 10 min.) Subsequent doses: over 30 min. (± 10 min.)

Interventions

Trastuzumab

First administration (loading dose) 8 mg/kg i.v. infusion over 90 min.

• then every 3 weeks until progression 6 mg/kg i.v. infusion over 30 to 90 min.

Intervention Type: DRUG

Pertuzumab

First administration (loading dose) 840 mg i.v. infusion over 60 min.

• then every 3 weeks until progression 420 mg i.v. infusion over 30 to 60 min.

Intervention Type: DRUG

Paclitaxel

Day 1, 8 and 15; every 4 weeks for ≥4 months 90 mg/m2 i.v. infusion

Intervention Type: DRUG

Vinorelbine

First administration: Day 1 and 8 25 mg/m2 i.v. infusion

• then day 1 and 8, every 3 weeks for ≥4 months 30 mg/m2 i.v. infusion

Intervention Type: DRUG

T-DM1

Every 3 weeks until unacceptable toxicity or progressive disease is observed 3.6 mg/kg i.v. infusion First dose: over 90 min (± 10 min.) Subsequent doses: over 30 min. (± 10 min.)

Intervention Type: DRUG

Other Intervention Names

Herceptin; Perjeta; Taxol; Navelbine; Trastuzumab emtansine

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed breast cancer with distant metastases

Note:

1. A biopsy from the primary tumor or a metastasis can be used for diagnosis.

2. Patients with non-measurable lesions are eligible.

3. Patients with inoperable, locally advanced breast cancer with lymph node metastases other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other distant metastases are eligible.

4. Patients with bone metastases with or without bone targeted therapy (bisphosphonates, denosumab) are eligible.

5. Patients with de-novo Stage IV disease are eligible.

• HER2-positive tumor according to central pathology testing for HER2

Note:

1. A formalin-fixed paraffin-embedded (FFPE) biopsy from the primary tumor or a metastasis has to be used for HER2 status determination. If a biopsy is available from a metastasis, the HER2 testing should be performed using the metastasis.

2. Fine needle aspiration is not acceptable for HER 2 testing. • Women aged ≥18 years

• WHO performance status 0 to 2
• Left Ventricular Ejection Fraction (LVEF) ≥50% as determined by either ECHO or MUGA
• Adequate organ function, evidenced by the following laboratory results:

Neutrophils >1.5x109/L, platelets >100x109/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert's disease), AST ≤3xULN, ALT ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5xULN

• • Proven disease progression on first-line therapy or radiotherapy of a bone metastasis

Notes:

First new parenchymal CNS metastases only do not count as progression requiring the initiation of second line trial treatment. Radiotherapy of a single area only for pain control is allowed and will not count as PD.

• Adequate organ function, evidenced by the following laboratory results: Neutrophils >1.5x109/L, platelets >100x109/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert's disease), AST ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5ULN

• LVEF ≥50% as determined by either ECHO or MUGA

• QoL questionnaire has been completed.

Exclusion Criteria

• Prior chemotherapy for inoperable locally advanced or metastatic breast cancer

Note:

Prior neoadjuvant/adjuvant chemotherapy is allowed if doses for anthracyclines have not exceeded 720mg/m2 and 240mg/m2 for epirubicin and doxorubicin, respectively.

• Re-exposure to paclitaxel is permitted, if the last dose of taxane was given at least 1 year before randomization.

• Re-exposure to vinorelbine is permitted, if the last dose of vinorelbine was given at least 1 year before randomization.
• Prior anti-HER2 treatment for metastatic or inoperable breast cancer

Note:

Prior neoadjuvant/adjuvant anti-HER2 treatment with trastuzumab and/or lapatinib is allowed.

• More than one endocrine treatment line for metastatic or inoperable breast cancer exceeding a duration of 1 month

Note:

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1. Adjuvant endocrine treatment is not counted as one line.

2. Patients progressing on endocrine treatment: this specific endocrine treatment must have been stopped at least 2 weeks prior to randomization.

• Prior treatment with pertuzumab and/or T-DM1

• Known leptomeningeal or CNS metastases

Note:

A brain MRI or CT scan is mandatory in case of clinical suspicion of CNS metastases.

• Single bone metastasis treated with radiotherapy (if the bone metastasis is the only tumor lesion)

• Termination of first-line therapy with trastuzumab/pertuzumab due to unacceptable toxicity without objective evidence of disease progression

• CNS metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, to control symptoms from CNS metastases within 2 months (60 days) before registration

• Peripheral neuropathy of CTCAE grade ≥3
• Interstitial lung disease (ILD) or pneumonitis grade ≥3
• Any other adverse event which has not recovered to CTCAE grade ≤1 (except alopecia)

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jens Huober, MD

Role: STUDY_CHAIR

University of Ulm

Patrik Weder, MD

Role: STUDY_CHAIR

Cantonal Hospital of St. Gallen

Hervé Bonnefoi, Prof

Role: STUDY_CHAIR

Institut Bergonié Bordeaux

Epie Boven, MD

Role: STUDY_CHAIR

Amsterdam UMC, location VUmc

Locations

Hopital Sud - Amiens

Amiens, , France

ICO - Paul Papin

Angers, , France

Institut Sainte Catherine

Avignon, , France

Centre Hospitalier de Blois

Blois, , France

Institut Bergonie

Bordeaux, , France

Hôpital Morvan (Brest)

Brest, , France

Centre Francois Baclesse

Caen, , France

Centre Hospitalier Alpes Leman

Contamine-sur-Arve, , France

Centre Georges François Leclerc

Dijon, , France

Centre Hospitalier de Dracenie

Draguignan, , France

Hopital Michallon - Centre Hospitalier Universitaire de Grenoble

Grenoble, , France

Clinique Hartmann

Levallois-Perret, , France

Centre Oscar Lambret

Lille, , France

Chu de Limoges - Hopital Dupuytren

Limoges, , France

Centre Hospitalier - Site Hopital du Scorff

Lorient, , France

Clinique de la Sauvegarde

Lyon, , France

Fondation Hopital Ambroise Pare - Hopital Europeen

Marseille, , France

Istitut Paoli Calmettes

Marseille, , France

Institut Regional du Cancer Montpellier Val d'Aurelle

Montpellier, , France

Centre Azureen de Cancerologie

Mougins, , France

Polyclinique de Gentilly

Nancy, , France

Centre Catherine de Sienne

Nantes, , France

Centre Antoine Lacassagne

Nice, , France

Hopital Saint Louis

Paris, , France

Centre Hospitalier de Pau

Pau, , France

Centre Hospitalier de Perpignan - Hopital Saint Jean

Perpignan, , France

Institut Jean Godinot

Reims, , France

Clinique Mathilde

Rouen, , France

Centre Henri Becquerel

Rouen, , France

Curie Site Saint-Cloud

Saint-Cloud, , France

ICO - Rene Gauducheau

Saint-Herblain, , France

Institut de Cancerologie de la Loire

Saint-Priest-en-Jarez, , France

Hopitaux Universitaire de Strasbourg - Hopital Civil

Strasbourg, , France

Hopitaux du Leman - Site Georges Pianta

Thonon-les-Bains, , France

Institut Claudius Regaud

Toulouse, , France

Centre Hospitalier de Valence

Valence, , France

Universitäts-Frauenklinik Ulm

Ulm, , Germany

Almelo_Ziekenhuisgroep Twente

Almelo, , Netherlands

VUmc University Medical Center

Amsterdam, , Netherlands

Antoni van Leeuwenhoek / Slotervaart hospital

Amsterdam, , Netherlands

Reinier de Graaf Gasthuis

Delft, , Netherlands

Deventer Ziekenhuis

Deventer, , Netherlands

Catharina Ziekenhuis

Eindhoven, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Leiden_Leids Universitair Medisch Centrum (LUMC)

Leiden, , Netherlands

St. Antonius Ziekenhuis, Ioc Nieuwegein

Nieuwegein, , Netherlands

St. Franciscus Gasthuis Rotterdam

Rotterdam, , Netherlands

Vlietland Ziekenhuis

Schiedam, , Netherlands

Orbis Medisch Centrum

Sittard, , Netherlands

Haga Ziekenhuis

The Hague, , Netherlands

Hirslanden Klinik Aarau

Aarau, , Switzerland

Kantonspital Aarau

Aarau, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

Universitaetsspital-Basel

Basel, , Switzerland

Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

Bellinzona, , Switzerland

Inselspital, Bern

Bern, , Switzerland

RSV-GNW Spitalzentrum Oberwallis

Brig, , Switzerland

Spitalzentrum Oberwallis

Brig, , Switzerland

Kantonsspital Graubuenden

Chur, , Switzerland

Kantonsspital Frauenfeld / Brustzentrum Thurgau

Frauenfeld, , Switzerland

Hopitaux Universitaires de Geneve

Geneva, , Switzerland

Centre Hospitalier Universitaire Vaudois CHUV

Lausanne, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Kantonsspital Liestal

Liestal, , Switzerland

Kantonsspital Luzern

Luzerne, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

Zentrum fuer Tumordiagnostik und Praevention

Sankt Gallen, , Switzerland

SpitalSTS AG Simmental-Thun-Saanenland

Thun, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Universitäts Spital Zürich

Zurich, , Switzerland

Countries

France; Germany; Netherlands; Switzerland

References

Huober J, Weder P, Ribi K, Thurlimann B, Thery JC, Li Q, Vanlemmens L, Guiu S, Brain E, Grenier J, Dalenc F, Levy C, Savoye AM, Muller A, Membrez-Antonioli V, Gerard MA, Lemonnier J, Hawle H, Dietrich D, Boven E, Bonnefoi H; Swiss Group for Clinical Cancer Research, Unicancer Breast Group, and Dutch Breast Cancer Research Group. Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2023 Oct 1;9(10):1381-1389. doi: 10.1001/jamaoncol.2023.2909.

Reference Type: DERIVED

PMID: 37561451 (View on PubMed)

Other Identifiers

2012-002556-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

UNICANCER UC-0140/1207

Identifier Type: OTHER

Identifier Source: secondary_id

SAKK 22/10

Identifier Type: -

Identifier Source: org_study_id