Trastuzumab & Pertuzumab Followed by T-DM1 in MBC

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Completed

CT.gov ID

NCT01835236

Collaborator

(none)

208

Enrollment

Locations

Arms

86.8

Actual Duration (Months)

2.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Trastuzumab Drug: Pertuzumab Drug: Paclitaxel Drug: Vinorelbine Drug: T-DM1	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

208 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 3, 2013

Actual Primary Completion Date :

Jan 11, 2018

Actual Study Completion Date :

May 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Trastuzumab, Pertuzumab, T-DM1 First line therapy: Trastuzumab, Pertuzumab Second line therapy: T-DM1	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. Other Names: Herceptin 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. Other Names: Perjeta 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.) Other Names: Trastuzumab emtansine
Active Comparator: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine plus T-DM1 First line therapy: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine Second line therapy: T-DM1	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. Other Names: Herceptin 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. Other Names: Perjeta Drug: Paclitaxel Day 1, 8 and 15; every 4 weeks for ≥4 months 90 mg/m2 i.v. infusion Other Names: Taxol 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 Other Names: Navelbine 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.) Other Names: Trastuzumab emtansine

Arm

Intervention/Treatment

Active Comparator: Trastuzumab, Pertuzumab, T-DM1

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

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.

Other Names:

Herceptin

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.

Other Names:

Perjeta

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.)

Other Names:

Trastuzumab emtansine

Active Comparator: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine plus T-DM1

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

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.

Other Names:

Herceptin

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.

Other Names:

Perjeta

Drug: Paclitaxel

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

Other Names:

Taxol

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

Other Names:

Navelbine

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.)

Other Names:

Trastuzumab emtansine

Outcome Measures

Primary Outcome Measures

Overall survival (OS) - Analysis Population: ITT Population 1 [24 months]
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

Secondary Outcome Measures

OS - Analysis Population: ITT Population 2 [24 months]
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
Progression Free Survival (PFS) of first-line treatment ignoring first Central Nervous System (CNS) lesion [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 )]
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
PFS of second-line treatment [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)]
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
PFS of second-line treatment ignoring first CNS lesion [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)]
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
Time to failure of strategy (TFS) of first- plus second-line treatment [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 )]
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
Overall survival OS [OS will be calculated from randomization until death (estimated median: 32 months)]
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
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)]
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)]
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)]
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)]
Adverse events (AEs) according to the NCI CTCAE v4.0 of first-line treatment [Throughout first-line treatment (estimated up to 16 months)]
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).
AEs according to the NCI CTCAE v4.0 of second-line treatment [Throughout second-line treatment (estimated up to 9 months)]
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.
AEs grade ≥2 until first progression (ignoring first CNS lesion) [Throughout first-line treatment (estimated up to 16 months)]
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)
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.]
PFS of third-line treatment [4 months]
PFS will be calculated sustained from start of third-line treatment to progression (PD, PD CNS or death)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

SELECTION OF PATIENTS (MOST IMPORTANT CRITERIA)

Inclusion criteria for first-line therapy

• Histologically confirmed breast cancer with distant metastases

Note:

A biopsy from the primary tumor or a metastasis can be used for diagnosis.
Patients with non-measurable lesions are eligible.
Patients with inoperable, locally advanced breast cancer with lymph node metastases other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other distant metastases are eligible.
Patients with bone metastases with or without bone targeted therapy (bisphosphonates, denosumab) are eligible.
Patients with de-novo Stage IV disease are eligible.

HER2-positive tumor according to central pathology testing for HER2

Note:

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.
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:

Adjuvant endocrine treatment is not counted as one line.
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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hopital Sud - Amiens	Amiens	France	80054
2	ICO - Paul Papin	Angers	France	49933
3	Institut Sainte Catherine	Avignon Cedex 9	France	84918
4	Centre Hospitalier de Blois	Blois	France	41016
5	Institut Bergonie	Bordeaux	France	33076
6	Hôpital Morvan (Brest)	Brest	France	29200
7	Centre Francois Baclesse	Caen	France	14076
8	Centre Hospitalier Alpes Leman	Contamine-Sur-Arve	France	74130
9	Centre Georges François Leclerc	Dijon Cedex	France	21079
10	Centre Hospitalier de Dracenie	Draguignan	France	83007
11	Hopital Michallon - Centre Hospitalier Universitaire de Grenoble	Grenoble	France	38043
12	Clinique Hartmann	Levallois-Perret	France	92300
13	Centre Oscar Lambret	Lille	France	59020
14	Chu de Limoges - Hopital Dupuytren	Limoges	France	87042
15	Centre Hospitalier - Site Hopital du Scorff	Lorient Cedex	France	56322
16	Clinique de la Sauvegarde	Lyon	France	69009
17	Fondation Hopital Ambroise Pare - Hopital Europeen	Marseille	France	13003
18	Istitut Paoli Calmettes	Marseille	France	13273
19	Institut Regional du Cancer Montpellier Val d'Aurelle	Montpellier	France	34298
20	Centre Azureen de Cancerologie	Mougins	France	6250
21	Polyclinique de Gentilly	Nancy	France	54100
22	Centre Catherine de Sienne	Nantes	France	44202
23	Centre Antoine Lacassagne	Nice Cedex 2	France	6189
24	Hopital Saint Louis	Paris	France	75475
25	Centre Hospitalier de Pau	Pau	France	64046
26	Centre Hospitalier de Perpignan - Hopital Saint Jean	Perpignan	France	66046
27	Institut Jean Godinot	Reims	France	51726
28	Clinique Mathilde	Rouen	France	76000
29	Centre Henri Becquerel	Rouen	France	76038
30	ICO - Rene Gauducheau	Saint Herblain	France	44805
31	Curie Site Saint-Cloud	Saint-Cloud	France	92210
32	Institut de Cancerologie de la Loire	Saint-Priest-En-Jarez	France	42271
33	Hopitaux Universitaire de Strasbourg - Hopital Civil	Strasbourg	France	67091
34	Hopitaux du Leman - Site Georges Pianta	Thonon Les Bains	France	74203
35	Institut Claudius Regaud	Toulouse Cedex 9	France	31059
36	Centre Hospitalier de Valence	Valence Cedex 9	France	26953
37	Universitäts-Frauenklinik Ulm	Ulm	Germany	89075
38	Almelo_Ziekenhuisgroep Twente	Almelo	Netherlands	7609 PP
39	VUmc University Medical Center	Amsterdam	Netherlands	1007
40	Antoni van Leeuwenhoek / Slotervaart hospital	Amsterdam	Netherlands	1066 CX
41	Reinier de Graaf Gasthuis	Delft	Netherlands	2625 AD
42	Haga Ziekenhuis	Den Haag	Netherlands	2545 CH
43	Deventer Ziekenhuis	Deventer	Netherlands	7416 SE
44	Catharina Ziekenhuis	Eindhoven	Netherlands	5623 EJ
45	Medisch Centrum Leeuwarden	Leeuwarden	Netherlands	8934 AD
46	Leiden_Leids Universitair Medisch Centrum (LUMC)	Leiden	Netherlands	2333 ZA
47	St. Antonius Ziekenhuis, Ioc Nieuwegein	Nieuwegein	Netherlands	3430 EM
48	St. Franciscus Gasthuis Rotterdam	Rotterdam	Netherlands	3045 PM
49	Vlietland Ziekenhuis	Schiedam	Netherlands	3118 JH
50	Orbis Medisch Centrum	Sittard	Netherlands	6162 BG
51	Hirslanden Klinik Aarau	Aarau	Switzerland	CH-5001
52	Kantonspital Aarau	Aarau	Switzerland	CH-5001
53	Kantonsspital Baden	Baden	Switzerland	5404
54	Universitaetsspital-Basel	Basel	Switzerland	4031
55	Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli	Bellinzona	Switzerland	6500
56	Inselspital, Bern	Bern	Switzerland	CH-3010
57	RSV-GNW Spitalzentrum Oberwallis	Brig	Switzerland	3900
58	Spitalzentrum Oberwallis	Brig	Switzerland	3900
59	Kantonsspital Graubuenden	Chur	Switzerland	7000
60	Kantonsspital Frauenfeld / Brustzentrum Thurgau	Frauenfeld	Switzerland	8501
61	Hopitaux Universitaires de Geneve	Genève 14	Switzerland	1211
62	Centre Hospitalier Universitaire Vaudois CHUV	Lausanne	Switzerland	CH-1011
63	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011
64	Kantonsspital Liestal	Liestal	Switzerland	CH-4410
65	Kantonsspital Luzern	Luzerne	Switzerland	CH-6000
66	Kantonsspital Olten	Olten	Switzerland	4600
67	Kantonsspital St. Gallen	St. Gallen	Switzerland	9007
68	Zentrum fuer Tumordiagnostik und Praevention	St. Gallen	Switzerland	CH-9006
69	SpitalSTS AG Simmental-Thun-Saanenland	Thun	Switzerland	3600
70	Kantonsspital Winterthur	Winterthur	Switzerland	8401
71	Universitäts Spital Zürich	Zürich	Switzerland	8091