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Trial registered on ANZCTR


Registration number
ACTRN12619001308189
Ethics application status
Approved
Date submitted
6/09/2019
Date registered
25/09/2019
Date last updated
11/02/2020
Date data sharing statement initially provided
25/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
In patients with previously untreated early stage triple negative breast cancer, how well does using Nivolumab before starting standard chemotherapy, OR starting treatment with Nivolumab and chemotherapy at the same time, help to reduce tumour size before surgery compared?
Scientific title
BCT 1902 (Neo-N): A randomised phase II trial evaluating the efficacy of a nivolumab monotherapy lead in “window” or commencement of nivolumab concurrently with paclitaxel and carboplatin as neoadjuvant therapy in early stage triple negative breast cancers.
Secondary ID [1] 298718 0
BCT 1902
Secondary ID [2] 299309 0
EudraCT: 2019-003465-18
Universal Trial Number (UTN)
Trial acronym
Neo-N
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Triple negative breast cancer 314318 0
Condition category
Condition code
Cancer 312669 312669 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ARM A - Nivolumab window
Nivolumab monotherapy 240 mg IV, 2 weeks later followed by Nivolumab 360 mg IV with Carboplatin AUC5 once every 3 weeks for 4 cycles and Paclitaxel 80 mg/m^2 every week for 12 weeks as an IV infusion administered per institutional guidelines. Nivolumab should be administered 30 minutes before administration of chemotherapy. This will be followed by surgery a minimum of 2 weeks and a maximum of 4 weeks after the last dose of paclitaxel.

ARM B - Concurrent Nivolumab
Nivolumab 360 mg IV with Carboplatin AUC5 once every 3 weeks for 4 cycles and Paclitaxel 80 mg/m^2 every week for 12 weeks. Nivolumab should be administered 30 minutes before administration with chemotherapy. 12 weeks of concurrent treatment will immediately followed by Nivolumab monotherapy 240 mg IV. Surgery will follow treatment a minimum of 2 weeks and a maximum of 4 weeks later after the last dose of paclitaxel.

Study treatment is administered at clinic/study visits.
Intervention code [1] 315168 0
Treatment: Drugs
Comparator / control treatment
This is a randomised, non-comparative, "pick-the-winner" study; the two arms are not being compared and one arm does not act as a control to the other. pCR rate will be assessed separately in each cohort.

The hypothesis is that participants with early stage triple negative breast cancer given a Nivolumab lead-in “window” treatment before neoadjuvant chemotherapy or given concurrent Nivolumab treatment with neoadjuvant chemotherapy will have different pCR rates at surgery.
Control group
Active

Outcomes
Primary outcome [1] 321318 0
Pathological complete response (pCR) in breast and nodes (ypT0/Tis/ypN0) as assessed by examination of the tissue (breast and nodes) removed at surgery.
Timepoint [1] 321318 0
At surgery.
Secondary outcome [1] 374626 0
To evaluate efficacy in the two cohorts in TNBC with higher tumour infiltrating lymphocyte (TIL) levels (% TIL on baseline pathology samples >= 30%), evaluated by pCR (ypT0/Tis/ypN0) as assessed by examination of the tissue (breast and nodes) removed at surgery.
Timepoint [1] 374626 0
At surgery.
Secondary outcome [2] 374627 0
To evaluate efficacy in the two cohorts in TNBC that are PD-L1 positive (>= 1% immune cell staining), evaluated by pCR (ypT0/Tis/ypN0) as assessed by examination of the tissue (breast and nodes) removed at surgery.
Timepoint [2] 374627 0
At surgery
Secondary outcome [3] 374628 0
To evaluate efficacy of treatment combinations using pCR in breast only (ypT0/Tis) as assessed by examination of the tissue removed at surgery.
Timepoint [3] 374628 0
At surgery
Secondary outcome [4] 374629 0
To evaluate efficacy of treatment combinations using Residual Cancer Burden (RCB)
Timepoint [4] 374629 0
At surgery
Secondary outcome [5] 374630 0
To evaluate efficacy of treatment combinations using tumour response by WHO criteria
Timepoint [5] 374630 0
At surgery
Secondary outcome [6] 374631 0
The evaluate efficacy of the treatment combinations using Ki67 proliferation marker changes from baseline to surgery as evaluated by Ki67 assay on tumour samples.
Timepoint [6] 374631 0
At surgery
Secondary outcome [7] 374632 0
To evaluate efficacy of the treatment combinations on event free survival as evaluated by the occurrence of invasive breast cancer events as confirmed by clinical and/or radiological examination.
Timepoint [7] 374632 0
Time from randomisation to time of an invasive breast cancer event, assessed for up to 3 years post-randomisation
Secondary outcome [8] 374633 0
To evaluate efficacy of treatment combinations on overall survival.
Timepoint [8] 374633 0
Time from randomisation to time of death from any cause, assessed for up to 3 years post-randomisation.
Secondary outcome [9] 374636 0
To investigate the safety of treatment combinations according to NCI-CTCAE V5.0
Timepoint [9] 374636 0
Adverse events documented from the time of informed consent to 100 days after the last dose of Nivolumab or 30 days after the last dose of neoadjuvant chemotherapy, whichever is later

Eligibility
Key inclusion criteria
1) Female or male, age >= 18 years.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
3) Previously untreated non-metastatic (M0) TNBC meeting Stage I or II criteria according to AJCC Cancer Staging Manual, 8th Edition, 2017 as assessed by the local investigator on the basis of mammogram (MMG) and/or ultrasound (US) of the breasts, and US or clinical examination of the axilla.
a) Stage I cT1c cN0;
Stage IIA cT1 cN1; cT2 cN0;
Stage IIB cT2 cN1; cT3 cN0.
b) Contralateral in situ only disease is permitted;
c) In the event of abnormal imaging of the axilla, nodal status should be confirmed by cytology.
4) Clinically node positive participants should undergo computed tomography (CT) scan or PET CT of chest/abdomen (and bone scan if clinically indicated) to exclude metastases. Those participants with equivocal finding on staging should have biopsies performed to confirm or exclude metastatic disease if possible.
5) Non-metastatic, potentially operably, unilateral triple negative breast cancer, histologically defined as:
a) ER negative: with < 1% of tumour cells positive for ER by IHC irrespective of staining intensity; AND
b) PR negative: with < 10% tumour cells positive for PR by IHC irrespective of staining intensity; AND
c) HER2 negative:
i) IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within <= 10% of the invasive tumour cells; OR
ii) IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
iii) ISH (FISH or SISH) negative based on:
* Single-probe average HER2 copy number < 4.0 signals/cell; OR
* Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell; OR
* As per ASCO-CAP 2018 Guidelines.
6) Able to commence study treatment within 14 days of randomisation.
7) Surgery is able to be undertaken within 4 weeks of final dose of neoadjuvant IV therapy. Pre-operative radiation is not permitted for any participant with operable cancer after final paclitaxel.
8) Adequate organ function. All screening laboratory tests should be performed within 14 days of randomisation.
9) Screening laboratory values must meet the following criteria (using NCI-CTCAE V5.0):
a) WBC >= 2 x 10^9/L;
b) Neutrophils >= 1.5 x 10^9/L;
c) Platelets >= 100 x 10^3/µL;
d) Haemoglobin >= 9.0 g/dL;
e) Serum creatinine <= 1.5 x ULN or calculated creatinine clearance >= 50 mL/min (using the Cockcroft Gault formula);
f) AST/ALT <= 3.0 x ULN;
g) Total bilirubin <= 1.5 x ULN except participants with Gilbert Syndrome who must have a total bilirubin level <= 3.0 x ULN.
10) Left ventricular ejection fraction (LVEF) of >= 50% assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening (no more than 4 weeks before study entry).
11) Negative pregnancy test or confirmation of post-menopausal status for female participants. Women who have undergone surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy/tubal ligation, or hysterectomy) do not require pregnancy testing.
a) Negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG within 14 days of randomisation and within 7 days before the first dose of study treatment. The pregnancy test will be repeated within 24 hours before the first dose if outside this window.
OR:
b) Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
i) Women < 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments with no Mirena® IUD in situ and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
ii) Women >= 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments with no Mirena IUD in situ or endometrial ablation. If Mirena IUD or endometrial ablation and age < 60 years, LH and FSH should be in the postmenopausal range.
12) Female participants of childbearing potential must agree to follow instruction for method(s) of contraception from the time of enrolment for the duration of treatment and for at least 5 months after completing Nivolumab treatment;
13) Male participants must agree to follow instructions for method(s) of contraception from the time of enrolment for the duration of treatment and for at least 7 months after completing Nivolumab treatment.
14) Be willing and able to provide written informed consent for the study. The participant may also provide consent for future unspecified biomedical research. However, the participant may participate in the main study without participating in future unspecified biomedical research.
15) The participant has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
16) The participant agrees to make tumour (diagnostic core biopsy and surgical specimen) available for submission for central pathology review and to conduct translational studies as part of this protocol.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Confirmed presence of AJCC 8th edition anatomic Stage 3 or 4 disease.
2) Tumour of any size considered inoperable at presentation.
3) Multifocal* or bilateral invasive breast cancer. * Refer to AJCC 8th Edition: use clinical judgement if satellite nodes are close as to whether this represents truly multifocal disease.
4) Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that target immune checkpoints, co-stimulatory or co-inhibitory pathways for T-cell receptors within the past 12 months.
5) Will be offered neoadjuvant breast radiation therapy.
6) Undergone or planned for sentinel lymph node biopsy before study therapy.
7) Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks before randomisation.
Note: participant will be excluded if he/she received an investigational agent with anticancer or anti-proliferative intent within the last 12 months.
8) Any concurrent anti-neoplastic therapy (i.e. chemotherapy, hormonal therapy, immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational agents for treatment of breast cancer) not already specified in the protocol.
9) Prior malignancy active within the previous 3 years before randomisation, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
10) Other active malignancy requiring concurrent intervention.
11) Has significant cardiovascular disease such as myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months, congestive cardiac failure (CHF) New York Heart Association (NYHA) classification IV or history of CHF NYHA III or IV.
12) Participants with an active, known or suspected autoimmune disease are not eligible. Participants with the following are eligible to participate:
a) Type I diabetes mellitus;
b) Hypothyroidism only requiring hormone replacement;
c) Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment; or
d) Conditions not expected to recur in the absence of an external trigger.
13) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomisation are not eligible. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted. Patients requiring steroids as a once-off, short term anti-emetics (such as that prescribed with chemotherapy) are eligible.
14) Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
15) Has a history of non-infectious pneumonitis requiring treatment with steroids.
16) Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
17) Treatment with botanical preparations (e.g. herbal supplements) and traditional Chinese medicines, intended for general health support or to treat the disease under study, within 7 days before randomisation.
18) Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
19) Pregnant; lactating participants must stop breast feeding before randomisation. Use of oral, injectable or implant hormonal contraceptives or medicated IUD must stop before randomisation.
20) Contraindications or known hypersensitivity to the study medication or excipients.
21) Administration of a a live vaccine within 30 days before randomisation
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
22) Known history of testing positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS).
23) Active Hepatitis B virus (known positive Hepatitis B surface antigen (HBsAg) result or Hepatitis C virus (HCV). Participants with past or resolved HBV infection (defined as the presence of Hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible if remaining on anti-viral medication. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
24) Active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 15851 0
Ballarat Oncology and Haematology Services - Wendouree
Recruitment hospital [2] 15852 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [3] 15853 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 15854 0
Frankston Hospital - Frankston
Recruitment hospital [5] 15855 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [6] 15856 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [7] 15857 0
Riverina Cancer Care Centre - Wagga Wagga
Recruitment hospital [8] 15858 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 15859 0
St George Hospital - Kogarah
Recruitment hospital [10] 15860 0
St John of God Hospital, Bunbury - Bunbury
Recruitment hospital [11] 15861 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [12] 15862 0
Toowoomba Hospital - Toowoomba
Recruitment postcode(s) [1] 29307 0
2065 - St Leonards
Recruitment postcode(s) [2] 29308 0
2217 - Kogarah
Recruitment postcode(s) [3] 29301 0
2450 - Coffs Harbour
Recruitment postcode(s) [4] 29306 0
2650 - Wagga Wagga
Recruitment postcode(s) [5] 29304 0
3000 - Melbourne
Recruitment postcode(s) [6] 29310 0
3065 - Fitzroy
Recruitment postcode(s) [7] 29303 0
3199 - Frankston
Recruitment postcode(s) [8] 29300 0
3355 - Wendouree
Recruitment postcode(s) [9] 29305 0
4020 - Redcliffe
Recruitment postcode(s) [10] 29311 0
4350 - Toowoomba
Recruitment postcode(s) [11] 29302 0
5042 - Bedford Park
Recruitment postcode(s) [12] 29309 0
6230 - Bunbury
Recruitment outside Australia
Country [1] 21839 0
New Zealand
State/province [1] 21839 0
Country [2] 21840 0
Belgium
State/province [2] 21840 0
Country [3] 21841 0
Italy
State/province [3] 21841 0
Country [4] 21842 0
Switzerland
State/province [4] 21842 0

Funding & Sponsors
Funding source category [1] 303271 0
Other Collaborative groups
Name [1] 303271 0
Breast Cancer Trials
Address [1] 303271 0
PO Box 283
The Junction NSW 2291
Country [1] 303271 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Breast Cancer Trials
Address
PO Box 283
The Junction NSW 2291
Country
Australia
Secondary sponsor category [1] 303280 0
None
Name [1] 303280 0
Address [1] 303280 0
Country [1] 303280 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303809 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 303809 0
Ethics Coordinator
Ethics Committee Secretariat
Peter MacCallum Cancer Centre
Locked Bag 1, A/Beckett Street
Victoria 8006
Ethics committee country [1] 303809 0
Australia
Date submitted for ethics approval [1] 303809 0
11/11/2019
Approval date [1] 303809 0
30/12/2019
Ethics approval number [1] 303809 0
HREC/58087/PMCC-2019

Summary
Brief summary
This study aims to find out how well using Nivolumab on its own before starting standard chemotherapy, or starting treatment with Nivolumab at the same time as standard chemotherapy, helps to reduce tumour size before surgery in patients with previously untreated early stage triple negative breast cancer.

Who is it for?
You may be eligible for this study if you are 18 years or older and have been diagnosed with triple negative breast cancer that is potentially operable and has not spread to other parts of your body. Tumour block/sections from the initial diagnostic core biopsy must be available.

Trial Details:
Participants will be randomised 1:1 to either:

Arm A: Nivolumab only for 2 weeks, followed by Nivolumab + Carboplatin + Paclitaxel for a further 12 weeks, followed by surgery. Paclitaxel is given weekly; Nivolumab and Carboplatin are given every 3 weeks for 4 cycles.

Arm B: Nivolumab + Carboplatin + Paclitaxel for 12 weeks. Paclitaxel is given weekly; Nivolumab and Carboplatin are given every 3 weeks for 4 cycles. After 12 weeks, there will be a further 2 weeks of treatment with Nivolumab only, followed by surgery.

All treatments are administered intravenously.

The following biological samples will be collected:
* Tumour biopsy at diagnosis, after Nivolumab monotherapy lead-in (Arm A) or before Cycle 2 (Arm B), and from the surgical specimen should invasive residual disease remain.
* Blood samples at Baseline (before the first dose of study treatment), after Cycle 1 (Arm A) or after Cycle 2 (Arm B) and at the End of Treatment Visit.

All participants will be regularly monitored throughout treatment to evaluate their health. There will be an end of treatment visit 30 days after surgery. Follow-up visits will occur every 6 months after surgery for up to 3 years post-randomisation. Further treatment will be at the discretion of the participant and their treating clinician.

It is hoped this research will provide a new treatment option for people with triple negative breast cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94886 0
Prof Sherene Loi
Address 94886 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 94886 0
Australia
Phone 94886 0
+61 2 4925 5235
Fax 94886 0
Email 94886 0
corinna.beckmore@bctrials.org.au
Contact person for public queries
Name 94887 0
Ms Corinna Beckmore
Address 94887 0
Breast Cancer Trials
PO Box 283
The Junction NSW 2291
Country 94887 0
Australia
Phone 94887 0
+61 2 4925 5235
Fax 94887 0
Email 94887 0
corinna.beckmore@bctrials.org.au
Contact person for scientific queries
Name 94888 0
Prof Sherene Loi
Address 94888 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 94888 0
Australia
Phone 94888 0
+61 2 4925 5235
Fax 94888 0
Email 94888 0
corinna.beckmore@bctrials.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data Sharing process for this study is in development and will be updated as soon as it is available.
What supporting documents are/will be available?
No other documents available
Summary results
No Results