Trastuzumab & Pertuzumab Followed by T-DM1 in MBC

Overview[ - collapse ][ - ]

Purpose 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.
ConditionHER2-positive Metastatic Breast Cancer
InterventionDrug: Trastuzumab
Drug: Pertuzumab
Drug: Paclitaxel
Drug: Vinorelbine
Drug: T-DM1
PhasePhase 2
SponsorSwiss Group for Clinical Cancer Research
Responsible PartySwiss Group for Clinical Cancer Research
ClinicalTrials.gov IdentifierNCT01835236
First ReceivedApril 15, 2013
Last UpdatedFebruary 7, 2014
Last verifiedFebruary 2014

Tracking Information[ + expand ][ + ]

First Received DateApril 15, 2013
Last Updated DateFebruary 7, 2014
Start DateJuly 2013
Estimated Primary Completion DateJune 2019
Current Primary Outcome MeasuresOverall survival (OS) - Analysis Population: ITT Population 1 [Time Frame: 24 months] [Designated as safety issue: No]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
Current Secondary Outcome Measures
  • OS - Analysis Population: ITT Population 2 [Time Frame: 24 months] [Designated as safety issue: No]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 [Time Frame: 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 )] [Designated as safety issue: No]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 [Time Frame: 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)] [Designated as safety issue: No]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 [Time Frame: 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)] [Designated as safety issue: No]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 [Time Frame: 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 )] [Designated as safety issue: No]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 [Time Frame: OS will be calculated from randomization until death (estimated median: 32 months)] [Designated as safety issue: No]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) [Time Frame: 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)] [Designated as safety issue: No]
  • Disease control (DC) of first-line treatment (based on investigator assessment) [Time Frame: 6 months (DC is defined as CR, PR or SD for 6 months after randomization and no PD at 6 month after randomization)] [Designated as safety issue: No]
  • OR of second-line treatment (based on investigator assessment) [Time Frame: 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)] [Designated as safety issue: No]
  • DC of second-line treatment (based on investigator assessment) [Time Frame: 6 months (DC is defined as the response CR, PR or SD for 6 months after registration of second-line treatment)] [Designated as safety issue: No]
  • Adverse events (AEs) according to the NCI CTCAE v4.0 of first-line treatment [Time Frame: Throughout first-line treatment (estimated up to 16 months)] [Designated as safety issue: Yes]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 [Time Frame: Throughout second-line treatment (estimated up to 9 months)] [Designated as safety issue: Yes]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) [Time Frame: Throughout first-line treatment (estimated up to 16 months)] [Designated as safety issue: Yes]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) [Time Frame: 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.] [Designated as safety issue: No]
  • PFS of third-line treatment [Time Frame: 4 months] [Designated as safety issue: No]PFS will be calculated sustained from start of third-line treatment to progression (PD, PD CNS or death)

Descriptive Information[ + expand ][ + ]

Brief TitleTrastuzumab & Pertuzumab Followed by T-DM1 in MBC
Official TitleA 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
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.
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionHER2-positive Metastatic Breast Cancer
InterventionDrug: 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:
HerceptinDrug: 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:
PerjetaDrug: Paclitaxel
Day 1, 8 and 15; every 4 weeks for ≥4 months 90 mg/m2 i.v. infusion
Other Names:
TaxolDrug: 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:
NavelbineDrug: 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
Study Arm (s)
  • Active Comparator: Trastuzumab, Pertuzumab, T-DM1
    First line therapy: Trastuzumab, Pertuzumab Second line therapy: T-DM1
  • Active Comparator: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine plus T-DM1
    First line therapy: Trastuzumab, Pertuzumab, Paclitaxel or Vinorelbine Second line therapy: T-DM1

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment208
Estimated Completion DateJune 2019
Estimated Primary Completion DateJune 2015
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:

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)
GenderFemale
Ages18 Years
Accepts Healthy VolunteersNo
ContactsContact: Marie-Aline Gerard, PhD
+41 31 389 91 84
marie-aline.gerard@sakk.ch
Location CountriesFrance, Switzerland

Administrative Information[ + expand ][ + ]

NCT Number NCT01835236
Other Study ID NumbersSAKK 22/10
Has Data Monitoring CommitteeNo
Information Provided BySwiss Group for Clinical Cancer Research
Study SponsorSwiss Group for Clinical Cancer Research
CollaboratorsNot Provided
Investigators Study Chair: Jens Huober, MD University of UlmStudy Chair: Patrik Weder, MD Cantonal Hospital of St. GallenStudy Chair: Hervé Bonnefoi, Prof Institut Bergonié, BordeauxStudy Chair: Epie Boven, MD VU University medical center Amsterdam
Verification DateFebruary 2014

Locations[ + expand ][ + ]

Centre Georges-François Leclerc
Dijon, France, 21079
Contact: Gilles Crehange, MD | +33 3 80 73 75 18 | gcrehange@cgfl.fr
Principal Investigator: Gilles Crehange, MD
Recruiting
CHU Le Bocage
Dijon Cedex, France, 21079
Contact: Laurent Bedenne, MD | +33 3 80 29 37 50 | lbedenne@u-bourgogne.fr
Principal Investigator: Laurent Bedenne, MD
Recruiting
Centre Bourgogne
Lille, France, 59000
Contact: Philippe Martin, MD | +33 3 20 00 97 57 | pmartin@centre-bourgogne.com
Principal Investigator: Philippe Martin, MD
Recruiting
Clinique François Chénieux
Limoges, France, 87000
Contact: Dominique Genet, MD | +33 5 55 45 48 00 | dg@imagemed-87.com
Principal Investigator: Dominique Genet, MD
Recruiting
Hopital Edouard Herriot - Lyon
Lyon, France, 69437
Contact: Contact Person | 33-4-72-11-7398
Recruiting
CHU la TIMONE
Marseille, France, 13385
Contact: Jean-François Seitz, MD | +33 4 91 38 60 23 | Jean-francois.SEITZ@ap-hm.fr
Principal Investigator: Jean-François Seitz, MD
Recruiting
CH Régional de la Source
Orleans, France, 45067
Contact: Rémy Leloup, MD | +33 2 38 51 47 78 | remy.leloup@chr-orleans.fr
Principal Investigator: Rémy Leloup, MD
Recruiting
CH Saint Jean
Perpignan Cedex, France, 66046
Contact: Faiza Khemissa Akouz, MD | +33 4 68 61 61 37 | faiza.khemissa@ch-perpignan.fr
Principal Investigator: Faiza Khemissa Akouz, MD
Recruiting
Hopital Haut Leveque
Pessac, France, 33604
Contact: Contact Person | 33-55-765-6565
Recruiting
Hôpital Haut Leveque
Pessac Cedex, France, 33604
Contact: Denis Collet, MD | +33 5 56 55 64 38 | denis.collet@chu-bordeaux.fr
Principal Investigator: Denis Collet, MD
Recruiting
CHU
Rennes Cedex 9, France, 35033
Contact: Bernard Meunier, MD | +33 2 99 28 90 03 | bernard.meunier@chu-rennes.fr
Principal Investigator: Bernard Meunier, MD
Recruiting
CHU de Saint Etienne - Hôpital Nord
St Priest En Jarez, France, 42277
Contact: Jean-Marc Phelip, MD | +33 4 77 82 83 20 | j.marc.phelip@chu-st-etienne.fr
Principal Investigator: Jean-Marc Phelip, MD
Recruiting
Centre Paul Strauss
Strasbourg, France, 67065
Contact: Contact Person | 33-3-88-252-401
Recruiting
Hôpital Purpan
Toulouse, France, 31509
Contact: Nicolas Carrere, MD | +33 5 61 77 76 10 | carrere.n@chu-toulouse.fr
Principal Investigator: Nicolas Carrere, MD
Recruiting
Centre Hospitalier Universitaire Bretonneau de Tours
Tours, France, 37044
Contact: Contact Person | 32-24-747-3712
Recruiting
Hirslanden Klinik Aarau
Aarau, Switzerland, CH-5001
Contact: Razvan Popescu, MD | 41-62-836-7800 | Razvan.Popescu@hirslanden.ch
Principal Investigator: Razvan Popescu, MD
Recruiting
Kantonspital Aarau
Aarau, Switzerland, CH-5001
Contact: Alexander Schreiber, MD | 41-62-838-6053 | alexander.schreiber@ksa.ch
Principal Investigator: Alexander Schreiber, MD
Recruiting
Zuger Kantonsspital AG - Frauenklinik
Baar, Switzerland, 6340
Contact: Christoph M. Honegger, MD | +41 41 399 32 00 | christoph.honegger@zgks.ch
Principal Investigator: Christoph M. Honegger, MD
Recruiting
Kantonsspital Baden
Baden, Switzerland, 5404
Contact: Clemens Caspar, MD | +41 56 486 25 11 | clemens.caspar@ksb.ch
Principal Investigator: Caspar Clemens, MD
Recruiting
Saint Claraspital AG
Basel, Switzerland, CH-4016
Contact: Christian Ulrich Ludwig, MD | 41-61-685-8470 | christian.ludwig@claraspital.ch
Principal Investigator: Christian Ulrich Ludwig, MD
Recruiting
Universitaetsspital-Basel
Basel, Switzerland, 4031
Contact: Christoph Rochlitz, Prof | +41 61 265 50 74 | crochlitz@uhbs.ch
Principal Investigator: Christoph Rochlitz, Prof
Recruiting
Inselspital, Bern
Bern, Switzerland, CH-3010
Contact: Manuela Rabaglio, MD | +41 31 632 41 14 | manuela.rabaglio@insel.ch
Principal Investigator: Manuela Rabaglio, MD
Recruiting
Spitalzentrum Biel
Biel, Switzerland, CH-2501
Contact: Markus Borner, Prof. | 41-32-324-3714 | markus.borner@szb-chb.ch
Principal Investigator: Markus Borner, Prof
Recruiting
Kantonsspital Bruderholz
Bruderholz, Switzerland, CH-4101
Contact: Lorenz M. Jost, MD | 41-61-436-3636 | lorenz.jost@ksbh.ch
Principal Investigator: Lorenz M. Jost, MD
Recruiting
Kantonsspital Graubuenden
Chur, Switzerland, 7000
Contact: Stefan Greuter, MD | +41 81 256 61 11 | stefan.greuter@ksgr.ch
Principal Investigator: Stefan Greuter, MD
Recruiting
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, CH-1011
Contact: Khalil Zaman, MD | 41-21-314-4658 | khalil.zaman@chuv.ch
Principal Investigator: Khalil Zaman, MD
Recruiting
Centre Hospitalier Universitaire Vaudois CHUV
Lausanne, Switzerland, CH-1011
Contact: Dominik Berthold, MD | +41 21 314 80 83 | Dominik.Berthold@chuv.ch
Principal Investigator: Dominik Berthold, MD
Recruiting
Kantonsspital Liestal
Liestal, Switzerland, CH-4410
Contact: Andreas Lohri, MD | 41-61-925-2710 | andreas.lohri@ksli.ch
Principal Investigator: Andreas Lohri, MD
Recruiting
Kantonsspital Luzern
Luzerne, Switzerland, CH-6000
Contact: Stefan Aebi, Prof | +41 41 205 58 60 | stefan.aebi@onkologie.ch
Principal Investigator: Stefan Aebi, Prof
Recruiting
Kantonsspital Olten
Olten, Switzerland, 4600
Contact: Catrina Uhlmann Nussbaum, MD | +41 62 311 42 41 | cuhlmann_ol@spital.ktso.ch
Principal Investigator: Catrina Uhlmann Nussbaum, MD
Recruiting
Zentrum fuer Tumordiagnostik und Praevention
St. Gallen, Switzerland, CH-9006
Contact: Rudolf Morant, MD | 41-71-243-0043 | rmorant@sg.zetup.ch
Principal Investigator: Rudolf Morant, MD
Recruiting
SpitalSTS AG Simmental-Thun-Saanenland
Thun, Switzerland, 3600
Contact: Daniel Rauch | +41 33 226 26 45 | daniel.rauch@spitalstsag.ch
Principal Investigator: Daniel Rauch, MD
Recruiting
Kantonsspital Winterthur
Winterthur, Switzerland, 8401
Contact: Andreas Müller, MD | +41 52 266 25 52 | andreas.mueller@ksw.ch
Principal Investigator: Andreas Müller, MD
Recruiting
Universitäts Spital Zürich
Zürich, Switzerland, 8091
Contact: Cornelia Leo, MD | +41 44 255 51 50 | cornelia.leo@usz.ch
Principal Investigator: Cornelia Leo, MD
Recruiting