GIADA: Neoadjuvant Chemo-endocrine Therapy and Immunotherapy for Pre-menopausal Luminal B Breast Cancer Patients

Sponsor

Istituto Oncologico Veneto IRCCS (Other)

Overall Status

Completed

CT.gov ID

NCT04659551

Collaborator

University of Padova (Other)

Enrollment

Locations

Arm

31.6

Actual Duration (Months)

8.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Multicentric, phase II neoadjuvant trial in hormone-positive, HER-negative, luminal B, premenopausal breast cancer patients stage II-IIIA. Patients receive as neoadjuvant treatment before surgery: three courses of anthracycline-based chemotherapy followed by exemestane p.o. daily plus nivolumab i.v. 2-weekly for 8 courses. GnRH analogues are started concomitantly with chemotherapy and maintained until the completion of neoadjuvant treatment.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Epirubicin Drug: Cyclophosphamide Drug: Triptorelin Drug: Exemestane Drug: Nivolumab	Phase 2

Detailed Description

This is a multicenter, phase II neoadjuvant trial in hormone-sensitive, HER-negative, luminal B, premenopausal breast cancer patients stage II-IIIA.

Patients will undergo a core-biopsy of the primary tumor, for the histological diagnosis and the biological characterization of the tumor.

After confirmation of eligibility and informed consent signature, the patients will start neoadjuvant treatment including:

Epirubicin 90 mg/mq + Cyclophosphamide 600 mg/mq i.v. every 3 weeks for 3 courses, followed by the combination of Nivolumab (240 mg flat dose i.v. each 2 weeks) for 8 courses and exemestane 25 mg (orally, continuous daily dose, to be continued until surgery). Patients will start LHRH analogue (Triptorelin 3.75mg 1 fl i.m. every 28 days) concomitantly to anthracycline-based chemotherapy, to be continued until surgery.

Study Design

Study Type:

Interventional

Actual Enrollment :

43 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Engaging the Immune System to Improve the Efficacy of Neoadjuvant Chemo-endocrine Therapy for Premenopausal Luminal B Breast Cancer Patients

Actual Study Start Date :

Oct 5, 2017

Actual Primary Completion Date :

May 25, 2020

Actual Study Completion Date :

May 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Epirubicin 90 mg/mq + Cyclophosphamide 600 mg/mq i.v. every 3 weeks for 3 courses, followed by Nivolumab (240 mg flat dose i.v. each 2 weeks) for 8 courses plus exemestane 25 mg (orally, continuous daily dose, to be continued until surgery). LHRH analogue (Triptorelin 3.75mg 1 fl i.m. every 28 days) started concomitantly to anthracycline based chemotherapy, to be continued until surgery.	Drug: Epirubicin Epirubicin 90 mg/mq i.v. every 3 weeks for three cycles Drug: Cyclophosphamide Cyclophosphamid 600 mg/mq i.v. every 3 weeks for three cycles Drug: Triptorelin Triptorelin 3.75 mg i.m. every 4 weeks until surgery Drug: Exemestane Exemestane 25 mg oral continuous daily dose until surgery Drug: Nivolumab Nivolumab 240 mg flat dose i.v. every two weeks for 8 cycles Other Names: BMS-936558

Arm

Intervention/Treatment

Experimental: Arm 1

Epirubicin 90 mg/mq + Cyclophosphamide 600 mg/mq i.v. every 3 weeks for 3 courses, followed by Nivolumab (240 mg flat dose i.v. each 2 weeks) for 8 courses plus exemestane 25 mg (orally, continuous daily dose, to be continued until surgery). LHRH analogue (Triptorelin 3.75mg 1 fl i.m. every 28 days) started concomitantly to anthracycline based chemotherapy, to be continued until surgery.

Drug: Epirubicin

Epirubicin 90 mg/mq i.v. every 3 weeks for three cycles

Drug: Cyclophosphamide

Cyclophosphamid 600 mg/mq i.v. every 3 weeks for three cycles

Drug: Triptorelin

Triptorelin 3.75 mg i.m. every 4 weeks until surgery

Drug: Exemestane

Exemestane 25 mg oral continuous daily dose until surgery

Drug: Nivolumab

Nivolumab 240 mg flat dose i.v. every two weeks for 8 cycles

Other Names:

BMS-936558

Outcome Measures

Primary Outcome Measures

pathological complete response (pCR) [up to 7 months from enrolment]
ypT0ypN0

Secondary Outcome Measures

clinical objective response [up to 6 months from enrolment]
cOR
molecular response [up to 7 months from enrolment]
Ki67
Breast conserving surgery [up to 7 months from enrolment]
Surgery type
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [up to 100 days from last nivolumab dose]
Adverse Events
Correlative biomarkers [Tumor samples will be collected at baseline, at 14 days after completion of anthracycline-based chemotherapy (about 7 weeks after first dose of Epirubicin), at surgery (about 30 weeks after first dose of Epirubicin)]
correlation between different biomarkers expression at baseline and pathological response

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients may be included in the study only if they met all the following criteria

age >18 yrs
female patients
ECOG Performance Status 0-1
must have signed and dated an IRB/IEC-approved written informed consent form in accordance with regulatory and institutional guidelines before the performance of any protocol-related procedures
Primary diagnosis of invasive breast cancer, HR positive (ER ≥ 10% and/or PgR ≥10% by IHC) and HER2 negative (IHC 0/1+ and/or FISH/CISH negative) according to local assessment.
Histologic grade 3 and/or Ki67 >20% according to local assessment.
Stage II-IIIA
Eligible for neoadjuvant chemotherapy according to multidisciplinary evaluation.
Premenopausal status
Normal organ and marrow function
Availability of tumor tissue suitable for biological and molecular examination before starting primary treatment
Ability to understand and willingness to sign a written informed consent document

Exclusion criteria:

Patients will be excluded from the study for any of the following reasons

Stage IIIB, IIIC, and inflammatory breast cancer
Stage IV breast cancer
Prior treatment with chemotherapy, biologic therapy, endocrine therapy or radiotherapy for the treatment of the newly-diagnosed breast cancer.
Contraindication to anthracycline-based chemotherapy.
Received any investigational treatment within 4 weeks of study start.
Any other concurrent chemotherapy, biologic therapy, endocrine therapy or radiotherapy for cancer treatment.
Known HIV, HBV, HCV infection or any positive tests for HBV and HCV indicating acute or chronic infection.
Known severe hypersensitivity to any of the study drugs or excipients or known severe hypersensitivity reactions to monoclonal antibodies.
Major surgical procedure or significant traumatic injury within 28 days prior to treatment initiation or anticipation of need for major surgery during the course of study treatment.
History of allogenic organ transplantation
Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident /stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication.
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment initiation.
Subjects with active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results.
Prisoners or subjects who are involuntarily incarcerated
Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medication.
Psychiatric illness/social situations that would limit compliance with study requirements
Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
Current pregnancy and/or lactation.
Refusal to adopt adequate (highly effective) contraception methods.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arcispedale S. Anna	Cona	FE	Italy
2	Centro di Riferimento Oncologico di Aviano (CRO)	Aviano	PN	Italy
3	Azienda Ospedaliera Universitaria di Parma	Parma	PR	Italy	43126
4	Arcispedale S. Maria Nuova	Reggio Emilia	RE	Italy
5	Istituto Oncologico veneto IRCCS	Padova		Italy	35128