This Phase I study is primarily designed to evaluate the safety and tolerability of AZD2811 at increasing doses in patients with advanced solid tumours and for whom no standard of care exists. The study will be conducted in two parts, a dose-escalation phase (Part A) and a dose expansion phase (Part B). During Part A, the dose-escalation phase, patient enrolment will proceed according to a 3+3 design where the maximum tolerated dose (MTD) or the recommended Phase II dose (RP2D) could be identified. The study will also characterize the pharmacokinetic (PK) profile of AZD2811 and will explore the potential biological activity by assessing anti-tumour activity in patients. Part B will further explore PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD2811 RP2D as monotherapy (Group 1) in patients with relapsed/refractory SCLC.
This is a first-time-in-patient (FTIP) study with the nanoparticle formulation of AZD2811 primarily designed to evaluate the safety and tolerability of AZD2811 at increasing doses in patients with advanced solid tumours and for whom no standard of care exists. The study will be conducted in two parts: Part A dose-escalation and Part B dose-expansion. In Part A, the dose-escalation phase, patient enrolment has proceeded according to a 3+3 design in order to identify the maximum-tolerated dose (MTD) or recommended Phase 2 dose (RP2D). AZD2811 monotherapy has been administered IV to patients with advanced solid tumours on Days 1 and 4 of a 28-day cycle in 6 dose levels without any relevant toxicities in the first 5 patient cohorts. In Cohort 6 (200 mg), grade 4 asymptomatic neutropenia was observed, and a dose-limiting toxicity was observed in 1 patient of the 5 evaluable patients. In Cohort 7 AZD2811 (200 mg) was given on Day 1 only of a 28-day cycle; in Cohort 8 AZD2811 (200 mg) was given on Day 1 only of a 21-day cycle. In Cohort 9, the AZD2811 dose was escalated to 400 mg on Day 1 every 21 days. The Safety Review Committee (SRC) will review the safety and tolerability of AZD2811 for each cohort and schedule to determine the next cohorts. The study will also characterize the pharmacokinetic (PK) profile of AZD2811 and will explore potential biological activity by assessing anti-tumour activity in patients. Once the MTD is established, Part B the dose expansion phase will continue to explore PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD2811 RP2D as monotherapy in 21 patients with relapsed/refractory SCLC.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
The study will be conducted in 2 parts, dose-escalation (A) and dose-expansion (B). All patients in both parts of the study with receive AZD2811.
Research Site
Denver, Colorado, United States
Research Site
Sarasota, Florida, United States
Research Site
Boston, Massachusetts, United States
Research Site
Nashville, Tennessee, United States
Research Site
Houston, Texas, United States
Research Site
Milwaukee, Wisconsin, United States
The incidence of dose-limiting toxicites (DLTs)
Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results. DLT is defined as: 1. Grade 4 neutropenia for \> 7 days, or febrile neutropenia. 2. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding. 3. Concurrent Grade ≥3 total bilirubin, ALT or AST or alkaline phosphatase lasting \> 48 hours, or any change in liver function test results consistent with Hy's Law. 4. Grade ≥3 non-hematologic AE except: a) Grade 3 diarrhoea controlled within 4 days with standard supportive care, b) Grade 3 elevations in ALT/AST that return to meet initial eligibility criteria within 7 days of study drug interruption. 5. Inability to receive all doses in Cycle 1 due to treatment-related toxicity. 6. Non-haematologic toxicity of ≥ Grade 2 (at any time during treatment) that, in the judgment of the Investigator and the Medical Monitor, is dose limiting.
Time frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of Dose Limiting Toxicities (DLTs).
The incidence of adverse events
Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results. At least 3 evaluable patients will be enrolled at each dose level (3+3 design) and will be evaluated for 21 or 28 days before escalation to the next dose level can occur. If one patient experiences a DLT, an additional 3 patients will be treated with the same dose. Therefore, a maximum of up to 6 patients may be enrolled per dose level.
Time frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of adverse events
The incidence of abnormal laboratory results
Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results. At least 3 evaluable patients will be enrolled at each dose level (3+3 design) and will be evaluated for 21 or 28 days before escalation to the next dose level can occur. If one patient experiences a DLT, an additional 3 patients will be treated with the same dose. Therefore, a maximum of up to 6 patients may be enrolled per dose level.
Time frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of abnormal laboratory results.
Maximum plasma concentration (Cmax) of encapsulated AZD2811, released AZD2811, and AZD2811 metabolites
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose, and Cycle 2/Day 1 pre-dose and 2 hr post dose.
Time to maximum plasma concentration (tmax) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose, and Cycle 2/Day 1 pre-dose and 2 hr post dose.
Area under the plasma concentration-time curve from zero to the last measurable concentration [AUC(0-t)] for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose.
Area under the plasma concentration-time curve from zero extrapolated to infinity [AUC(0-inf)] for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose.
Terminal rate constant (λz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose.
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Terminal elimination half-life for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose.
Volume of distribution (Vz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites.
PK parameters will be derived by non-compartment analysis.
Time frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose.
Objective Response Rate (ORR), including the number of complete and partial responses
Baseline tumour imaging studies \[computerized tomography (CT)\] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.
Time frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter
The incidence of Stable Disease (SD)
Baseline tumour imaging studies \[computerized tomography (CT)\] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.
Time frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter
The incidence of Progressive Disease (PD)
Baseline tumour imaging studies \[computerized tomography (CT)\] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.
Time frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter
The proportion of patients surviving at 6 months will assessed in Part B.
Time frame: Survival will be determined at 6 months