In Part A to investigate the safety and tolerability of AZD6738 when given orally to patients with relapsed/refractory CLL, PLL or B cell lymphoma. In Part B to investigate the safety and tolerability of AZD6738 when given orally to patients with prospectively identified 11q deleted or ATM deficient, relapsed/refractory CLL
In this first time in patient study, AZD6738 will be administered to patients with relapsed/refractory chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL) or B cell lymphomas, primarily to determine the safety and tolerability of AZD6738. Pharmacokinetics of AZD6738 and potential biological activity will also be investigated. An oral formulation of AZD6738 will be used. The starting dose of 20 mg twice daily (BD) will be escalated to reach a maximum tolerated dose in patients as defined by dose-limiting toxicity. A '3 week on, 1 week off' schedule, as deemed optimal in modelling of data from non-clinical studies, will be used initially. Following the dose escalation phase of the study, additional patients with prospectively identified 11q-deleted or ATM deficient relapsed/refractory CLL will be enrolled to a dose expansion phase to explore further the safety, tolerability, pharmacokinetics and biological activity at selected dose(s)/schedule(s).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
2
An oral formulation of AZD6738 will be used. The starting dose of 20 mg BD will be escalated to reach a maximum tolerated dose in patients as defined by dose-limiting toxicity. A '3 week on, 1 week off' schedule, as deemed optimal in modelling of data from non-clinical studies, will be used initially
Research Site
La Jolla, California, United States
Parts A and B: Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures.
Safety measures include ECG, physical examination, pulse, blood pressure, body temperature, respiratory rate, weight and laboratory variables
Time frame: From baseline until 28 days after discontinuation of study treatment, assessed up to 29 months
Part A only: Define either the Maximum tolerated dose (MTD), if possible, or maximum feasible dose (MFD)
Define optimum dosing schedule in Part A of the study
Time frame: DLT's assessed during the 21 day assessment period
Part B only: Preliminary assessment of the effect of food on the Pharmacokinetic (PK) parameters of AZD6738 via plasma analysis
Plasma sample parameters: Cmin, Cmax, tmax, tmax ss, tlast, AUC(0-t), AUC(0-12), volume of distribution at steady state (ss) and terminal phase, plasma clearance following single dose and at ss, mean resistance time, t1/2, accumulation ratio for Cmax, accumulation ratio for AUC(0-12), linearity factor AUCss(day8)/AUC(day1). Following PK parameters listed but not summarised, time interval of log linear regression to determine t1/2, coefficient of determination of terminal elimination rate constant and % of AUC extrapolated
Time frame: Blood Samples - Cycle 1 Day 1 for fasted patients at: Pre-Dose, 0.25,0.5,1,2,3,4,6 and 8 hrs post dose. For fed patients Cycle 1, Day 2 :Pre-Dose, 0.25,0.5,1,2,3,4,6 and 8 post dose.
Parts A&B: Establish pharmacokinetics characteristics of AZD6738 and its active metabolite from plasma analysis
Plasma samples for AZD6738 and the active metabolite: Cmin, Cmax, tmax, tmax ss, tlast, AUC(0-t), AUC(0-12), volume of distribution at ss and terminal phase, plasma clearance following single dose and at ss, mean resistance time, t1/2, accumulation ratio for Cmax, accumulation ratio for AUC(0-12), linearity factor AUCss(day8)/AUC(day1). Following PK parameters listed but not summarised, time interval of log linear regression to determine t1/2, coefficient of determination of terminal elimination rate constant and % of AUC extrapolated
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Time frame: Part A Day 1 Single Dosing (predose, 0.25.0.5,1,2,3,4,6,8 24h); Part A - Multiple Dosing Cycle 1 Day 1 and Day 8 (pre-dose, 0.25,0.51,2,3,4,6 and 8). C1D15 (Pre-dose, 1hr). Part B: C1D1: (Pre-dose,0.25.5,1,2,3,4,6,8,24) and at C1D15(pre-dose,1)
Part A and B: Anti tumour activity by assessing tumour response via CT or MRI scans
Anti tumour activity will be assessed using CT / MRI scans to assess the response criteria. For CLL and PLL patients, partial response must be confirmed at least 8 weeks after the initial assessment. No confirmation is required for B cell lymphoma patients.
Time frame: CT/MRI - Baseline, weeks 8, 16 and every 16 weeks thereafter.
Part A and B: Measuring 4 beta-hydroxy cholesterol concentration for assessment of CYP3A4 induction potential
Blood samples will be collected from all patients at timeframe specified for the determination of 4-beta-hydroxy cholesterol concentrations in plasma.
Time frame: Part A: Cycle 0 day 1 and cycle 1 day 15. Part B: Cycle 1 day 1 and cycle 1 day 15
Part B: Pharmacokinetic profile of AZD6738 and its active metabolite from urinalysis
Urine sample parameters: Amount of drug excreted unchanged into urine, fraction dose excreted, (% dose), renal and non renal clearance.
Time frame: Part B C1D1: Pre-dose,0-3, 3-6, 6-9 and 9-24 hr post dose
Part B only: Preliminary assessment of the effect of food on the PK parameters of AZD6738 via urinalysis
Urine sample measures: Amount of drug excreted unchanged into urine, fraction dose excreted, (% dose), renal and non renal clearance.
Time frame: Urine Samples collected at cycle 1, day 2 at: Pre-dose,0-3,3-6,6-9,9-24 hr post dose
Part A: Determine the extent of ATR target inhibition using pharmacodynamic biomarkers
Mandated blood samples collected for downstream analysis of downstream analysis of ATR pathway biomarkers in CLL cells
Time frame: Part A:screening, C0D1, C1D1, C1D8, C1D15, C1D22, C2D1, C3D1, C4D1, every 28 days during maintenance, discontinuation, and 28 days post last dose, then every 4 months during monitoring post last dose.
Part A and B: Biomarker analysis using lymph node biopsies
Optional lymph node core needle biopsy
Time frame: Optional in both Parts A and B at following timepoints: screening, Cycle 1 (C1D8 or C1D15 in Part A and C1D15 in Part B), C2D1, C3D1 and at discontinuation
Part A and B: Confirmation of tumour response assessment by analysing bone marrow / aspirate
Bone marrow aspirtate/biopsy will be used to confirm marrow assessments to fufil the requirements for complete response.
Time frame: Post-dose samples will be collected if clinically indicated for disease assessment. Post dose samples to be collected at approximately 1 month and 2 months after the first dose for both Parts A and B, and every 2 months during maintenance
Part A and B: Bone marrow biopsy or aspirate will be analysed for biomarkers
Biomarkers analysed include, but not limited to H2AX, pCHK, pATR and ATM functional status
Time frame: Pre dose / screening, post dose samples collected at approximately 1 month and 2 months after the first dose, i.e., at C2D1 and C3D1(if clinically indicated for disease assessment), for both Parts A and Part B, and every 2 months during maintenance.
Part A and B: Determination of 11q del status to investigate any potential changes in FISH cytogenetic's post treatment
Testing performed using 5 individual FISH probes in peripheral blood specimens
Time frame: Screening and post-treatment blood samples (10 mL) will be collected at C1D8, C1D15, C2D1, C3D1 (+/- 7 days) in Part A and C1D15, C2D1, and C3D1 (+/- 7 days) in Part B, every 8 weeks during maintenance, and at discontinuation
Parts A and B: Identify patients with ATM deficient status, determine ATM mutation load and correlate this with clinical efficacy in order to better understand patient population which will most likely benefit from AZD6738 treatment
Part A screening is for retrospective analysis. In Part B, the screening blood sample will be tested prospectively.
Time frame: At screening for Part A and B. In Part A during treatment at C1D8, C1D15, C2D1, C3D1, C4D1, during maintenance and at discontinuation. In Part B, post treatment testing performed at C1D15, C2D1, C3D1, C4D1, during maintenance, and at discontinuation.
Part B: The extent of ATR target inhibition identified using pharmacodynamic biomarkers
Mandated blood samples collected for downstream analysis of downstream analysis of ATR pathway biomarkers in CLL cells
Time frame: Part B:screening, C1D1, C1D2, C1D15, C1D22, C2D1, C3D1,C4D1, every 28 days during maintenance, discontinuation, and 28 days post last dose, then every 4 months during monitoring post last dose.