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 (BCT 1702 CHARIOT)

Funding

Other Collaborative groups,Breast Cancer Trials

Scientific enquiries

A/Prof Sherene Loi

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 y .... 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.
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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 .... 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.
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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 chemother .... 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.
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