Clinical trial NCT01835236: Trastuzumab & Pertuzumab Followed by T-DM1 in MBC
Official title: A Randomized Phase II Trial of Pertuzumab in Combination With Trastuzumab With or Without Chemotherapy, Both Followed by T-DM1 in Case of Progression, in Patients With HER2-positive Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Breast cancer
HER2-positive
Metastases
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2013-04-18
Enrollment: 208
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: SELECTION OF PATIENTS (MOST IMPORTANT CRITERIA)

Inclusion criteria for first-line therapy

• 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

   Exclusion criteria for first-line therapy

   • 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)

   Inclusion criteria for second-line therapy • At least one dose of trial therapy in the first-line treatment phase of this trial

   • • 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 for second-line therapy

   • 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)

Primary outcomes:
measure: Overall survival (OS) - Analysis Population: ITT Population 1
timeFrame: 24 months
Secondary outcomes:
measure: OS - Analysis Population: ITT Population 2
timeFrame: 24 months
measure: Progression Free Survival (PFS) of first-line treatment ignoring first Central Nervous System (CNS) lesion
timeFrame: 10 / 16 months (PFS will be calculated sustained from randomization until documented PD (ignoring first CNS lesion) or death, whichever occurs first during first-line treatment )
measure: PFS of second-line treatment
timeFrame: 8 months (PFS will be calculated sustained from registration of second line treatment until documented PD, PD CNS or death, whichever occurs first during second-line treatment)
measure: PFS of second-line treatment ignoring first CNS lesion
timeFrame: 9 months (PFS will be calculated sustained from registration of second line treatment until documented PD (ignoring first CNS lesion) or death, whichever occurs first during second-line treatment)
measure: Time to failure of strategy (TFS) of first- plus second-line treatment
timeFrame: 18 / 24 months (TFS will be calculated sustained from randomization until documented PD, PD CNS or death, whichever occurs first before starting third-line therapy )
measure: Overall survival OS
timeFrame: OS will be calculated from randomization until death (estimated median: 32 months)
measure: Objective response (OR) of first-line treatment (based on investigator assessment)
timeFrame: 10 / 16 months (OR is defined as the best status of response CR or PR up to first progression or start of a new treatment)
measure: Disease control (DC) of first-line treatment (based on investigator assessment)
timeFrame: 6 months (DC is defined as CR, PR or SD for 6 months after randomization and no PD at 6 month after randomization)
measure: OR of second-line treatment (based on investigator assessment)
timeFrame: 9 months (OR is defined as the best status of response CR or PR after registration for second-line treatment up to second progression or start of a new treatment)
measure: DC of second-line treatment (based on investigator assessment)
timeFrame: 6 months (DC is defined as the response CR, PR or SD for 6 months after registration of second-line treatment)
measure: Adverse events (AEs) according to the NCI CTCAE v4.0 of first-line treatment
timeFrame: Throughout first-line treatment (estimated up to 16 months)
measure: AEs according to the NCI CTCAE v4.0 of second-line treatment
timeFrame: Throughout second-line treatment (estimated up to 9 months)
measure: AEs grade ≥2 until first progression (ignoring first CNS lesion)
timeFrame: Throughout first-line treatment (estimated up to 16 months)
measure: Quality of Life (QoL)
timeFrame: At baseline and every 12 weeks (three-monthly) until progression or up to a maximum of 24 months during 1st line therapy. Within 3 weeks prior to registration, after 12 and 24 weeks during 2nd line therapy.
measure: PFS of third-line treatment
timeFrame: 4 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: Hopital Sud - Amiens
city: Angers
country: France
facility: ICO - Paul Papin
city: Avignon Cedex 9
country: France
facility: Institut Sainte Catherine
city: Blois
country: France
facility: Centre Hospitalier de Blois
city: Bordeaux
country: France
facility: Institut Bergonie
city: Brest
country: France
facility: Hôpital Morvan (Brest)
city: Caen
country: France
facility: Centre Francois Baclesse
city: Contamine-Sur-Arve
country: France
facility: Centre Hospitalier Alpes Leman
city: Dijon Cedex
country: France
facility: Centre Georges François Leclerc
city: Draguignan
country: France
facility: Centre Hospitalier de Dracenie
city: Grenoble
country: France
facility: Hopital Michallon - Centre Hospitalier Universitaire de Grenoble
city: Levallois-Perret
country: France
facility: Clinique Hartmann
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Chu de Limoges - Hopital Dupuytren
city: Lorient Cedex
country: France
facility: Centre Hospitalier - Site Hopital du Scorff
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Marseille
country: France
facility: Fondation Hopital Ambroise Pare - Hopital Europeen
city: Marseille
country: France
facility: Istitut Paoli Calmettes
city: Montpellier
country: France
facility: Institut Regional du Cancer Montpellier Val d'Aurelle
city: Mougins
country: France
facility: Centre Azureen de Cancerologie
city: Nancy
country: France
facility: Polyclinique de Gentilly
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Nice Cedex 2
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Saint Louis
city: Pau
country: France
facility: Centre Hospitalier de Pau
city: Perpignan
country: France
facility: Centre Hospitalier de Perpignan - Hopital Saint Jean
city: Reims
country: France
facility: Institut Jean Godinot
city: Rouen
country: France
facility: Clinique Mathilde
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Herblain
country: France
facility: ICO - Rene Gauducheau
city: Saint-Cloud
country: France
facility: Curie Site Saint-Cloud
city: Saint-Priest-En-Jarez
country: France
facility: Institut de Cancerologie de la Loire
city: Strasbourg
country: France
facility: Hopitaux Universitaire de Strasbourg - Hopital Civil
city: Thonon Les Bains
country: France
facility: Hopitaux du Leman - Site Georges Pianta
city: Toulouse Cedex 9
country: France
facility: Institut Claudius Regaud
city: Valence Cedex 9
country: France
facility: Centre Hospitalier de Valence
city: Ulm
country: Germany
facility: Universitäts-Frauenklinik Ulm
city: Almelo
country: Netherlands
facility: Almelo_Ziekenhuisgroep Twente
city: Amsterdam
country: Netherlands
facility: VUmc University Medical Center
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek / Slotervaart hospital
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haga Ziekenhuis
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Leiden_Leids Universitair Medisch Centrum (LUMC)
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis, Ioc Nieuwegein
city: Rotterdam
country: Netherlands
facility: St. Franciscus Gasthuis Rotterdam
city: Schiedam
country: Netherlands
facility: Vlietland Ziekenhuis
city: Sittard
country: Netherlands
facility: Orbis Medisch Centrum
city: Aarau
country: Switzerland
facility: Hirslanden Klinik Aarau
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Brig
country: Switzerland
facility: RSV-GNW Spitalzentrum Oberwallis
city: Brig
country: Switzerland
facility: Spitalzentrum Oberwallis
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Frauenfeld
country: Switzerland
facility: Kantonsspital Frauenfeld / Brustzentrum Thurgau
city: Genève 14
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois CHUV
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Liestal
country: Switzerland
facility: Kantonsspital Liestal
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: St. Gallen
country: Switzerland
facility: Zentrum fuer Tumordiagnostik und Praevention
city: Thun
country: Switzerland
facility: SpitalSTS AG Simmental-Thun-Saanenland
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: Universitäts Spital Zürich
Study officials:
affiliation: University of Ulm
name: Jens Huober, MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Patrik Weder, MD
role: STUDY_CHAIR
affiliation: Institut Bergonié Bordeaux
name: Hervé Bonnefoi, Prof
role: STUDY_CHAIR
affiliation: Amsterdam UMC, location VUmc
name: Epie Boven, MD
role: STUDY_CHAIR
References: