Study design and participants
bleeding, death, toxicity, haemoptysis, cavitating lung metastases, tumour, Toxicity
ADVERSE REACTIONS, DISEASE PROGRESSION, BLEEDING, ADVERSE EVENT, DISEASE, RECRUITMENT, BONE SARCOMA, SOFT TISSUE SARCOMA, TUMOUR, DISEASE, METASTASES, SOFT TISSUE TUMOURS
Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II clinical trial of oral axitinib in patients with advanced soft tissue sarcoma. Patients were recruited to one of four separate pathological strata according to the World Health Organisation 2002 classification for soft tissue tumours [Eligible patients were aged ≥16 years, WHO performance status ≤2, with pathologically confirmed locally advanced or metastatic soft tissue sarcoma, incurable by surgery or radiotherapy, and had received no more than two prior lines of chemotherapy for advanced disease. Patients had measurable disease according to RECIST 1.1 criteria [Following the reporting of two suspected unexpected serious adverse reactions (SUSARs), patients with cavitating lung metastases, or any metastases abutting or invading a major pulmonary blood vessel, were also deemed ineligible; and patients were excluded if they had a history of haemoptysis. Furthermore, exclusion due to history of bleeding was extended from the previous three to 12 months, and with chest x-rays added at four and eight weeks into the trial patient pathway. The full eligibility criteria are detailed in the trial protocol (supplementary appendix ProceduresAxitinib (Inlyta, Pfizer) was taken orally as 5 mg tablets, twice daily continuously in 28-day cycles until disease progression, death, unacceptable toxicity, or withdrawal of patient consent. One dose reduction to 3 mg twice daily was permitted.The pre-treatment evaluation included medical history, physical examination, full blood count, clinical biochemistry, urinary protein, chest x-ray, 12 lead-ECG and cardiac ECHO/MUGA. Disease assessment via CT or MRI scans and photos (where indicated) were performed within four weeks prior to starting trial treatment, and then 12-weekly until disease progression. Treatment responses were assessed by RECIST 1.1 [Adverse events (AE) according to NCI-CTCAE v4.03 [After disease progression, patients were followed up every three months for survival.OutcomesThe primary outcome measure was progression free-survival at 12 weeks from trial entry (PFS12), in patients who received at least one cycle of treatment; patients who were alive with stable or responding disease at this time were defined as success. Secondary outcome measures included tumour response (i.e., complete or partial response as per RECIST 1.1 [Circulating biomarker analysisSerum samples for biomarker analysis were collected pre-treatment, and at the start of each cycle until treatment discontinuation. Peripheral blood was collected in 8.5 ml BD no additive Vacutainers, kept at room temperature for 30 min to ensure complete clotting, and then centrifuged at 2000 Statistical analysisThe trial used a Simon’s two-stage phase II minimax design, with each pathological stratum analysed separately. Consistent with EORTC Soft Tissue and Bone Sarcoma Group guidance [An independent data monitoring committee (DMC) reviewed interim data annually to ensure patient safety. A planned interim analysis was scheduled in each stratum when 18 patients had completed a minimum of 12 weeks follow-up. If fewer than five successes were observed, recruitment to the stratum would be closed; if five or more successes were observed, the stratum would continue to recruit.The final analysis of the primary outcome was conducted using a modified intention-to-treat (ITT) approach and took place after all patients within a stratum had been followed for a minimum of 12 weeks and is reported as PFS12 rate with a one-sided 95% lower confidence interval (LCI) in accordance with the type I error rate used in the design. The tumour response rate is reported as the proportion of patients who experience complete or partial response with 95% confidence intervals (CI). PFS, PFI, and OS were analysed using the Kaplan-Meier method of estimation, with median survival and survival rates at one year reported alongside 95% CI. Baseline performance status is reported against the status recorded at the end of cycle 3. Toxicity rates are reported with 95% CI.For the analysis of PFS12 and tumour response at 12 weeks, evaluable patients were defined as those patients who received at least one cycle of treatment. For all other outcomes, evaluable patients were defined as those who received at least one dose of treatment. Both populations included ineligible patients who received sufficient treatment to be considered evaluable, if the reason for ineligibility was not deemed to influence the outcome being analysed. For PFI, patients who died of disease without any recorded disease progression have been defined as having progressed at the date of death, whilst those who died of other causes were censored at their date of death. For PFS and PFI, patients alive and progression-free at the time of analysis were censored at their date last known to be in this state. Similarly, for OS, patients alive at the time of analysis were censored at the date last seen alive.The best percentage change from baseline in the total sum of diameters of target lesions is presented incorporating the best response (at any timepoint) of each patient using waterfall plots; the total sum of diameters (measured in mm) at baseline was calculated and compared to each subsequent disease evaluation visit.Analyses were performed using Stata 17.0.The trial was prospectively registered: ISRCTN 60791336.