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Trial registered on ANZCTR


Registration number
ACTRN12617000651381
Ethics application status
Approved
Date submitted
3/05/2017
Date registered
5/05/2017
Date last updated
5/03/2019
Date data sharing statement initially provided
19/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
BCT 1702 (CHARIOT): Patients with high-risk primary triple negative breast cancer who have had anthracycline-based chemotherapy will receive Ipilimumab and Nivolumab with weekly paclitaxel, followed by definitive surgery and further treatment with Nivolumab to evaluate the safety, feasibility and efficacy of this treatment.
Scientific title
BCT 1702 (CHARIOT): A phase II study evaluating efficacy and safety of Ipilimumab and Nivolumab with neoadjuvant weekly paclitaxel after anthracycline based chemotherapy in high-risk primary triple negative breast cancer, followed by definitive surgery and one year total duration of Nivolumab.
Secondary ID [1] 285491 0
BCT 1702
Universal Trial Number (UTN)
Trial acronym
CHARIOT: CHeckpoint therApy in tRiple negatIve breasT Cancer.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary triple negative breast cancer 303094 0
Condition category
Condition code
Cancer 302553 302553 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Before surgery, participants will receive the following treatment simultaneously over a 12 week period:
* Nivolumab intravenously at 240 mg every 2 weeks for 6 doses;
* Ipilimumab intravenously at 1mg/kg every 6 weeks for 2 doses;
* Paclitaxel intravenously at 80 mg/m^2 weekly for 12 doses.

Where administration of the study drugs happens on the same day, nivolumab is administered first, ipilimumab is administered 30 minutes after nivolumab, and paclitaxel is administered last. Study treatment is administered at clinic/study visits.

Surgery will take place within 4 weeks of the last paclitaxel dose. Surgery may be either breast conserving surgery or mastectomy as decided between the participant and surgeon.

Participants will recommence Nivolumab 2-6 weeks after surgery as determined by the investigator. Nivolumab is administered intravenously at 480 mg dose every 4 weeks for 9 doses at clinic/study visits.
Intervention code [1] 290431 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301974 0
The rate of pathological complete response (pCR) in the breast and axilla as defined by no histologic evidence of residual invasive cancer cells on haematoxylin and eosin (H&E) evaluation of the resected breast and lymph node specimens.
Timepoint [1] 301974 0
Definitive surgery.
Secondary outcome [1] 334411 0
The proportion of participants with a pCR rate in the breast (ypT0/is) as defined by no histologic evidence of residual invasive cancer cells on haematoxylin and eosin (H&E) evaluation of the resected breast and lymph node specimens.
Timepoint [1] 334411 0
Definitive surgery.
Secondary outcome [2] 334412 0
Residual disease as per residual cancer burden (RCB) as assessed by the local pathologist.
Timepoint [2] 334412 0
Definitive surgery.
Secondary outcome [3] 334413 0
The objective response rate (ORR) (complete and partial) in the breast by ultrasound (bidimensional) and calliper measurement (as per RECIST 1.1).
Timepoint [3] 334413 0
Prior to definitive surgery
Secondary outcome [4] 334414 0
The proportion of participants experiencing Serious Adverse Events as per CTCAE V4.0.
Timepoint [4] 334414 0
SAEs are assessed pror to Cycle 1, every 2 weeks during the Treatment Phase, 1-4 weeks post-surgery, every 4 weeks during post-surgery treatment with Nivolumab and up to 30 days after the last dose of Nivolumab.
Secondary outcome [5] 334415 0
The proportion of participants with detectable ctDNA as assessed by plasma assay.
Timepoint [5] 334415 0
1 year post-therapy.
Secondary outcome [6] 334416 0
Event free survival (EFS) as assessed by local investigator standard of care.
Timepoint [6] 334416 0
6 months, 12 months, 24 months and 36 months from the start of study treatment.
Secondary outcome [7] 334417 0
Overall survival (OS) as assessed by local investigator standard of care.
Timepoint [7] 334417 0
6 months, 12 months, 24 months and 36 months from the start of study treatment.

Eligibility
Key inclusion criteria
For inclusion in the study, participants must fulfil all of the following criteria:

1) Female or male, age >= 18 years.

2) Non-metastatic, 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 < 1% tumour cells positive for PR by IHC irrespective of staining intensity; AND
c) HER2 negative:
i) IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
ii) 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
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.

3) At the time of diagnosis, have previously untreated non-metastatic (M0) TNBC fulfilling the following combined primary tumour (T) and regional lymph node (N) staging per AJCC Cancer Staging Manual, 8th Edition (2017) as assessed by the local investigator on the basis of US of the breasts, and US or clinical examination of the axilla, respectively (prior to any anthracycline-based chemotherapy):
a) Note: ipsilateral multifocal or multicentric primary disease is allowed and the tumour focus with the most advanced T stage should be used to assess eligibility; all tumours must be confirmed TN phenotype;
b) Note: participants entering the trial after undergoing a sentinel lymph node biopsy will not be eligible;
c) The residual primary tumour (or at least one of the primary tumours in the presence of multifocal or multicentric disease) post anthracycline-based chemotherapy must be at least 15 mm at the time of study treatment commencement and be amenable to biopsy. Residual skin disease that is >= 15 mm is acceptable;
d) An assessment of tumour response prior to study entry is required by serial US and clinical examination;
e) The tumour measurement at study entry (pre-C1) can be used and compared to measurements from the diagnostic imaging performed at diagnosis (prior to the start of anthracycline-based chemotherapy).

4) Computed tomography (CT) scan of chest/abdomen (and bone scan if clinically indicated) at diagnosis or any time prior to study entry to exclude metastases. Those participants with equivocal finding on staging at diagnosis should have staging repeated prior to study entry. Biopsies should be performed to confirm or exclude metastatic disease if possible.

5) A tumour block or representative 15-20 sections from the diagnstic core biopsy prior to anthracycline-based chemotherapy must be available.

6) The participant must have completed 4 cycles of anthracycline-based chemotherapy (AC (or EC) x 4 (3 weekly or dose dense) at standard dosing; FEC X 4).

7) The participant must consent to have research core needle biopsies of the primary tumour prior to the start of study treatment. The biopsy must be judged feasible by the investigator and at least two core biopsies are required.

8) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

9) Able to commence study treatment within 14 days of study registration.

10) Surgery is able to be undertaken within 4 weeks of final paclitaxel dose. Surgeon must not offer pre-operative radiation for any patient with operable cancer after final paclitaxel.

11) Adequate organ function. All screening laboratory results should be performed within 14 days of treatment initiation.

12) Screening laboratory values must meet the following criteria (using CTCAE V4):
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 mg/dL).

13) Left ventricular ejection fraction (LVEF) of >= 50% or >= institution lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening (no more than 4 weeks prior to study entry).

14) Negative pregnancy test or confirmation of post-menopausal status.
a) Negative urine or serum pregnancy (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
i) Female Pparticipants must agree to follow instructions for method(s) of contraception from the time of enrolment for the duration of treatment plus 5 half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) and for a total of 23 weeksat least 5 months post treatment completion.;
ii) 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 post treatment completion.
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 and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
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, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

15) Women must not be breastfeeding.

16) Be willing and able to provide written informed consent for the trial. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any one of the following is regarded as a criterion for exclusion from the study:
1) Has evidence of metastatic breast cancer or concurrent bilateral invasive breast cancer. Staging must be performed as clinically appropriate. Biopsies should be performed to confirm or exclude metastatic disease if possible.

2) Has received prior chemotherapy (apart from pre-study anthracycline component), targeted therapy, radiation therapy, immunotherapy that target immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell receptors within the past 12 months.
a) Participants who are planned to receive further chemotherapy post-surgery if residual disease is present are ineligible.

3) Is 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 of the first dose of study treatment.
Note: participant will be excluded if she received an investigational agent with anticancer or anti-proliferative intent within the last 12 months.

4) Has received a live vaccine within 30 days of the first dose of study treatment.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however are strongly cautioned against; intranasal influenza vaccines (e.g. FluMist(R)) are live attenuated vaccines, and are not allowed.

5) Participants must have recovered from the effects of any major surgery for causes unrelated to breast cancer or significant traumatic injury at least 14 days before registration.

6) Participants with previous malignancies (except non-melanoma skin cancer, melanoma in situ, and in situ cancers of the following: stomach, colon, cervix, endometrium, or breast) are excluded unless a complete remission was achieved at least 2 years prior to registration and no additional therapy is required or anticipated to be required during the study period.

7) Other active malignancy requiring concurrent intervention.

8) Participants with an active, known or suspected autoimmune disease. Participants 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 register.

9) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomisation. 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 not considered a form of systemic treatment. Patients requiring steroids as a once-off, short term anti-emetics (such as that prescribed with chemotherapy) are allowed.

10) Participants with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.

11) Has a history of non-infectious pneumonitis requiring treatment with steroids.

12) Has active infection requiring systemic therapy.

13) 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 UV.

14) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

15) 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.

16) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.

17) Active tuberculosis.

18) Participants with Grade 1 peripheral neuropathy.

19) Patients 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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)
ACT,NSW,QLD,WA,VIC
Recruitment hospital [1] 12162 0
Breast Cancer Research Centre - Western Australia - Perth
Recruitment hospital [2] 12163 0
The Canberra Hospital - Garran
Recruitment hospital [3] 12164 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [4] 12165 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 12166 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [6] 12167 0
Lake Macquarie Private Hospital - Gateshead
Recruitment hospital [7] 12168 0
Macarthur Cancer Therapy Centre - Campbelltown
Recruitment hospital [8] 12169 0
Macquarie University Hospital - Macquarie Park
Recruitment hospital [9] 12170 0
Mater Private Hospital - South Brisbane
Recruitment hospital [10] 12171 0
Mater Sydney - North Sydney
Recruitment hospital [11] 12172 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [12] 12173 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [13] 12174 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 24331 0
6000 - Perth
Recruitment postcode(s) [2] 24332 0
2605 - Garran
Recruitment postcode(s) [3] 24333 0
2050 - Camperdown
Recruitment postcode(s) [4] 24334 0
6150 - Murdoch
Recruitment postcode(s) [5] 24335 0
4066 - Auchenflower
Recruitment postcode(s) [6] 24336 0
2290 - Gateshead
Recruitment postcode(s) [7] 24337 0
2560 - Campbelltown
Recruitment postcode(s) [8] 24338 0
2109 - Macquarie Park
Recruitment postcode(s) [9] 24339 0
4101 - South Brisbane
Recruitment postcode(s) [10] 24340 0
2060 - North Sydney
Recruitment postcode(s) [11] 24341 0
3168 - Clayton
Recruitment postcode(s) [12] 24342 0
3000 - Melbourne
Recruitment postcode(s) [13] 24343 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 290092 0
Other Collaborative groups
Name [1] 290092 0
Breast Cancer Trials
Address [1] 290092 0
PO Box 283
The Junction NSW 2291
Country [1] 290092 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] 288791 0
None
Name [1] 288791 0
Address [1] 288791 0
Country [1] 288791 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297573 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 297573 0
Ethics Coordinator
Ethics Committee Secretariat
Peter MacCallum Cancer Centre
Locked Bag 1, A/Beckett Street
Victoria 8006
Ethics committee country [1] 297573 0
Australia
Date submitted for ethics approval [1] 297573 0
01/12/2017
Approval date [1] 297573 0
30/05/2018
Ethics approval number [1] 297573 0
HREC/17/PMCC/236

Summary
Brief summary
This study aims to find out if treatment with a combination of Ipilimumab and Nivolumab, with weekly paclitaxel before surgery, and treatment with Nivolumab after surgery, is safe and effective in women and men diagnosed with triple negative breast cancer.

Who is it for?
You may be eligible for this study if you are 18 years or older, have been diagnosed with triple negative breast cancer, will be having neoadjuvant treatment (treatment with anthracycline-based chemotherapy before surgery) and your tumour is >= 15mm in size after anthracycline-based chemotherapy.

Trial Details.
Participants may have commenced anthracycline based chemotherapy prior to signing consent to this study. Tumour block/sections from the initial diagnostic core biopsy must be available.

Up to 3 weeks before starting study treatment, all participants will have a breast and axillary ultrasound, and provide research core biopsies and research blood tests. The tumour must be biopsied prior to the start of neoadjuvant study therapy and a primary tumour size of >= 15 mm on imaging (mammogram or ultrasound) is required for eligibility.

Participants will have clinic visits every 2 weeks during pre-surgery treatment (nivolumab, ipilimumab and paclitaxel) for 12 weeks. They will receive nivolumab every 2 weeks (6 doses), ipilimumab every 6 weeks (2 doses) and paclitaxel every week (12 doses).

Participants will have a breast and axilla ultrasound repeated before surgery. If tumour is available at surgery, research biopsies will be collected.

Nivolumab will re-start when safe to do so 3-6 weeks post-surgery. All participants will have clinic visits with the first dose of nivolumab after surgery, and then every 4 weeks for 9 visits (36 weeks). Nivolumab is dosed every 4 weeks post-surgery for up to 9 doses.

The total duration of study treatment is 1 year.

Participants will be followed as per local investigator standard of care (SOC) at 6 months, 12 months, 24 months and 36 months following start of study treatment by phone or SOC visits.
Trial website
www.breastcancertrials.org.au
Trial related presentations / publications
Public notes
Breast Cancer Trials formerly known as Australia & New Zealand Breast Cancer Trials Group.

Contacts
Principal investigator
Name 52078 0
A/Prof Sherene Loi
Address 52078 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 52078 0
Australia
Phone 52078 0
+61 3 8559 5935
Fax 52078 0
Email 52078 0
corinna.beckmore@bctrials.org.au
Contact person for public queries
Name 52079 0
Ms Corinna Beckmore
Address 52079 0
BCT
PO BOX 283
The Junction NSW 2291
Country 52079 0
Australia
Phone 52079 0
+61 2 4925 5235
Fax 52079 0
Email 52079 0
corinna.beckmore@bctrials.org.au
Contact person for scientific queries
Name 52080 0
A/Prof Sherene Loi
Address 52080 0
Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006
Country 52080 0
Australia
Phone 52080 0
+61 3 8559 5935
Fax 52080 0
Email 52080 0
corinna.beckmore@bctrials.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
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?
Other
'Other' documents specified
Available documents to be confirmed.
Summary results
No Results