AZD6738 First Time in Patient Multiple Ascending Dose Study

NCT01955668 | Completed Phase 1

• 1 other identifier: D5330C00001
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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

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

Outcome Measures

Primary Outcomes (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

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

Secondary Outcomes (14)

• Part A only: Define either the Maximum tolerated dose (MTD), if possible, or maximum feasible dose (MFD)

  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

  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

  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

  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

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

Study Arms (1)

AZD6738

EXPERIMENTAL

Patients will receive a single dose on day 1 followed by ongoing multiple dosing until MTD or MFD is reached.

Drug: Administration of AZD6738

Interventions

Administration of AZD6738 DRUG

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

AZD6738

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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

You may not qualify if:

• 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:
• 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

Sponsors & Collaborators

• AstraZeneca: lead
• CLL Consortium: collaborator

Study Sites (1)

Research Site

La Jolla, California, United States

Location

MeSH Terms

Conditions

Leukemia, B-Cell; Leukemia, Prolymphocytic; Lymphoma, B-Cell

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Lymphoma

Study Officials

• Michael Choi, MD

  UCSD and CLL Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2013
• First Posted: October 7, 2013
• Study Start: November 1, 2013
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: June 19, 2014

Record last verified: 2014-06

Locations

US (1)