Interventions
diarrhoea, bleeding, Tumour, neutropenia, stomatitis, toxicity, toxicities, malignancy, thrombocytopenia, dose-limiting, ≤28, nausea, vomiting
DISEASE PROGRESSION, BLEEDING, TUMOUR, NEUTROPENIA, FEBRILE NEUTROPENIA, STOMATITIS, THROMBOCYTOPENIA, ADVERSE EVENT
AZD2811 was administered as an IV infusion over 2 h. The study included 12 dose-escalation cohorts. In Cohorts 1–6, dosing took place on Days 1 and 4 of a 28-day cycle, at 15 mg, 25 mg, 38 mg, 51 mg, 100 mg, and 200 mg. In Cohort 1, the starting dose was to be administered to a single patient on Days 1 and 4. If this patient had a dose-limiting toxicity (DLT) or grade ≥2 adverse event (AE), more patients could be added to Cohort 1, up to a maximum of 6. Starting with Cohort 2, at least 3 evaluable patients were enrolled at each dose level (3 + 3 design) and were evaluated for 1 cycle before escalation to the next dose level. If one patient experienced a DLT, an additional 3 patients were treated with the same dose. Therefore, a maximum of 6 evaluable patients could be enrolled per dose level.In Cohort 7, the Day 4 dose was removed from the schedule, and patients received AZD2811 200 mg on Day 1 of a 28-day cycle. Granulocyte colony-stimulating factor (G-CSF; filgrastim [short-acting G-CSF] or pegfilgrastim [long-acting G-CSF]) as primary prophylaxis for neutropenia was optional in Cohorts 7–9. In Cohorts 8–12, the cycle length was reduced, so dosing occurred on Day 1 of a 21-day cycle, at doses of 200–600 mg. Patients in Cohorts 10–12 received mandatory G-CSF on Day 8 after dosing in Cycle 1 as primary prophylaxis for neutropenia. PEGylated G-CSF (e.g. pegfilgrastim) could not be given later than Day 8 (in a 21-day cycle) due to its long half-life. G-CSF had to be discontinued at least 48 h prior to the next dose of AZD2811.Patients could continue to receive AZD2811 as long as they continued to show clinical benefit, as judged by the investigator, and did not meet discontinuation criteria. Treatment could be discontinued due to patient decision, investigator decision, AEs, severe noncompliance with the protocol, confirmed disease progression, or incorrect initiation of the investigational drug.A DLT was defined as any of the following toxicities that occurred during the DLT evaluation period (the first 28 days [if a 28-day cycle] or the first 21 days [if a 21-day cycle] from the start of AZD2811), unless unequivocally due to underlying malignancy or an extraneous cause: grade 4 neutropenia for >7 days or febrile neutropenia; grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding; concurrent grade ≥3 elevation of total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) lasting >48 h, or any change in liver function test results consistent with Hy’s Law; any grade ≥3 non-haematological AE (except grade 3 nausea, vomiting, stomatitis and/or diarrhoea that was controlled within 4 days with standard supportive care, or grade 3 elevations in ALT/AST that return to meet initial eligibility criteria within 7 days of study drug interruption); inability to receive all doses in Cycle 1 due to treatment-related toxicity; or grade ≥2 non-haematological toxicity at any time during treatment that was deemed to be dose-limiting by the investigator and the medical monitor. The MTD/RP2D was evaluated in patients who received all AZD2811 doses in Cycle 1 and completed all safety evaluations, or had a DLT in Cycle 1.AEs were assessed throughout the treatment and follow-up periods. Patients were followed until all treatment-related toxicity resolved, or for at least 30 days post-study drug discontinuation. AEs were graded according to CTCAE v4.03. Venous blood samples (4 mL) for measurement of AZD2811 concentrations were collected at Cycle 1 Days 1–6, 8, 15, 16, and 22 and Cycle 2 Day 1 in Cohorts 1–6; Cycle 1 Days 1, 4, 8, 12, and 22 in Cohort 7; Cycle 1 Days 1, 4, 8, 12, and 15 and Cycle 2 Day 1 in Cohorts 8–12. Tumour imaging assessments using computed tomography or magnetic resonance imaging of the chest and abdomen/pelvis were performed at screening (≤28 days prior to initiation of treatment), and then every 2 cycles.