Clinical Trials /

Study of AZD5991 in Relapsed or Refractory Haematologic Malignancies.

NCT03218683

Description:

This study is a multicenter, open-label, nonrandomized, sequential group, dose-escalation study to assess safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ascending doses of AZD5991 in subjects with relapsed or refractory hematologic malignancies. Part 1 of the study is monotherapy dose escalation. Part 2 of the study is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL), AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM) Part 3 is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in subjects with relapsed/refractory AML/MDS

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of AZD5991 in Relapsed or Refractory Haematologic Malignancies.
  • Official Title: A Phase 1/1b/2a, 3-Part, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ascending Doses of AZD5991 in Subjects With Relapsed or Refractory Haematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: D6910C00001
  • NCT ID: NCT03218683

Conditions

  • Relapsed or Refractory Hematologic Malignancies
  • Non-Hodgkin Lymphoma
  • Richter Syndrome
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • T-cell Lymphoma
  • Multiple Myeloma
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphocytic Leukemia (ALL)
  • Myelodysplastic Syndrome (MDS)
  • Cutaneous T-cell Lymphoma

Interventions

DrugSynonymsArms
AZD5991Monotherapy AZD5991
AZD5991 + VenetoclaxAZD5991 + venetoclax

Purpose

This study is a multicenter, open-label, nonrandomized, sequential group, dose-escalation study to assess safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ascending doses of AZD5991 in subjects with relapsed or refractory hematologic malignancies. Part 1 of the study is monotherapy dose escalation. Part 2 of the study is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL), AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM) Part 3 is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in subjects with relapsed/refractory AML/MDS

Trial Arms

NameTypeDescriptionInterventions
Monotherapy AZD5991ExperimentalDose escalation - multiple dose levels
  • AZD5991
Monotherapy AZD5991 expansionExperimentalDose expansion
  • AZD5991
AZD5991 + venetoclaxExperimentalDose escalation - multiple dose levels
  • AZD5991 + Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of signed and dated, written informed consent prior to any study-specific
             procedures, sampling and analyses.

          -  Men and women 18 to 85 years of age, inclusive.

          -  Diagnosis of any of the following hematologic malignancies:

               -  non-Hodgkin lymphoma

               -  Richter syndrome

               -  Chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL)

               -  T-cell lymphoma

               -  multiple myeloma (MM)

               -  Acute Myeloid Leukemia (AML)

               -  Acute Lymphocytic Leukemia (ALL)

               -  Myelodysplastic Syndrome (MDS)

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

          -  Must have received at least 2 prior lines of therapy for the treatment of current
             histology; there are no treatment options available known to provide clinical benefit.
             Refer to National Comprehensive Cancer Network (NCCN) guidelines of each respective
             histology for guidance.

          -  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.

        Inclusion criteria for expansion cohorts in CLL and MM (Part 2 only):

          -  To be eligible for the CLL expansion cohort, subjects must have received at least 2
             prior lines of therapy for CLL including a Bruton tyrosine kinase (BTK) inhibitor and
             venetoclax.

          -  To be eligible for the MM expansion cohort, subjects must have received at least 2
             prior lines of therapy for MM including an immunomodulatory agent (eg, lenalidamide),
             a proteasome inhibitor and daratumumab.

        Inclusion for AZD5991+venetoclax:

          -  Must have received at least 2 prior lines of therapy for the treatment of AML or MDS;
             there are no treatment options available known to provide clinical benefit. Refer to
             National Comprehensive Cancer Network (NCCN) guidelines.

          -  Documented active disease requiring treatment per respective NCCN 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.

          -  WBC ≤25,000 cells/mm3 (25 x 109/L); use of leukapheresis or hydroxyurea before study
             drug initiation is allowed to achieve this entry criterion.

          -  Adequate hepatic and renal function at screening defined as:

          -  Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper
             limit of normal (ULN).

          -  Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin).

          -  Serum creatinine ≤1.5 times ULN and creatinine clearance ≥50 mL/min (measured or
             calculated by Cockcroft and Gault equation [(140-Age) • Mass (kg)/(72 • creatinine
             mg/dL) • multiply by 0.85 if female]).

          -  Lipase ≤1.5 x ULN and serum amylase ≤1.5 x ULN and no history of pancreatitis.

        Exclusion Criteria:

          -  Treatment with any of the following:

               -  Any investigational agents from a previous clinical study within 4 half-lives of
                  said prior investigational agent(s) with regard to the first dose of study
                  treatment on this protocol. Washout period not required in subjects with
                  aggressive disease who require treatment sooner.

               -  Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the
                  first dose of study treatment. Washout period not required in subjects with
                  aggressive disease who require treatment sooner.

               -  Any hematopoietic growth factors (eg, filgrastim [granulocyte colony-stimulating
                  factor; G-CSF], sargramostin [granulocyte-macrophage colony-stimulating factor;
                  GM-CSF]) within 7 days of the first dose of study drug or pegylated G-CSF
                  (pegfilgrastim) or darbepoetin within 14 days of the first dose of study drug.

          -  Major surgery (excluding placement of vascular access) within 4 weeks of the first
             dose of study treatment.

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

          -  Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal
             disease or spinal cord compression.

          -  As judged by the Investigator, any evidence of severe or uncontrolled systemic disease
             (eg, severe hepatic impairment, interstitial lung disease [bilateral, diffuse,
             parenchymal lung disease]), or current unstable or uncompensated respiratory or
             cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding
             diatheses (eg, hemophilia or von Willebrand disease) or uncontrolled active systemic
             fungal, bacterial, viral, or other infection (defined as exhibiting ongoing
             signs/symptoms related to the infection and without improvement, despite appropriate
             antibiotics or other treatment), or intravenous anti-infective treatment within 2
             weeks before first dose of study drug.

        Exclusion AZD5991 + venetoclax

          -  AML with known active central nervous system involvement.

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration.

          -  Chronic respiratory disease that requires continuous oxygen use.

          -  Known diagnosis of a hypercoagulable disorder other than malignancy

          -  High risk of developing renal impairment, per investigator discretion.

          -  Hyperuricemia (defined as uric acid above laboratory normal range) present at
             screening or hyperphosphatemia (defined as phosphate/phosphorus levels above
             laboratory normal range) present at screening.

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTcF) ≥ 450 msec obtained from 3
                  electrocardiograms (ECGs)

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG eg, 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, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age.
                  Concomitant medications known to prolong QTc should be used with caution and
                  cannot be used starting with the first dose of study drug and through the DLT
                  review period.

               -  Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline
                  (left ventricular ejection fraction [LVEF] <40%). Appropriate correction to be
                  used, if a MUGA is performed.

          -  History of severe allergic or anaphylactic reactions to BH3 mimetics or history of
             hypersensitivity to active or inactive excipients of AZD5991.

          -  Received the following within 7 days before initiation of venetoclax:

          -  Strong or moderate cytochrome P450 3A (CYP3A) inducers

          -  Strong or moderate CYP3A inhibitors

          -  Pg-P inhibitors

          -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
             containing Seville oranges) or star fruit within 3 days before the initiation of
             venetoclax.
      
Maximum Eligible Age:85 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 until disease progression. Expected to be for up to 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 AZD5991 monotherapy and AZD5991+venetoclax
Time Frame:Predose and through 24 hours postdose
Safety Issue:
Description:To assess the pharmacokinetics of AZD5991 monotherapy and AZD5991+venetoclax
Measure:Area under the concentration-time curve for plasma concentrations of AZD5991 monotherapy and AZD5991+venetoclax
Time Frame:Predose and through 24 hours postdose
Safety Issue:
Description:To assess the pharmacokinetics of AZD5991 monotherapy and AZD5991+venetoclax
Measure:Objective response rate (ORR)
Time Frame:From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months
Safety Issue:
Description:To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.
Measure:Duration of response (DOR)
Time Frame:From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months
Safety Issue:
Description:To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.
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 antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.
Measure:Complete remission rate (CRR)
Time Frame:From time of first dose until discontinuation of AZD5991 monotherapy and AZD5991+venetoclax expected to be for up to 12 months
Safety Issue:
Description:To assess the antitumor activity of AZD5991 monotherapy and AZD5991+venetoclax. Response will be evaluated every 8-12 weeks during treatment until progression.

Details

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

Trial Keywords

  • relapsed
  • refractory
  • AZD5991
  • Non-Hodgkin lymphoma
  • Richter syndrome
  • Chronic lymphocytic leukemia
  • Small lymphocytic lymphoma
  • T-cell lymphoma, Multiple myeloma
  • Acute Myeloid Leukemia (AML)
  • Acute Lymphocytic Leukemia (ALL)
  • Myelodysplastic Syndrome (MDS)
  • Cutaneous T-cell Lymphoma

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