2.1 Objectives
Primary
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Assessment of toxicity
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Assessment of progression-free survival (PFS)
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Secondary
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Assessment of clinical response in ipi/nivo/chemo group compared to chemo only group: Objective tumor response rate (ORR), duration of response (DR), durable tumor response rate (DRR; >6 months), clinical benefit rate (CBR), overall survival (OS)
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Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm
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Assessment of ORR, DR, DRR, CBR, PFS and OS in cross-over arm receiving ipi/nivo (without chemotherapy)
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Assessment of PD-L1 expression, mutation load and immune gene expression as biomarkers for clinical response
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Comparison of clinical and biological response in molecular subtypes of breast cancer
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Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ), an 11 point Numerical Rating Scale (NRS) for pain intensity and EORTC QLQ-C15-PAL
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Exploratory
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Assessment of immunological response
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Identification of biomarkers for clinical response, toxicity and immune response
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Characterization of tumor evolution and changes in immunological milieu induced by the combination therapy (ipi/nivo/chemo), as compared to chemo only, and by ipi/nivo without concomitant chemotherapy
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2.2 Study design
This is a randomized phase IIb study evaluating the safety and efficacy of combining nivolumab and ipilimumab with immunogenic chemotherapy in subjects with metastatic HR+ breast cancer. The patients will be randomized 2:3 into two arms (A:B):
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Arm A: Chemotherapy only (pegylated liposomal doxorubicin + cyclophosphamide)
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Arm B: Chemotherapy + ipilimumab + nivolumab
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Upon progression, patients may continue study treatment until loss of clinical benefit.
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The patients in arm A will be offered nivo/ipi (without chemotherapy) after disease progression..
2.3 Study treatment
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Nivolumab 240mg intravenously (i.v.) every 2nd week until disease progression or for a maximum of 24 months (flat dose of 240mg recommended by BMS)
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Ipilimumab 1mg v. every 6th week until disease progression (maximum 24 months)
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Pegylated liposomal doxorubicin (PLD; Caelyx) 20mg/m2 i.v. every 2nd
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Cyclophosphamide tablets 50 mg per day, daily for 2 first weeks in each 4 week cycle.
Rationale for immunotherapy regime: The combination of CTLA-4 and PD-1 checkpoint blockade has shown high efficacy in melanoma, but also a relatively high frequency of grade 3 and 4 adverse events. This toxicity mainly correlates with the Ipilimumab dosage. We therefore use a low dosage of Ipilimumab (1 mg/kg vs 3 mg/kg in melanoma) and prolonged intervals between treatments (6 weeks). This regime has in recent studies shown good efficacy and a much safer toxicity profile [6, 17].
Rationale for chemotherapy regime: Doxorubicin and cyclophosphamide are particularly powerful inducers of immunogenic cell death and thus attractive for combination with immune checkpoint inhibitors. We employ a semi-metronomic regime, rather than a high dose regime administered every 3rd/4th week, to maintain the ability of the effector immune cells to respond. Further, metronomic cyclophosphamide has been used to counter regulatory T cells (Tregs) and myeloid suppressor cells (MDSCs) [18], and has also been applied against metastatic breast cancer [19]. We use pegylated liposomal doxorubicin to avoid steroids, minimize the adverse effects of antracyclins on the heart and allow for continued treatment beyond otherwise mandatory antracyclin limits.
2.4 Sample collection/biobanking
Samples are collected before, during and after therapy (time of progression/treatment discontinuation). Some of the biobanking procedures are not performed at all study centers. The following samles are collected: Biopsies, Peripheral blood mononuclear cells (PBMC), plasma, serum, urine, feces, circulating tumor cells.
2.5 Selected inclusion criteria
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Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ >1% in metastatic biopsy (archival material or study biopsy) or cytology and HER2 negative in the last biopsy or cytology evaluable for HER2.
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Adequate core or excisional study biopsy of a tumor lesion.
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Measurable metastatic disease according to RECIST
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
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Signed Informed Consent Form
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Women or men aged ≥ 18 years
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A minimum of 12 months from adjuvant/neoadjuvant chemotherapy with antracyclins to relapse of disease.
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A maximum of one previous line with chemotherapy in the metastatic setting
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Previous endocrine and targeted therapy is allowed
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Adequate organ function as defined in the protocol
2.6 Selected exclusion criteria
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Malignancies other than breast cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome
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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
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Known CNS disease, except for asymptomatic CNS metastases, provided all of the following criteria are met:
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Measurable disease outside the CNS
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Asymptomatic for CNS disease > 4 weeks
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No ongoing requirement for corticosteroids as therapy for CNS disease
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No radiation of brain lesions within 2 weeks prior to randomization
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No leptomeningeal disease
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Uncontrolled pleural effusion, pericardial effusion, or ascites.
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Pregnant or breastfeeding
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Received treatment with immune checkpoint modulators
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Received treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
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Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
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Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
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The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
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Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to study Cycle 1, Day 1. Palliative radiotherapy for bone lesions is allowed up to 7 days before start of therapy.
2.7 Outcome measures
2.7. 1 Safety Outcome Measures
The safety outcome measures will be evaluated in the ITT population, as follows:
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Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0
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Changes in vital signs, physical findings, and clinical laboratory results
2.7.2 Efficacy Outcome Measures
The PFS is defined as the time from randomization to the time of radiographic progression (as assessed by RECIST v1.1) or death from any cause during the study. Data for patients with a PFS event who missed two or more assessments scheduled immediately prior to the date of the PFS event will be censored at the last tumor assessment prior to the missed visits. If no tumor assessment was performed after randomization, data will be censored at the date of randomization +1 day. Clinical deterioration without objective radiological evidence will not be considered as documented disease progression. The primary efficacy outcome measure (PFS) is to be assessed in patients evaluable per protocol (PP).
The secondary efficacy outcome measures will be assessed in the PP population, ITT population and in the PD-L1-positive subpopulation. The ITT population is defined as a full analysis set (FAS). The FAS is defined as all patients that have started therapy with at least one of the IMPs, and where data on the relevant endpoint is obtained. The safety will be evaluated in the ITT (FAS) population.
2.8 Statistics
A descriptive analysis of demographics, medical history, and clinical data will be performed.
The primary efficacy analysis will be an analysis of PFS in the combination arm(B), compared to the control arm(A). Comparison between treatment arms will also be given by HR for disease progression or death using a Cox proportional hazards model. The HR will be adjusted for the relevant variables (e.g. from list below). The confidence interval for the HR will be provided. Kaplan-Meier methodology will be used, and Kaplan-Meier curves will be produced.
Overall survival (OS) will be calculated from time of randomization until death. Patients alive at the time of data analysis will be treated as censored. OS will be estimated by the Kaplan Meier method.
Exploratory analyses will be carried out to evaluate the data of the immunological and molecular analyses (e.g. biomarker studies) carried out. The statistical analyses will be dependent on the biological factors investigated and the analysis methodology used, and will be defined separately for each molecular study.
A data-driven time point for PFS-analysis has been defined, as 70 PFS events in the PP population. If this is not met within 24 months after inclusion of the last patient, the PFS-analysis will be performed at this time point.
The primary data analysis will be performed on the PP population and analyzed according to the following factors:
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Tumor PD-L1 status
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Disease free interval between end of (neo)adjuvant chemotherapy or surgery, whichever was last, and relapse
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Time from diagnosis of metastatic disease to start of therapy in the ICON-study
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Prior chemotherapy against metastatic disease (no previous chemo vs. previous chemo).
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Sites of metastases
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Molecular breast cancer profile, including PAM50 subtype, and immune gene profile
Exploratory analyses will be carried out to evaluate data from translational studies. Here, statistical methods will be defined separately for each study, as advised by the statisticians.