Clinical trial NCT01955668: AZD6738 First Time in Patient Multiple Ascending Dose Study
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 Patients With Relapsed/Refractory B Cell Malignancies With Expansion to Patients With Prospectively Identified 11q-deleted or ATM-deficient, Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 11q-deleted Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL),
Prolymphocytic Leukaemia (PLL)
B Cell Lymphomas
Keywords: 11q-deleted relapsed/refractory chronic lymphocytic leukaemia
Prolymphocytic leukaemia
B cell lymphomas
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: CLL Consortium
First posted: 2013-10-07
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 description: 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).

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
2. For the dose escalation phase, Part A, histological or cytological confirmation of relapsed or refractory B cell malignancy, including CLL, PLL, Burkitt lymphoma/Burkitt cell leukaemia, acute lymphocytic leukaemia, hairy cell leukaemia (HCL) and aggressive and indolent B cell lymphoma, not considered to be appropriate for further conventional treatment.

   For the dose expansion phase, Part B, histological or cytological confirmation of relapsed or refractory 11q-deleted or ATM-deficient CLL, not considered to be appropriate for further conventional treatment.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with no deterioration over the previous 2 weeks and an estimated life expectancy of greater than 16 weeks.
4. Not known to be positive for HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody.
5. Females must be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

   * Post menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
   * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
   * Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution.
6. Ability to swallow and retain oral medication

Exclusion Criteria:

1. Receiving, or having received during the four weeks prior to study entry (signing of consent), treatment for their malignancy.
2. Receiving, or having received during the four weeks prior to study entry (signing of consent), corticosteroids (at a dose \> 10 mg prednisone/day or equivalent) for any reason.
3. A known hypersensitivity to AZD6738 or any excipient of the product.
4. Treatment with any investigational medicinal product (IMP) within 28 days prior to signing of consent.
5. Receiving, or having received, concomitant medications, herbal supplements and/or foods that significantly modulate CYP3A4 or Pgp activity (wash out periods of two weeks, but three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics.
6. Impaired hepatic or renal function as demonstrated by any of the following laboratory values:

   1. Albumin \< 33g/L
   2. AST or ALT \> 2.5 x ULN
   3. Total bilirubin \> 1.5 x ULN
   4. Alkaline phosphatase \> 2.5 x ULN
   5. Glomerular filtration rate (GFR) \< 50 mL/min, as assessed using the standard methodology at the investigating centre (i.e. Cockroft-Gault, MDRD or CKD-EPI formulae, EDTA clearance or 24 h urine collection)
   6. Serum creatinine \> 1.5 x ULN
   7. Haematuria: +++ on microscopy or dipstick
   8. AST, ALT, ALP, bilirubin or renal function that, in the opinion of the investigator, is unstable or worsening
7. INR \> 1.5 or other evidence of impaired hepatic synthesis function Persisting (\> 8 weeks) severe pancytopenia due to previous therapy rather than disease (ANC \< 0.5 x 109/L or platelets \< 50 x 109/L) - to be confirmed via bone marrow biopsy, as part of normal clinical care, prior to signing of consent
8. CNS involvement with malignancy
9. Cardiac dysfunction as defined as: Myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or reduced LVEF \< 55%
10. Any of the following cardiac criteria:

    1. Mean resting corrected QT interval (QTc) \>470 msec obtained from 3 electrocardiograms (ECGs) in 24 hours
    2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age
11. Patients at risk of brain perfusion problems, e.g., carotid stenosis
12. Patients with relative hypotension (\< 100/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of \>20mm Hg
13. Uncontrolled hypertension requiring clinical intervention
14. Any other malignancy which has been active or treated within the past three years, with the exception of cervical intra-epithelial neoplasia and non-melanoma skin cancer
15. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection that would preclude adequate absorption of AZD6738
16. Patients with uncontrolled seizures
17. Active infection requiring systemic antibiotics, antifungal or antiviral drugs
18. Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition

Primary outcomes:
measure: Parts A and B: Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures.
timeFrame: From baseline until 28 days after discontinuation of study treatment, assessed up to 29 months
Secondary outcomes:
measure: Part A only: Define either the Maximum tolerated dose (MTD), if possible, or maximum feasible dose (MFD)
timeFrame: DLT's assessed during the 21 day assessment period
measure: Part B only: Preliminary assessment of the effect of food on the Pharmacokinetic (PK) parameters of AZD6738 via plasma analysis
timeFrame: 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.
measure: Parts A&B: Establish pharmacokinetics characteristics of AZD6738 and its active metabolite from plasma analysis
timeFrame: 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)
measure: Part A and B: Anti tumour activity by assessing tumour response via CT or MRI scans
timeFrame: CT/MRI - Baseline, weeks 8, 16 and every 16 weeks thereafter.
measure: Part A and B: Measuring 4 beta-hydroxy cholesterol concentration for assessment of CYP3A4 induction potential
timeFrame: Part A: Cycle 0 day 1 and cycle 1 day 15. Part B: Cycle 1 day 1 and cycle 1 day 15
measure: Part B: Pharmacokinetic profile of AZD6738 and its active metabolite from urinalysis
timeFrame: Part B C1D1: Pre-dose,0-3, 3-6, 6-9 and 9-24 hr post dose
measure: Part B only: Preliminary assessment of the effect of food on the PK parameters of AZD6738 via urinalysis
timeFrame: Urine Samples collected at cycle 1, day 2 at: Pre-dose,0-3,3-6,6-9,9-24 hr post dose
measure: Part A: Determine the extent of ATR target inhibition using pharmacodynamic biomarkers
timeFrame: 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.
measure: Part A and B: Biomarker analysis using lymph node biopsies
timeFrame: 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
measure: Part A and B: Confirmation of tumour response assessment by analysing bone marrow / aspirate
timeFrame: 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
measure: Part A and B: Bone marrow biopsy or aspirate will be analysed for biomarkers
timeFrame: 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.
measure: Part A and B: Determination of 11q del status to investigate any potential changes in FISH cytogenetic's post treatment
timeFrame: 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
measure: 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
timeFrame: 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.
measure: Part B: The extent of ATR target inhibition identified using pharmacodynamic biomarkers
timeFrame: 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.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
Study officials:
affiliation: UCSD and CLL Consortium
name: Michael Choi, MD
role: PRINCIPAL_INVESTIGATOR
References: