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11q-deleted Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL),Phase 1NCT01955668

AZD6738 First Time in Patient Multiple Ascending Dose Study

A Phase 1 study testing Administration of AZD6738 in people with 11q-deleted Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL), and Prolymphocytic Leukaemia (PLL), run by AstraZeneca at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Administration of AZD6738
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
Nov 2013to Dec 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
  • 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.
  • 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.
  • Not known to be positive for HIV antibody, Hepatitis B surface antigen and Hepatitis C antibody.
  • 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:
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  • 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.
  • Ability to swallow and retain oral medication

Who cannot join

  • Receiving, or having received during the four weeks prior to study entry (signing of consent), treatment for their malignancy.
  • 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.
  • A known hypersensitivity to AZD6738 or any excipient of the product.
  • Treatment with any investigational medicinal product (IMP) within 28 days prior to signing of consent.
  • 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.
  • Impaired hepatic or renal function as demonstrated by any of the following laboratory values:
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  • Albumin < 33g/L
  • AST or ALT > 2.5 x ULN
  • Total bilirubin > 1.5 x ULN
  • Alkaline phosphatase > 2.5 x ULN
  • 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)
  • Serum creatinine > 1.5 x ULN
  • Haematuria: +++ on microscopy or dipstick
  • AST, ALT, ALP, bilirubin or renal function that, in the opinion of the investigator, is unstable or worsening
  • 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
  • CNS involvement with malignancy
  • 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%
  • Any of the following cardiac criteria:
  • Mean resting corrected QT interval (QTc) >470 msec obtained from 3 electrocardiograms (ECGs) in 24 hours
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
  • 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
  • Patients at risk of brain perfusion problems, e.g., carotid stenosis
  • Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of >20mm Hg
  • Uncontrolled hypertension requiring clinical intervention
  • 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
  • Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection that would preclude adequate absorption of AZD6738
  • Patients with uncontrolled seizures
  • Active infection requiring systemic antibiotics, antifungal or antiviral drugs
  • Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Research Site

    La Jolla, California

Other trials in United States

About this 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)

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

Read the 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).

Being tested
Administration of AZD6738
Keywords
11q-deleted relapsed/refractory chronic lymphocytic leukaemia, Prolymphocytic leukaemia, B cell lymphomas
Medical subject headings
Leukemia, B-Cell, Leukemia, Prolymphocytic, Lymphoma, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Administration of AZD6738Drug

    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

Study groups in NCT01955668
Study groupRoleWhat they receive
AZD6738ExperimentalPatients will receive a single dose on day 1 followed by ongoing multiple dosing until MTD or MFD is reached.
Receives: Drug: Administration of AZD6738

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: From baseline until 28 days after discontinuation of study treatment, assessed up to 29 months

Secondary outcomes (14)

  1. 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

    Measured: DLT's assessed during the 21 day assessment period

  2. 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

    Measured: 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.

  3. 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

    Measured: 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)

  4. 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.

    Measured: CT/MRI - Baseline, weeks 8, 16 and every 16 weeks thereafter.

  5. 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.

    Measured: Part A: Cycle 0 day 1 and cycle 1 day 15. Part B: Cycle 1 day 1 and cycle 1 day 15

  6. 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.

    Measured: Part B C1D1: Pre-dose,0-3, 3-6, 6-9 and 9-24 hr post dose

  7. 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.

    Measured: Urine Samples collected at cycle 1, day 2 at: Pre-dose,0-3,3-6,6-9,9-24 hr post dose

  8. 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

    Measured: 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.

  9. Part A and B: Biomarker analysis using lymph node biopsies

    Optional lymph node core needle biopsy

    Measured: 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

  10. 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.

    Measured: 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

  11. 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

    Measured: 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.

  12. 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

    Measured: 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

  13. 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.

    Measured: 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.

  14. 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

    Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Oct 2013 (estimated)
  2. Study startNov 2013
  3. Primary completionDec 2013
  4. Study completionDec 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01955668
Sponsor's protocol ID
D5330C00001
Status last verified
Jun 2014
First submitted
30 Sep 2013
Last updated
19 Jun 2014
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Administration of AZD6738 in people with 11q-deleted Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL), and Prolymphocytic Leukaemia (PLL), run by AstraZeneca at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01955668.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2014.

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