An investigator-initiated, non-randomised, phase II study of combination CTLA-4 and PD-L1 blockade in combination with HER2 blockade in advanced HER2-positive breast cancers that have progressed on prior trastuzumab-based therapy (BCT 1703 DIAmOND)

Brief Summary

This study aims to find out if the combination of trastuzumab (anti-HER2 therapy) with durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA4 inhibitor) will reactivate anti-tumour immune response and improve clinical outcomes in trastuzumab-resistant, advanced HER2-positive breast cancer. Who is it for? You may be eligible for this study if you are 18 years or older, male or female, and have HER2-positive metastatic or incurable breast cancer that has progressed on previous trastuzumab treatment. .... This study aims to find out if the combination of trastuzumab (anti-HER2 therapy) with durvalumab (PD-L1 inhibitor) and tremelimumab (CTLA4 inhibitor) will reactivate anti-tumour immune response and improve clinical outcomes in trastuzumab-resistant, advanced HER2-positive breast cancer. Who is it for? You may be eligible for this study if you are 18 years or older, male or female, and have HER2-positive metastatic or incurable breast cancer that has progressed on previous trastuzumab treatment. Trial Details. Up to 4 weeks before starting study treatment, all participants will have either a CT Scan, MRI, or PET with dedicated CT Scan, provide a research tumour biopsy of the cancer (taken within 1 year of starting the study) and research blood tests. TREMELIMUMAB 75 mg DOSE ER-POSITIVE AND ER-NEGATIVE COHORTS: Study treatment takes place in 2 phases: 1) Induction Phase (weeks 1-16); and 2) Treatment Phase (weeks 17-52). Induction Phase During the Induction Phase, participants will receive: 1) 4 doses of durvalumab (1 dose every 4 weeks), administered intravenously; 2) 4 doses of tremelimumab (1 dose every 4 weeks), administered intravenously; 3) 16 doses of trastuzumab (1 dose every week), administered intravenously. Treatment Phase Participants will receive durvalumab and trastuzumab every 3 weeks for 12 doses (total 36 weeks). Tremelimumab will not be given. A research blood sample will be taken every 9 weeks, before each dose of study treatment. TREMELIMUMAB SINGLE 300 mg PRIMING DOSE COHORT One cycle is 3 weeks (maximum of 18 cycles). 1) Tremelimumab 300 mg Day 1, Cycle 1 only (1 dose only) 2) Durvalumab 1120 mg Day 1, Cycle 1 then every 3 weeks for up to 1 year (18 doses) PLUS 3) Trastuzumab: * 6 mg/kg Day 1, Cycle 1 then every 3 weeks for up to 1 year (18 doses) * Loading dose of 8 mg/kg Cycle 1 Day 1 if > 6 weeks since the last trastuzumab or TDM-1 dose. Research blood samples will be collected at Week 10 and Week 16. For all cohorts: Oestrogen-receptor-positive patients will also start or continue endocrine therapy (aromatase inhibitor and/or GnRH agonist). Two core biopsies, if feasible, will be taken from the same site as the initial biopsy about 3 weeks after starting study treatment. During the study heart function tests (ECHO or MUGA) will be performed every 3 months as per standard of care, or as clinically indicated. Participants will be clinically assessed before each study treatment. The full length of treatment is 52 weeks (1 year). After completing study treatment, patients will be followed every 3 months by either clinic visits or via telephone. Read more

Key Inclusion Criteria

1) Written informed consent prior to performing any protocol-related procedures, including screening evaluations. 2) Written consent to biological material submission. 3) Female or Male, age >= 18 years. 4) Local histologically confirmed HER2-positive on a recent biopsy. This can be as per ASCO-CAP guidelines: IHC testing with a result of IHC 3+, or IHC 2+ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres >= 2.0 or mean gene copy number >= 6, unresectable loco-region .... 1) Written informed consent prior to performing any protocol-related procedures, including screening evaluations. 2) Written consent to biological material submission. 3) Female or Male, age >= 18 years. 4) Local histologically confirmed HER2-positive on a recent biopsy. This can be as per ASCO-CAP guidelines: IHC testing with a result of IHC 3+, or IHC 2+ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres >= 2.0 or mean gene copy number >= 6, unresectable loco-regional or metastatic breast cancer. HER2 status will be confirmed centrally retrospectively. 5) Locally assessed oestrogen receptor status based on mandatory biopsy. ER-positive is defined as >= 1% (any PR expression). ER-negative is defined as ER < 1% (any PR expression); 6) Must have previously received trastuzumab and pertuzumab in either the (neo)adjuvant or advanced disease setting where appropriate in the first line advanced setting. 7) Must have trastuzumab resistant disease, defined by any of the following: * Demonstrated progression of disease while on-treatment with trastuzumab (monotherapy or combination-based therapy) or trastuzumab emtansine (TDM-1) for metastatic or unresectable loco-regional disease; * Recurrence considered incurable while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab; * Any number of prior lines of anti-HER2 therapy is acceptable. Patients who have not received any HER2 therapy in the advanced disease setting, must have received prior pertuzumab in the neo/adjuvant setting; * Progression/recurrence must have been demonstrated by radiological or clinical assessment. 8) If a participant has received a subsequent anti-HER2 therapy, she/he must also have progressed on the subsequent therapy. Progression must have been demonstrated by radiological or clinical assessment. 9) Body weight > 30 kg. 10) Able to commence treatment within 7 days of registration. 11) Availability of 2 FFPE tumour biopsies or 15-20 slides for retrospective central testing of HER2 positivity, assessment of PD-L1 status, TIL level, and for translational research taken from unresectable loco-regional or metastatic disease obtained =< 1 year prior to enrolment. Alternatively, new tissue material from a recently obtained surgical or diagnostic biopsy can be submitted. Tissue obtained for the biopsy must not have been previously irradiated. Note: Submission of a tumour biopsy for central pathology review and translational research is mandatory for this study, however central confirmation of HER2-positivity is not required for eligibility. At least two core biopsies should be available. 12) Measurable disease per RECIST v1.1. 13) Have 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 within 3 months of registration. 14) Participant has ECOG 0-1. 15) Life expectancy > 3 months. 16) Adequate organ and marrow function as defined below: * Haemoglobin >= 9.0 g/dL; * Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3); * Platelet count >= 75 x 10^9/L (> 75,000 per mm^3) * Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed; * AST (SGOT)/ALT (SGPT) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN; * Creatinine =< 1.5 x ULN or serum creatinine clearance > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. * International Normalized Ratio (INR) or Prothrombin Time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as INR, PT or APTT is within therapeutic range of intended use of anticoagulant. 17) Agrees to use of condoms and non-hormonal IUD from screening to 7 months after the last dose of trastuzumab, or 180 days after the last dose of durvalumab + tremelimumab combination therapy, or 90 days after the last dose of durvalumab monotherapy (whichever is longest). 18) Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. 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: * 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). * 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). 19) Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations during both the treatment and follow-up phases. 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Key Exclusion Criteria

1) Previous history of primary HER2 non-amplified invasive breast cancer (of different subtype) in the last 3 years. 2) Participation in another clinical study with an investigational product during the last 4 weeks before enrolment. 3) Prior cytotoxic treatment less than 2 weeks before the planned first dose of Durvalumab and Tremelimumab. 4) Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA-4, including tremelimumab. 5) No FFPE material to centrally ass .... 1) Previous history of primary HER2 non-amplified invasive breast cancer (of different subtype) in the last 3 years. 2) Participation in another clinical study with an investigational product during the last 4 weeks before enrolment. 3) Prior cytotoxic treatment less than 2 weeks before the planned first dose of Durvalumab and Tremelimumab. 4) Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA-4, including tremelimumab. 5) No FFPE material to centrally assess HER2-positivity, PD-L1 expression and TIL levels. 6) Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational study treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable. 7) Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >=470 ms calculated from a single ECG. 8) Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 7 months after the last dose of trastuzumab, or 180 days after the last dose of durvalumab + tremelimumab combination therapy, or 90 days after the last dose of durvalumab monotherapy – whichever is longest will apply. 9) Interstitial lung disease. 10) History of, or active drug-related pneumonitis requiring treatment with steroids. 11) Patients with symptomatic central nervous system (CNS) disease or known leptomeningeal disease are not eligible except for treated asymptomatic CNS metastases, provided that all of the following criteria are met: * Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord). * No ongoing requirement for corticosteroids as therapy for CNS disease. * No ongoing generalized or complex partial seizures. * No stereotactic radiation or whole brain radiotherapy within 14 days prior to study treatment. No evidence of interim progression (clinical or radiological) between the completion of prior CNS-directed therapy and commencement of study. Repeat CNS imaging should be done as clinically indicated. * Note: Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may be eligible without the need for an additional brain scan prior to enrollment, if all other criteria are met. * Patients who have CNS metastases deemed too small to treat and detected at screening must demonstrate stability in size (=/<5mm) on a follow-up scan minimum of 3 weeks later. 12) Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization. 13) Leptomeningeal disease. 14) Symptomatic pleural effusion, pericardial effusion, or ascites requiring frequent drainage (< 2 weekly). 15) History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification > 3), angina, myocardial infarction or ventricular arrhythmia. 16) Previous severe hypersensitivity reaction to treatment with another monoclonal antibody. 17) Active or uncontrolled infection CTCAE V4.03 grade 2 or higher. 18) Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 19) Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. 20) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia; * Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement; * Any chronic skin condition that does not require systemic therapy; *Patients with celiac disease controlled by diet alone. 21) History of primary immunodeficiency. 22) History of allogeneic organ transplant. 23) Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 24) Chemotherapy, radiotherapy, and/or biological cancer therapy (except trastuzumab and endocrine therapy) within 2 weeks prior to the first study dose and has not recovered to CTCAE V4.03 grade 1 or better from adverse events (except alopecia grade 2). Prior chemotherapy induced neuropathy should be grade 2 or better. 25) Any unresolved toxicity NCI CTCAE Grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Chair and the Director/Deputy Director of Research. 26) Live vaccines within 30 days prior to the first dose of investigational study treatment and during investigational study treatment. 27) Previous or concomitant invasive malignancy (except breast cancer). The exceptions are: * participants with non-breast malignancy >= 3 years ago, treated with curative intent and without evidence of recurrence; * basal or squamous cell carcinoma of the skin; * in situ carcinoma without invasion (includes in situ breast carcinoma). 28) Any condition that, in the opinion of the investigator, would interfere with evaluation of investigational study treatment or interpretation of participant safety or study results. Read more

Can healthy volunteers participate?

No