Clinical Trial: AZD6738 First Time in Patient Multiple Ascending Dose Study

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Two-part Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti-tumour Activity of Multiple Ascending Doses of AZD6738 in

Brief Summary:

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

Detailed Summary:

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).

Current Primary Outcome: Parts A and B: Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures. [ Time Frame: From baseline until 28 days after discontinuation of study treatment, assessed up to 29 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Part A only: Define either the Maximum tolerated dose (MTD), if possible, or maximum feasible dose (MFD) [ Time Frame: DLT's assessed during the 21 day assessment period ]
  Define optimum dosing schedule in Part A of the study
• Part B only: Preliminary assessment of the effect of food on the Pharmacokinetic (PK) parameters of AZD6738 via plasma analysis [ 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. ]
  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
• Parts A&B: Establish pharmacokinetics characteristics of AZD6738 and its active metabolite from plasma analysis [ 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) ]
  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
• Part A and B: Anti tumour activity by assessing tumour response via CT or MRI scans [ Time Frame: CT/MRI - Baseline, weeks 8, 16 and every 16 weeks thereafter. ]
  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.
• Part A and B: Measuring 4 beta-hydroxy cholesterol concentration for assessment of CYP3A4 induction potential [ Time Frame: Part A: Cycle 0 day 1 and cycle 1 day 15. Part B: Cycle 1 day 1 and cycle 1 day 15 ]
  Blood samples will be collected from all patients at timeframe specified for the determination of 4-beta-hydroxy cholesterol concentrations in plasma.
• Part B: Pharmacokinetic profile of AZD6738 and its active metabolite from urinalysis [ Time Frame: Part B C1D1: Pre-dose,0-3, 3-6, 6-9 and 9-24 hr post dose ]
  Urine sample parameters: Amount of drug excreted unchanged into urine, fraction dose excreted, (% dose), renal and non renal clearance.
• Part B only: Preliminary assessment of the effect of food on the PK parameters of AZD6738 via urinalysis [ Time Frame: Urine Samples collected at cycle 1, day 2 at: Pre-dose,0-3,3-6,6-9,9-24 hr post dose ]
  Urine sample measures: Amount of drug excreted unchanged into urine, fraction dose excreted, (% dose), renal and non renal clearance.
• Part A: Determine the extent of ATR target inhibition using pharmacodynamic biomarkers [ 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. ]
  Mandated blood samples collected for downstream analysis of downstream analysis of ATR pathway biomarkers in CLL cells
• Part A and B: Biomarker analysis using lymph node biopsies [ 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 ]
  Optional lymph node core needle biopsy
• Part A and B: Confirmation of tumour response assessment by analysing bone marrow / aspirate [ 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 ]
  Bone marrow aspirtate/biopsy will be used to confirm marrow assessments to fufil the requirements for complete response.
• Part A and B: Bone marrow biopsy or aspirate will be analysed for biomarkers [ 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
  
  

  Original Secondary Outcome: Same as current
  
  Information By: AstraZeneca
  

  Dates:
  Date Received: September 30, 2013
  Date Started: November 2013
  Date Completion:
  Last Updated: June 18, 2014
  Last Verified: June 2014