IMMUN-HER: Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Trastuzumab in HER2+ Breast Cancer Patients

Sponsor

Gruppo Oncologico Italiano di Ricerca Clinica (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03144947

Collaborator

University Hospital of Parma: Department of Biomedical, Biotechnological and Translational Sciences, Pathological Anatomy and Histology Unit (Other), University Hospital of Parma:Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology (Other), University Hospital of Parma:Statistica medica ed epidemiologia clinica-UO Ricerca e Innovazione (Other), Clirest s.r.l. (Other), Mipharm SpA (Other), Arithmos srl (Other), Temas srl (Other)

Enrollment

Locations

Arms

59.1

Anticipated Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase II, Open Label, Randomized, Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Subcutaneous (SC) Trastuzumab in Patients with Operable or Locally Advanced /Inflammatory HER2-positive Breast Cancer (ImmunHER)

Condition or Disease	Intervention/Treatment	Phase
Cancer, Breast	Biological: Trastuzumab IV Biological: Trastuzumab SC Biological: Pertuzumab Drug: Docetaxel	Phase 2

Detailed Description

Women with histologically confirmed HER2-positive breast cancer with locally advanced, inflammatory,or early stage tumor (either greater than 2 cm in diameter or node positive) with no evidence of metastatic disease.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

65 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Non comparative, multi-center, open-label, neoadjuvant, randomized study, the purpose of randomization is to reduce bias owing to patient selection into treatments groups.Non comparative, multi-center, open-label, neoadjuvant, randomized study, the purpose of randomization is to reduce bias owing to patient selection into treatments groups.

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Phase II, Open Label, Randomized, Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Subcutaneous (SC) Trastuzumab in Patients With Operable or Locally Advanced/Inflammatory HER2-positive Breast Cancer (ImmunHER)

Actual Study Start Date :

Nov 29, 2016

Anticipated Primary Completion Date :

Mar 15, 2021

Anticipated Study Completion Date :

Nov 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. After surgery, study patients will receive trastuzumab IV x 14 cycles	Biological: Trastuzumab IV Pre-randomization phase: FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) x 3 cycles Post-randomization phase: Group A: Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2), every 3 weeks for 4 cycles. by 420 mg) plus docetaxel (75 mg/m2), every 3 weeks for 4 cycles. The dose of docetaxel may be escalated to 100 mg/m 2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. After surgery, study patients will receive trastuzumab x 14 cycles using the same formulation (SC or IV) of the preoperative phase. Other Names: Herceptin-150 mg Biological: Pertuzumab* pertuzumab IV (840 mg loading dose, followed by 420 mg) weeks for 4 cycles (both arms) Other Names: PerJeta 420 mg Drug: Docetaxel docetaxel (75 mg/m2), every 3 weeks for 4 cycles (both arms). The dose of docetaxel may be escalated to 100 mg/m2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. Other Names: Docetaxel 20 MG/ML
Experimental: Group B Trastuzumab SC (fixed dose of 600 mg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. After surgery, study patients will receive trastuzumab SC x 14 cycles	Biological: Trastuzumab SC Pre-randomization phase: FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; Group B: Trastuzumab SC (fixed dose of 600 mg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2), every 3 weeks for 4 cycles. The dose of docetaxel may be escalated to 100 mg/m 2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. After surgery, study patients will receive trastuzumab x 14 cycles using the same formulation (SC or IV) of the preoperative phase. Other Names: Herceptin-600 mg/5 mL Biological: Pertuzumab pertuzumab IV (840 mg loading dose, followed by 420 mg) weeks for 4 cycles (both arms) Other Names: PerJeta 420 mg Drug: Docetaxel docetaxel (75 mg/m2), every 3 weeks for 4 cycles (both arms). The dose of docetaxel may be escalated to 100 mg/m2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. Other Names: Docetaxel 20 MG/ML

Arm

Intervention/Treatment

Experimental: Group A

Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. After surgery, study patients will receive trastuzumab IV x 14 cycles

Biological: Trastuzumab IV

Pre-randomization phase: FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) x 3 cycles Post-randomization phase: Group A: Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. *The dose of docetaxel may be escalated to 100 mg/m 2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. After surgery, study patients will receive trastuzumab x 14 cycles using the same formulation (SC or IV) of the preoperative phase.

Other Names:

Herceptin-150 mg

Biological: Pertuzumab

pertuzumab IV (840 mg loading dose, followed by 420 mg) weeks for 4 cycles (both arms)

Other Names:

PerJeta 420 mg

Drug: Docetaxel

docetaxel (75 mg/m2), every 3 weeks for 4 cycles (both arms). The dose of docetaxel may be escalated to 100 mg/m2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated.

Other Names:

Docetaxel 20 MG/ML

Experimental: Group B

Trastuzumab SC (fixed dose of 600 mg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. After surgery, study patients will receive trastuzumab SC x 14 cycles

Biological: Trastuzumab SC

Pre-randomization phase: FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; Group B: Trastuzumab SC (fixed dose of 600 mg) plus pertuzumab IV (840 mg loading dose, followed by 420 mg) plus docetaxel (75 mg/m2)*, every 3 weeks for 4 cycles. *The dose of docetaxel may be escalated to 100 mg/m 2 at the investigator's discretion on subsequent cycles if the initial dose is well tolerated. After surgery, study patients will receive trastuzumab x 14 cycles using the same formulation (SC or IV) of the preoperative phase.

Other Names:

Herceptin-600 mg/5 mL

Biological: Pertuzumab

pertuzumab IV (840 mg loading dose, followed by 420 mg) weeks for 4 cycles (both arms)

Other Names:

PerJeta 420 mg

Drug: Docetaxel

Other Names:

Docetaxel 20 MG/ML

Outcome Measures

Primary Outcome Measures

Tumor Infiltrating lymphocites (TIL) rate on residual disease after either IV trastuzumab or SC trastuzumab (see related paragraph) [6 months after last patient in]
stromal lymphocytes will be scored quantitatively on H&E stained whole-tumor slides as a continuous variable expressed as stromal percentage area within the tumor boundaries. For tumors with heterogeneous TILs, median values will be calculated from multiple counts from different tumor areas. Intra-epithelial TILs will also be recorded as well as tertiary lymphoid structures. Tumor regression will be scored based on recommended criteria.

Secondary Outcome Measures

Associations between biomarkers (TIL, Tumor specific lymphocyte cell activity (TLA), and Fc-gamma-R polymorphisms) and between each biomarker with clinical outcome variables. [at baseline, 6 months and 5 years after last patient in]
Frequency of toxicity Events: frequency of moderate and severe toxicity events and drop-out rate due to theraphy related toxicity (NCICommon Toxicity Criteria v 4.0) [3.5 years]
HRQOL during study treatment based on FACT-B [at baseline, and 6 months after last patient in]
mean FACT-B scores assessed at enrolment and mean FACT-B scores assessed before surgery.
Complete pathological response rate by treatment arm [6 months after last patient in]
5-year disease-free survival by treatment arm between treatment arms [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Previously untreated, infiltrating primary breast cancer with locally advanced, inflammatory, or early stage tumor (either greater than 2 cm in diameter or node positive) with no evidence of metastatic disease.
HER2 positivity (either immunohistochemistry 3+ or fluorescent in situ hybridization amplification).
Age 18 or older.
Eastern Cooperative Oncology Group performance status of 0 to 1.
Availability of tumor tissue for biologic and molecular examination before starting primary treatment.
Left ventricular ejection fraction within the institutional range of normal.
Normal organ and marrow function.
Adequate contraception methods for women of childbearing potential.
Prior diagnosis of cancer is allowed as long as patient is free of disease and has been off treatment for the prior malignancy for a minimal interval of 3 years.
Written informed consent.

Exclusion Criteria:

Either stage I or IV breast cancer.
Prior trastuzumab or pertuzumab.
Any prior chemotherapy.
Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment.
Undergone major surgery (e.g., intrathoracic, intra-abdominal or intra-pelvic) 4 weeks prior to starting study drug or who have not recovered from side effects of such surgery.
Breast radiotherapy prior to starting study.
Known hypersensitivity to the investigational drugs or any of their excipients.
Evidence of any disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an GOIRC-01-2016 ImmunHER Protocol Version 1.0, 11 April 2016 Page 6 of 140 investigational drug, or puts the patient at high risk for treatment-related complications.
Moderate/severe hepatic impairment (Child- Pugh B/C).
Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Concurrent malignancy or malignancy within 3 years prior to study enrollment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or insitu carcinoma of the uterine cervix.
Pregnancy or breastfeeding (breast feeding should be discontinued to be enrolled in the study).
Women of childbearing potential that refusal to adopt adequate contraceptive measures.
Unwilling or unable to comply with the protocol. -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UO di Oncologia Ematologia, Azienda Ospedaliero Universitaria di Ferrara	Cona	Ferrara	Italy	44124
2	UOC Oncologia Medica, Azienda ULSS21 di Legnago	Legnago	Verona	Italy	37045
3	Oncologia Medica, Ospedale Sacro Cuore - Don Calabria - Negrar (VR)	Negrar	Verona	Italy	37024
4	UOC Oncologia-A.O. PAPA GIOVANNI XXIII Bergamo	Bergamo		Italy	24127
5	SSD di Oncologia Medica Addarii, Policlinico S. Orsola-Malpighi,	Bologna		Italy	40138
6	UOC di Oncologia. Azienda USL di Bologna, Ospedale Bellaria,	Bologna		Italy	40139
7	Divisione di Oncologia Medica - Ospedale di Bolzano,	Bolzano		Italy	39100
8	Breast Unit Spedali Civili di Brescia	Brescia		Italy
9	Investigational Clinical Oncology - INCOIRCCS-Fondazione del Piemonte per l'Oncologia (FPO)	Candiolo		Italy	10060
10	Chirurgia generale ad indirizzo senologico-Breast Unit Azienda Istituti Ospitalieri di Cremona	Cremona		Italy	26100
11	Dipartimento di Medicina Interna e Specialità Mediche (DI.M.I.)-Università di Genova Clinica di Medicina Interna ad indirizzo oncologico	Genova		Italy	16132
12	Oncologia Medica, IRST. Istituto Scientifico Romagnolo per lo studio e la cura dei Tumori, IRCCS di Meldola	Meldola (FC)		Italy	47014
13	Dipartimento di Scienze Mediche e Chirurgiche, Materno Infantili e dell'adulto. Policlinico di Modena	Modena		Italy	41124
14	SC di Oncologia Medica, A.O. San Gerardo	Monza		Italy	20900
15	Azienda Ospedaliero-Universitaria di Parma, UOC di Oncologia Medica	Parma		Italy	43100
16	Dipartimento di Oncologia e Ematologia, UO di Oncologia Medica Azienda USL di Piacenza	Piacenza		Italy	29121
17	Struttura Complessa di OncologiaIRCCS- Istituto in Tecnologie Avanzate e Modelli Assistenziali in Oncologia Arcispedale Santa Maria Nuova	Reggio Emilia		Italy	42123
18	UO di Oncologia. Azienda USL di Rimini	Rimini		Italy	47923
19	Day Hospital, Ospedale di Sassuolo	Sassuolo		Italy	41049
20	U.O. di Oncologia Medica PO "S. Chiara"	Trento		Italy	38122
21	Oncologia Medica Az. Ospedaliera di Verona	Verona		Italy	37126

Sponsors and Collaborators

Gruppo Oncologico Italiano di Ricerca Clinica
University Hospital of Parma: Department of Biomedical, Biotechnological and Translational Sciences, Pathological Anatomy and Histology Unit
University Hospital of Parma:Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology
University Hospital of Parma:Statistica medica ed epidemiologia clinica-UO Ricerca e Innovazione
Clirest s.r.l.
Mipharm SpA
Arithmos srl
Temas srl

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Gruppo Oncologico Italiano di Ricerca Clinica

ClinicalTrials.gov Identifier:

NCT03144947

Other Study ID Numbers:

GOIRC-01-2016

First Posted:

May 9, 2017

Last Update Posted:

Oct 14, 2020

Last Verified:

Oct 1, 2020

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 14, 2020