Trastuzumab & Pertuzumab Followed by T-DM1 in MBC

Metastatic Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01835236
• Other study ID #: SAKK 22/10
• Secondary ID: 2012-002556-17UN
• Status: Completed
• Phase: Phase 2
• Start date: March 3, 2013
• Est. completion date: May 26, 2020

Study information

• Verified date: March 2021
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 208
• Est. completion date: May 26, 2020
• Est. primary completion date: January 11, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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:

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)

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• 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.
• 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.
• Paclitaxel
Day 1, 8 and 15; every 4 weeks for =4 months 90 mg/m2 i.v. infusion
• 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
• 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.)

Locations

Country	Name	City	State
France	Hopital Sud - Amiens	Amiens
France	ICO - Paul Papin	Angers
France	Institut Sainte Catherine	Avignon Cedex 9
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 Cedex
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 Cedex
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 Cedex 2
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	Centre Henri Becquerel	Rouen
France	Clinique Mathilde	Rouen
France	ICO - Rene Gauducheau	Saint Herblain
France	Curie Site Saint-Cloud	Saint-Cloud
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 Cedex 9
France	Centre Hospitalier de Valence	Valence Cedex 9
Germany	Universitäts-Frauenklinik Ulm	Ulm
Netherlands	Almelo_Ziekenhuisgroep Twente	Almelo
Netherlands	Antoni van Leeuwenhoek / Slotervaart hospital	Amsterdam
Netherlands	VUmc University Medical Center	Amsterdam
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	Haga Ziekenhuis	Den Haag
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
Switzerland	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	Genève 14
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Centre Hospitalier Universitaire Vaudois CHUV	Lausanne
Switzerland	Kantonsspital Liestal	Liestal
Switzerland	Kantonsspital Luzern	Luzerne
Switzerland	Kantonsspital Olten	Olten
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Zentrum fuer Tumordiagnostik und Praevention	St. Gallen
Switzerland	SpitalSTS AG Simmental-Thun-Saanenland	Thun
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Universitäts Spital Zürich	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

France,  Germany,  Netherlands,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS) - Analysis Population: ITT Population 1	Patients being alive 24 months after randomization. A success is considered if a patient is alive at least 24 months after randomization. Analysis Population: ITT Population 1	24 months
Secondary	OS - Analysis Population: ITT Population 2	Proportion of patients being alive 24 months after randomization. A success is considered if a patient is alive at least 24 months after randomization. Analysis Population: ITT Population 2	24 months
Secondary	Progression Free Survival (PFS) of first-line treatment ignoring first Central Nervous System (CNS) lesion	PFS of first-line treatment ignoring first CNS lesion is the time from randomization to first event progression. A PFS of first-line treatment ignoring first CNS lesion event is defined as (whichever occurs first): Disease progression (PD) after having received first-line treatment and prior to the next treatment; Death due to any reason Patients without events will be censored at last tumor assessment date without PFS ignoring first CNS lesion event during the first-line treatment period or prior to starting new treatment.; Analysis population: ITT Population 1	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 )
Secondary	PFS of second-line treatment	PFS of second-line treatment is the time from registration of second-line treatment to progression. A PFS event of second-line treatment is defined as (whichever occurs first): Disease progression after having received second-line treatment and prior to the next treatment; PD CNS after having received first-line treatment and prior to the next treatment; Death due any reason during the second-line treatment period Patients without events will be censored at last tumor assessment date without PD and PD CNS during the second-line treatment period or prior to starting new treatment.; Analysis Population: ITT Population 2	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)
Secondary	PFS of second-line treatment ignoring first CNS lesion	PFS of second-line treatment ignoring first CNS lesion is the time from registration of second-line treatment to the first event occurs. A PFS of second-line treatment ignoring first CNS lesion event is defined as (whichever occurs first): Disease progression after having received second-line treatment and prior to the next treatment; Death due any reason during the second-line treatment period Patients without events will be censored at last tumor assessment date without PFS ignoring first CNS lesion event during the second-line treatment period or prior to starting new treatment.; Analysis Population: ITT Population 2	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)
Secondary	Time to failure of strategy (TFS) of first- plus second-line treatment	TFS of first plus second-line treatment is the time from randomization to TFS event occurs. A TFS event of first plus second-line treatment is defined as (whichever occurs first): Disease progression after having received the first and second-line treatment and prior to the next treatment; PD CNS after having received first- and second-line treatment and prior to the next treatment; Death due to tumor prior to the third-line treatment Patients without events will be censored at last tumor assessment without PD and PD CNS during first and second-line treatment period or prior to starting new treatment.; Analysis Population: ITT Population 1	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 )
Secondary	Overall survival OS	OS will be calculated from randomization until death. Patients still alive or lost of follow up are censored at their last date known alive.; Analysis Population: ITT Population 1	OS will be calculated from randomization until death (estimated median: 32 months)
Secondary	Objective response (OR) of first-line treatment (based on investigator assessment)		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)
Secondary	Disease control (DC) of first-line treatment (based on investigator assessment)		6 months (DC is defined as CR, PR or SD for 6 months after randomization and no PD at 6 month after randomization)
Secondary	OR of second-line treatment (based on investigator assessment)		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)
Secondary	DC of second-line treatment (based on investigator assessment)		6 months (DC is defined as the response CR, PR or SD for 6 months after registration of second-line treatment)
Secondary	Adverse events (AEs) according to the NCI CTCAE v4.0 of first-line treatment	Adverse events are assessed by the NCI CTCAE v4.0. from registration until registration of second-line treatment or start of follow-up (which occurs first).	Throughout first-line treatment (estimated up to 16 months)
Secondary	AEs according to the NCI CTCAE v4.0 of second-line treatment	Adverse events are assessed by the NCI CTCAE v4.0.from second-line registration until PD or start of follow-up (which occurs first) plus 30 days.	Throughout second-line treatment (estimated up to 9 months)
Secondary	AEs grade =2 until first progression (ignoring first CNS lesion)	Adverse events are assessed by Common terminology criteria for adverse events (CTCAE) v4.0. From randomization until first progression (documented PD, PD CNS or death)	Throughout first-line treatment (estimated up to 16 months)
Secondary	Quality of Life (QoL)		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.
Secondary	PFS of third-line treatment	PFS will be calculated sustained from start of third-line treatment to progression (PD, PD CNS or death)	4 months