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Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies

NCT03263637

Description:

The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed or refractory haematological malignancies

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • B-Cell Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia
  • Chronic Myelomonocytic Leukemia
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Richter Syndrome
  • Small Lymphocytic Leukemia
  • T-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies
  • Official Title: A Phase 1, Open-Label, Multicentre, Non-Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of AZD4573, a Potent and Selective CDK9 Inhibitor, in Subjects With Relapsed or Refractory Haematological Malignancies

Clinical Trial IDs

  • ORG STUDY ID: D8230C00001
  • NCT ID: NCT03263637

Conditions

  • Relapsed or Refractory Haematological Malignancies Including
  • Acute Myeloid Leukemia
  • Acute Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • High Risk Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Richter's Syndrome
  • B-cell Non-Hodgkin Lymphoma
  • T-cell Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
  • Multiple Myeloma

Interventions

DrugSynonymsArms
AZD4573Arm A: (Cohort 1-6)

Purpose

The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed or refractory haematological malignancies

Trial Arms

NameTypeDescriptionInterventions
Arm A: (Cohort 1-6)ExperimentalDose level 1-6 in subjects with relapsed or refractory haematological malignancies
  • AZD4573
Arm B: (Cohort 1-6)Experimentaldose level 1-6 in subjects with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and Richter's syndrome.
  • AZD4573

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects with histologically confirmed, relapsed or refractory haematological
             malignancies Subjects will include but are not limited to the following:

        Arm A : B-cell Non-Hodgkin lymphoma , T-cell Non-Hodgkin lymphoma , Small lymphocytic
        lymphoma (SLL) , Multiple myeloma (MM) Arm B: CLL (chronic lymphocytic leukaemia),
        Richter's syndrome , AML/secondary AML, ALL , High-risk myelodysplastic syndrome (MDS),
        CMML (chronic myelomonocytic leukemia)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

          -  Must have received at least 2 prior lines of therapy

          -  Documented active disease requiring treatment per respective NCCN/ESMO guideline that
             is relapsed or refractory defined as: Recurrence of disease after response to prior
             line(s) of therapy Or progressive disease after completion of the treatment regimen
             preceding entry into the study

          -  Adequate hematologic, hepatic and renal function

          -  Women should be using adequate contraceptive measures, should not be breast feeding
             and must have a negative pregnancy test before start of dosing if of child-bearing
             potential or must have evidence of nonchildbearing potential

          -  Men should be willing to use barrier contraception (ie, condoms) and refrain from
             sperm donation during and after the conduct of the trial.

        Exclusion Criteria:

          -  Treatment with any investigational agents within 4 half-lives of said prior
             investigational agent(s), any other chemotherapy, immunotherapy or anticancer agents
             within 2 weeks, any hematopoietic growth factors (e.g., filgrastim; [G-CSF] or
             sargramostin [GM-CSF]) within 7 days of the first dose of investigational product or
             pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days or Major surgery
             (excluding placement of vascular access) within 4 weeks (with regard to the first dose
             of study treatment on this protocol).

               -  With the exception of alopecia, any unresolved toxicities from prior therapy
                  greater than CTCAE Grade 1 at the time of starting study treatment.

               -  Presence of, or history of, CNS lymphoma, leptomeningeal disease or spinal cord
                  compression.

               -  History of prior nonhematologic malignancy with exceptions mentioned in protocol

               -  Undergone any procedures or experienced any of the conditions listed in protocol
                  exclusion criteria currently or in the preceding 6 months

               -  History of severe allergic or anaphylactic reactions to BH3 mimetics or history
                  of hypersensitivity to active or inactive excipients of AZD4573.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:At every treatment and follow up visit from the time of informed consent up to 8 months initially or if clinical benefit continues, until disease progression. Expected to be for 12 months
Safety Issue:
Description:Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

Secondary Outcome Measures

Measure:Maximum observed plasma concentration of AZD4573
Time Frame:Pre-post dose PK samples on days 1 & 2 every 2 weeks upto week 8
Safety Issue:
Description:The concentration of AZD4573 and its metabolites in blood will be determined (Cmax will be derived).
Measure:Area under the concentration-time curve for plasma concentrations of AZD4573
Time Frame:Pre-post dose PK samples on days 1 & 2 every 2 weeks upto week 8
Safety Issue:
Description:The Area under the curve of AZD4573 and its metabolites in blood will be determined
Measure:Volume of distribution (Vd).
Time Frame:Pre-post dose PK samples on days 1 & 2 every 2 weeks upto week 8
Safety Issue:
Description:The concentration of AZD4573 and its metabolites in blood will be determined. Volume of distribution (Vd) is the apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Measure:Clearance (CL).
Time Frame:Pre-post dose PK samples on days 1 & 2 every 2 weeks upto week 8
Safety Issue:
Description:The concentration of AZD4573 and its co-former in blood will be determined. Clearance (CL) is the volume of plasma cleared of the drug per unit time.
Measure:Urine PK for AZD4573
Time Frame:Pre and post dose urine samples will be collected on Day 1 of Cycle 1 (28 day cycle)
Safety Issue:
Description:Urine PK parameters will include renal clearance and amount excreted unchanged.
Measure:Antitumor activity of AZD4573 in patients by assessing overall response rate (ORR).
Time Frame:From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
Safety Issue:
Description:To assess proportion of patients with anti tumor response to AZD4573. response assessment by Cheson (2014) criteria for for NHL, SLL, T-cell lymphoma and Richter syndrome, IWG criteria for CLL (Hallek 2008) and myeloma (Palumbo 2014), AML response criteria for AML (Doner 2010), SWOG (2016) criteria for ALL and MDS and CMML by IWG (Savona 2015) .Response will be evaluated every 4-12 weeks (based on disease type) until progression
Measure:Duration of response (DOR)
Time Frame:From time of first dose until disease progression expected to be for up to 12 months
Safety Issue:
Description:To assess the duration of anti tumor activity of AZD4573. To assess the progression free survival of AZD4573. response assessment by Cheson (2014) criteria for for NHL, SLL, T-cell lymphoma and Richter syndrome, IWG criteria for CLL (Hallek 2008) and myeloma (Palumbo 2014), AML response criteria for AML (Doner 2010), SWOG (2016) criteria for ALL and MDS and CMML by IWG (Savona 2015) . Response will be evaluated every 4-12 weeks (based on disease type) until progression
Measure:Antitumor activity of AZD4573 in patients by assessing overall survival (OS).
Time Frame:From time of first dose until death or study end whatever is earlier expected to be for up to 12 months
Safety Issue:
Description:Proportion of patients alive at 12 months post treatment start or other defined timepoints
Measure:Minimal Residual Disease (MRD)
Time Frame:From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
Safety Issue:
Description:For applicable histologies/disease indications (e.g., CLL) using IWG criteria for response assessment every 4-12 weeks from start of treatment.
Measure:Progression free survival (PFS)
Time Frame:From time of first dose until first observation of progression expected to be for up to 12 months
Safety Issue:
Description:To assess the progression free survival of AZD4573. response assessment by Cheson (2014) criteria for for NHL, SLL, T-cell lymphoma and Richter syndrome, IWG criteria for CLL (Hallek 2008) and myeloma (Palumbo 2014), AML response criteria for AML (Doner 2010), SWOG (2016) criteria for ALL and MDS and CMML by IWG (Savona 2015) . Response will be evaluated every 4-12 weeks (based on disease type) until progression

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Relapsed or refractory haematological malignancies
  • AZD4573
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphocytic Leukemia (ALL)
  • Chronic lymphocytic Leukemia (CLL)
  • High risk Myelodysplastic syndrome (MDS)
  • Chronic Myelomonocytic Leukemia (CML)
  • Richter's syndrome
  • B-cell Non-Hodgkin Lymphoma (B-cell NHL)
  • T-cell Non-Hodgkin Lymphoma (T-cell NHL)
  • Small lymphocytic Lymphoma (SLL)
  • Multiple Myeloma (MM)

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