ANZCTR - Registration

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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

17/02/2023

Date data sharing statement initially provided

19/12/2018

Date results information initially provided

22/04/2020

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]

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

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

None

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Definitive surgery.

Secondary outcome [1]

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]

Definitive surgery.

Secondary outcome [2]

Residual disease as per residual cancer burden (RCB) as assessed by the local pathologist.

Timepoint [2]

Definitive surgery.

Secondary outcome [3]

The objective response rate (ORR) (complete and partial) in the breast by ultrasound (bidimensional) (as per WHO criteria) and calliper measurement (as per RECIST 1.1).

Timepoint [3]

Prior to definitive surgery

Secondary outcome [4]

The proportion of participants experiencing Serious Adverse Events as per CTCAE V4.0.

Timepoint [4]

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]

The proportion of participants with detectable ctDNA as assessed by plasma assay.

Timepoint [5]

1 year post-therapy.

Secondary outcome [6]

Event free survival (EFS) as assessed by local investigator standard of care.

Timepoint [6]

6 months, 12 months, 24 months and 36 months from the start of study treatment.

Secondary outcome [7]

Overall survival (OS) as assessed by local investigator standard of care.

Timepoint [7]

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, potentially operable, 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) 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) Participants undergoing a sentinel lymph node biopsy prior to study entry will not be eligible;
c) Residual tumour requirements (post anthracycline-based chemotherapy):
i) Node Negative: The residual primary tumour (or at least one of the primary tumours in the presence of multifocal ro multicentric disease ( must be at least 15mm prior to study treatment commencement, or
ii) Residual invasive skin disease measuring >= 10 mm, or
iii) Node positive: Residual primary tumour at least 10 mm for patients with clear remaining node positive disease (at least one persisting abnormal node).
d) Invasive disease must be detectable in the post-anthrcycline biopsy taken from the breast or lymph node.
e) An assessment of tumour response prior to study entry is required by serial US and clinical examination;
f) 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) or PET CT 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 FFPE 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). First dose of study therapy must be planned to commence within 4 weeks of last dose of anthracycline based chemotherapy. It is recommended that patients who have received dose dense anthracycline chemotherapy wait at least 3 weeks from the last cycle of anthracycline, to planned first dose of study therapy, to ensure adequate recovery.

7) The participant must consent to have research core needle biopsies of the primary tumour post-administration of last anthracycline-containing chemotherapy, and prior to the start of study treatment. The biopsy must be judged feasible by the investigator and at least two core biopsies are required. If the breast primary cannot be biopsied, core biopsies of involved axillary lymph nodes are acceptable.

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.Pre-operative radiation is not permitted for any patient with operable cancer after final paclitaxel.

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

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% and >= 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 for female participants.
a) Negative urine or serum pregnancy (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days prior to registration. Note – a pregnancy test is also required within24 hours prior to the start of study drug.
i) Female participants must agree to follow instructions for method(s) of contraception from the time of enrolment until at least 5 months post-immunotherapytreatment completion.;
ii) Male participants must agree to follow instructions for method(s) of contraception from the time of enrolment until at least 7 months post-immunotherapy 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 sterilisation (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. Women who have undergone surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy/tubal ligation or hysterectomy) do not require pregnancy testing.

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

Sex

Both males and females

Can healthy volunteers participate?

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) Inoperable breast cancer at completion of 4 cycles of anthracycline-based chemotherapy.

3) Patients planned to receive neoadjuvant breast radiation therapy

4) 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.

5) 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.

6) 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.

7) Has received an inactivated influenza vaccines within 6 weeks of study treatment commencement.

8) 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.

9) 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.

10) Other active malignancy requiring concurrent intervention.

11) Participants with an active, known or suspected autoimmune disease are excluded. The following are permitted to participate:
* 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.

12) 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 allowed. Patients requiring steroids as a once-off, short term anti-emetics (such as that prescribed with chemotherapy) are allowed.

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

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

15) Has active infection requiring systemic therapy.

16) 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.

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

18) 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.

19) Active hepatitis B virus (HBV) (known positive hepatitis B surface antigen (HBsAg) result) or hepatitis C virus (HCV). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) must have undetectable viral load at baseline (<2000IU/mL) and remain on anti-viral medication for the duration of study therapy. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

20) Active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).

21) Participants with Grade 1 peripheral neuropathy.

22) Participants who are unwilling to cease treatment with botanical preparations (eg herbal supplements) and traditional Chinese medicines, intended for general health support or to treat the disease under study, within 14 days prior to registration.

23) 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

Active, not recruiting

Date of first participant enrolment

Anticipated

15/10/2018

Actual

12/12/2018

Date of last participant enrolment

Anticipated

28/02/2020

Actual

7/04/2020

Date of last data collection

Anticipated

30/06/2023

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,WA,VIC

Recruitment hospital [1]

Breast Cancer Research Centre - Western Australia - Perth

Recruitment hospital [2]

The Canberra Hospital - Garran

Recruitment hospital [3]

The Chris O’Brien Lifehouse - Camperdown

Recruitment hospital [4]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [5]

Icon Cancer Care Wesley - Auchenflower

Recruitment hospital [6]

Lake Macquarie Private Hospital - Gateshead

Recruitment hospital [7]

Macarthur Cancer Therapy Centre - Campbelltown

Recruitment hospital [8]

Macquarie University Hospital - Macquarie Park

Recruitment hospital [9]

Mater Private Hospital - South Brisbane

Recruitment hospital [10]

Mater Sydney - North Sydney

Recruitment hospital [11]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [12]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [13]

Westmead Hospital - Westmead

Recruitment postcode(s) [1]

6000 - Perth

Recruitment postcode(s) [2]

2605 - Garran

Recruitment postcode(s) [3]

2050 - Camperdown

Recruitment postcode(s) [4]

6150 - Murdoch

Recruitment postcode(s) [5]

4066 - Auchenflower

Recruitment postcode(s) [6]

2290 - Gateshead

Recruitment postcode(s) [7]

2560 - Campbelltown

Recruitment postcode(s) [8]

2109 - Macquarie Park

Recruitment postcode(s) [9]

4101 - South Brisbane

Recruitment postcode(s) [10]

2060 - North Sydney

Recruitment postcode(s) [11]

3168 - Clayton

Recruitment postcode(s) [12]

3000 - Melbourne

Recruitment postcode(s) [13]

2145 - Westmead

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Breast Cancer Trials

Address [1]

PO Box 283
The Junction NSW 2291

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Peter MacCallum Cancer Centre HREC

Ethics committee address [1]

Ethics Coordinator
Ethics Committee Secretariat
Peter MacCallum Cancer Centre
Locked Bag 1, A/Beckett Street
Victoria 8006

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/12/2017

Approval date [1]

30/05/2018

Ethics approval number [1]

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

https://www.breastcancertrials.org.au/current-clinical-trials/chariot

Trial related presentations / publications

Public notes

Breast Cancer Trials formerly known as Australia & New Zealand Breast Cancer Trials Group.

Contacts

Principal investigator

Name

A/Prof Sherene Loi

Address

Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006

Country

Australia

Phone

+61 3 8559 5935

Fax

corinna.beckmore@bctrials.org.au

Contact person for public queries

Name

Ms Corinna Beckmore

Address

BCT
PO BOX 283
The Junction NSW 2291

Country

Australia

Phone

+61 2 4925 5235

Fax

corinna.beckmore@bctrials.org.au

Contact person for scientific queries

Name

A/Prof Sherene Loi

Address

Division of Cancer Medicine, Department of Medical Oncology
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett Street
MELBOURNE VIC 8006

Country

Australia

Phone

+61 3 8559 5935

Fax

corinna.beckmore@bctrials.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Anonymised Individual Patient Data (IPD) collected during the trial. The specific IPD to be shared (e.g. all data, published data, data of primary outcomes) will be as per the submitted research proposal and as assessed as appropriate by BCT.

When will data be available (start and end dates)?

Data will be made available for request after publication of the main/final study results; no end date.

Note that there may be additional circumstances preventing BCT from sharing requested data as outlined in the BCT Data Sharing Guidelines.

Available to whom?

Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Refer to the BCT Data Sharing Guidelines.

Available for what types of analyses?

To achieve the aims in the approved proposal.

How or where can data be obtained?

Subject to approval by Breast Cancer Trials concept@bctrials.org.au (refer to BCT Data Sharing Guidelines).

What supporting documents are/will be available?

Other

'Other' documents specified

BCT Data Sharing Guidelines

How or where can supporting documents be obtained?

Type [1]

Other

Citation [1]

Link [1]

Email [1]

Other [1]

Attachment [1]

/Steps11and12/367255-(Uploaded-17-02-2023-09-56-57)-Study-related document.pdf

Summary results

Have study results been published in a peer-reviewed journal?

Other publications

Have study results been made publicly available in another format?

Results – basic reporting

Results – plain English summary

Trial Review