Neoadjuvant Chemotherapy in HER2 Positive Breast Cancer, TRAIN-2

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01996267

Collaborator

Roche Pharma AG (Industry), Borstkanker Onderzoek Groep (Other)

437

Enrollment

Locations

Arms

132

Duration (Months)

13.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study compares two schedules of upfront chemotherapy in HER positive breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer HER2 Positive	Drug: PTC+Pertuzumab Drug: FEC-T+Pertuzumab	Phase 3

Detailed Description

Upfront trastuzumab treatment is beneficial to patients with HER2 positive breast cancer. The potential synergistic cardiotoxicity of trastuzumab and anthracyclines has led to the development of non-anthracycline containing regimens, which have shown high pathologic complete response rates. Anthracyclines remain very active in HER2 positive breast cancer, however, and increasing evidence now supports safe combination of trastuzumab and epirubicin. Therefore, the addition of epirubicin to a non-anthracycline containing regimen may further improve outcome for patients with HER2 positive breast cancer.

Several reports confirmed benefit of dual HER2 blockade by adding pertuzumab to a trastuzumab containing neoadjuvant regimen. The results of the combined treatment in the Neosphere study, however, are similar to what we found in a phase II trial using a weekly paclitaxel, trastuzumab, carboplatin combination with pCR rates of approximately 44%. Adding pertuzumab to this regimen is likely to also increase the high pCR rate and to add substantial benefit to patients.

Study Design

Study Type:

Interventional

Actual Enrollment :

437 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Optimizing Neoadjuvant Systemic Treatment for HER2 Positive Breast Cancer - the TRAIN-2 Study

Study Start Date :

Dec 1, 2013

Actual Primary Completion Date :

Dec 1, 2018

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: FEC-T +Pertuzumab Fluorouracil; 500 mg/m2; day 1 Epirubicine; 90 mg/m2; day 1 Cyclophosphamide; 500 mg/m2; day 1 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg) Pertuzumab; 420 mg (loading dose 840 mg); day 1 Cycle is repeated every 21 days	Drug: FEC-T+Pertuzumab Cycle is repeated every 21 days Other Names: Fluorouracil; 500 mg/m2; day 1 Epirubicine; 90 mg/m2; day 1 Cyclophosphamide 500 mg/m2; day 1 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg) Pertuzumab; 420 mg (loading dose 840 mg); day 1
Active Comparator: PTC+Pertuzumab Paclitaxel; 80 mg/m2; day 1,8 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg); day 1 Carboplatin; AUC=6; day 1 Pertuzumab; 420 mg (loading dose 840 mg); day 1 Cycle repeated every 21 days	Drug: PTC+Pertuzumab Cycle repeated every 21 days Other Names: Paclitaxel; 80 mg/m2; day 1,8 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg); day 1 Carboplatin; AUC=6; day 1 Pertuzumab; 420 mg (loading dose 840 mg); day 1

Arm

Intervention/Treatment

Active Comparator: FEC-T +Pertuzumab

Fluorouracil; 500 mg/m2; day 1 Epirubicine; 90 mg/m2; day 1 Cyclophosphamide; 500 mg/m2; day 1 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg) Pertuzumab; 420 mg (loading dose 840 mg); day 1 Cycle is repeated every 21 days

Drug: FEC-T+Pertuzumab

Cycle is repeated every 21 days

Other Names:

Fluorouracil; 500 mg/m2; day 1

Epirubicine; 90 mg/m2; day 1

Cyclophosphamide 500 mg/m2; day 1

Trastuzumab; 6 mg/kg (loading dose 8 mg/kg)

Pertuzumab; 420 mg (loading dose 840 mg); day 1

Active Comparator: PTC+Pertuzumab

Paclitaxel; 80 mg/m2; day 1,8 Trastuzumab; 6 mg/kg (loading dose 8 mg/kg); day 1 Carboplatin; AUC=6; day 1 Pertuzumab; 420 mg (loading dose 840 mg); day 1 Cycle repeated every 21 days

Drug: PTC+Pertuzumab

Cycle repeated every 21 days

Other Names:

Paclitaxel; 80 mg/m2; day 1,8

Trastuzumab; 6 mg/kg (loading dose 8 mg/kg); day 1

Carboplatin; AUC=6; day 1

Pertuzumab; 420 mg (loading dose 840 mg); day 1

Outcome Measures

Primary Outcome Measures

Number of patients with pathological complete response [at week 30]
To compare the efficacy of six cycles neoadjuvant PTC plus pertuzumab preceded by either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab in HER2 positive breast cancer

Secondary Outcome Measures

Number of patients with grade >2 adverse events as a measure of safety and tolerability [up to week 35]
to describe the safety of the various regimens toxicity is compared between the two arms
identify prognostic and predictive biomarkers for pCR [within one year after end of treatment]
To identify prognostic and predictive biomarkers for pCR after neoadjuvant treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed infiltrating breast cancer
Stage II or stage III disease. Nodal status must be examined by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan.
Overexpression and/or amplification of HER2 in an invasive component of the core biopsy, according to one of the following definitions:

•>30% of invasive tumor cells showing strong complete circumferential membrane staining (score 3+)

•HER2 gene amplification defined as >6 HER2 gene copies per nucleus by in situ hybridization.

Age ≥18
Eastern Cooperative Oncology Group performance status ≤1
Adequate bone marrow function (ANC >1.5 x 109/l, platelets >100 x 109/l)
Adequate hepatic function (ALAT, ASAT and bilirubin <2.5 times upper limit of normal)
Adequate renal function (creatinine clearance >50 ml/min)
LVEF ≥50% measured by echocardiography or MUGA
Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Absence of any medical condition that would place the patient at unusual risk.
Signed written informed consent

Exclusion Criteria:

previous radiation therapy or chemotherapy
other malignancy except carcinoma in situ, unless the other malignancy was treated ≥5 years ago with curative intent without the use of chemotherapy or radiation therapy.
current pregnancy or breastfeeding. Women of childbearing potential must use adequate contraceptive protection
evidence of distant metastases. Evaluation of the presence of distant metastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of chest and abdomen and/or FDG-PET scan, according to local procedures.
evidence of bilateral infiltrating breast cancer. Evaluation of the presence of bilateral infiltrating breast cancer may include mammography, breast ultrasound and/or MRI breast.
concurrent anti-cancer treatment or another investigational drug.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	MCA	Alkmaar	Netherlands	1815 JD
2	ZGT	Almelo	Netherlands	7609 PP
3	Antoni van Leeuwenhoek	Amsterdam	Netherlands	1066 CX
4	AZVU	Amsterdam	Netherlands	1081 HV
5	OLVG	Amsterdam	Netherlands	1090 HM
6	Rode Kruis Ziekenhuis	Beverwijk	Netherlands	1940 EB
7	Amphia ziekenhuis	Breda	Netherlands	4819 EV
8	Reinier de Graaf Groep	Delft	Netherlands	2625 AD
9	Jeroen Bosch Hospital	Den Bosch	Netherlands
10	Haga	Den Haag	Netherlands	2545 CH
11	Bronovo Ziekenhuis	den Haag	Netherlands	2597 AX
12	Deventer ziekenhuis	Deventer	Netherlands	7416 SE
13	Ziekenhuis Gelderse Vallei	Ede	Netherlands	6716 RP
14	Catharina Ziekenhuis	Eindhoven	Netherlands	5602 ZA
15	Maxima Medisch Centrum	Eindhoven	Netherlands	5631 BM
16	St Anna Geldrop	Geldrop	Netherlands	5664 EH
17	Orbis Medisch Centrum	Geleen	Netherlands	6162 BG
18	Groene Hart	Gouda	Netherlands	2803 HH
19	Kennemer Gasthuis	Haarlem	Netherlands	2035 RC
20	Atrium Medisch Centrum Parkstad	Heerlen	Netherlands	6401 CX
21	Spaarne ziekenhuis	Hoofddorp	Netherlands	2134 TM
22	Westfries Gasthuis	Hoorn	Netherlands	1624 NP
23	MCL	Leeuwarden	Netherlands	8934 AD
24	LUMC	Leiden	Netherlands	2300 RC
25	Diaconessenhuis Meppel	Meppel	Netherlands	7943 KA
26	Canisius-Wilhelmina Hospital	Nijmegen	Netherlands
27	Waterlandziekenhuis	Purmerend	Netherlands	1441 RN
28	Vlietland Ziekenhuis	Schiedam	Netherlands	3100 AE
29	St. Elisabeth	Tilburg	Netherlands	5022 GC
30	Diaconessenhuis Utrecht	Utrecht	Netherlands	3582 KE
31	VieCuri Medisch Centrum voor Noord-Limburg	Venlo	Netherlands
32	Zaans Medisch Centrum	Zaandam	Netherlands	1502 DV
33	Isala Klinieken	Zwolle	Netherlands	8025 AB