Background
Methods
Objectives
Primary objective
Secondary objectives
Trial design
Run-in period | Study period | Observation period | ||
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SBRT | Three fractions of 8 Gy every other day | |||
Anti-PD-1 treatment | First cycle | Second cycle | Continuation |
Outcome measures
Primary endpoint
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Objective response rate of the non-irradiated metastases as determined by the response evaluation criteria in solid tumours (RECIST) v1.1 [13]. Response rate will be defined as the percentage of subjects achieving either a complete or partial response at 6 weeks after the start of anti-PD-1 treatment. Further follow up imaging will be performed at the discretion of the treating physician.
Secondary endpoints
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Objective response rate of the non-irradiated metastases as determined by immune related response criteria (irRC) [14].
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Metabolic response of the irradiated and non-irradiated metastases based on the European Organization of Research and Treatment of Cancer (EORTC) 1999 criteria [15].
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Local control defined as the time between local irradiation and the moment the irradiated lesion shows an increase in size of ≥20%, according to the RECIST V1.1, confirmed by a consecutive assessment at least 4 weeks after first documentation.
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PFS: two types of PFS will be defined. One as the time from inclusion to documented disease progression according to RECIST v1.1 or death from any cause. The other as the time from inclusion to documented disease progression according to irRC or death from any cause.
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Acute and late toxicity due to the combination treatment will be scored using the Common terminology criteria for adverse events (CTCAE) version 4.0.
Exploratory endpoint
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Immunologic responses assessed using peripheral blood samples and analysed with fluorescence-activated cell sorting (FACS) phenotyping, functional testing, ultra-performance liquid chromatography (UPLC) and enzyme-linked immunosorbent assay (ELISA). If feasible, immunologic responses will also be assessed on tumour tissue using IHC.
Study population
Inclusion criteria
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Before patient registration, written informed consent must be given according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP), and national/local regulations.
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Histologically confirmed diagnosis of melanoma.
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Be able to provide tissue from an archival primary tissue sample or a newly obtained biopsy, for the evaluation of PD-L1 and other immune markers using immunohistochemistry (IHC).
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At least two extracranial measurable metastatic lesions per RECIST v1.1 and irRC. All radiological studies must be performed within 28 days prior to registration.
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Previous BRAF inhibitor when elevated lactate dehydrogenase (LDH) in patients with BRAF V600 mutations is allowed.
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Karnofsky Performance status >60.
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Age 18 years or older.
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Female participants of childbearing potential must be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment.
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Female participants who are breastfeeding or plan to breastfeed should be instructed to discontinue nursing during treatment.
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Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study treatment.
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Demonstrate adequate organ function defined as the following:
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Serum aspartate and alanine aminotransferase (AST and ALT) levels ≤2.5× upper limit of normal (ULN) or ≤5× ULN in patients with liver metastases.
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Serum total bilirubin ≤1.5× ULN or direct bilirubin ≤ULN for patients with total bilirubin level >1.5 ULN.
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Serum creatinine ≤1.5× ULN.
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Absolute neutrophil count ≥1000/mcL.
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Platelets ≥75,000/mcL.
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Hemoglobin ≥9 g/dL or ≥5.6 mmol/L.
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No history of active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents.
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Subjects who have had another malignancy should be disease-free for 5 years, or should have a history of completely resected non-melanoma skin carcinoma or successfully treated in situ carcinoma.
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No evidence of interstitial lung disease.
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No uncontrolled central nervous metastases and/or carcinomatous meningitis.
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No prior radiotherapy interfering with the radiotherapy treatment in the study.
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No concomitant therapy with interleukin-2, interferon, other immunotherapy regimens, chemotherapy, immunosuppressive agent or chronic use of systemic corticosteroids.
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No active infection requiring systemic therapy.
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No known history of human immunodeficiency virus.
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No known active Hepatitis B or Hepatitis C infection.
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Subjects should not have received a live vaccine within 30 days prior to start of study treatment.
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Subjects without a mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study.
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Subjects who are likely to comply with the protocol; i.e. no uncooperative attitude, no inability to return for follow-up visits, and likely to complete the study.
Evaluation and randomization
Intervention
SBRT
Systemic therapy
Evaluation of pre-treatment PD-L1 expression
Evaluation of the immunological response
Follow-up
Sample size
Optimal two stage design | Optimum design |
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First stage sample size (n1) | 20 |
a1 | 6 |
b1 | 12 |
Maximum sample size (n) | 40 |
b2 | 17 |
Data analysis
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The goal of the proposed trial is to determine the efficacy of the proposed combination sequence of anti-PD-1 treatment and radiotherapy. The primary endpoint is the objective response rate as per RECIST v1.1. The null hypothesis that the true response rate is 0.34 [3] will be tested against a one-sided alternative. The null hypothesis will be rejected if 18 or more responses are observed in 40 patients.
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PFS is defined from the day of randomization until progression or last follow-up. Cases will be censored at last follow up visit if no progression was observed. Multivariate analysis will be performed according to the Cox-Regression method.
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For the evaluation of immunological markers over time, differences between groups will be tested by using the Friedman test. To compare proportions of categorical variables, the Pearson’s Chi2 test or Fisher’s Exact test will be used. To evaluate correlations, Spearman correlation coefficients will be calculated. All statistical analyses will be done on an ‘intention-to-treat’ basis and performed using SPSS 24.0 (SPSS Inc, Chicago, IL, USA), a P-value less than 0.05 will be considered statistically significant.