Study of AZD5991 in Relapsed or Refractory Haematologic Malignancies.

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Brief Title

Study of AZD5991 Alone or in Combination With Venetoclax 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 Monotherapy and in Combination With Venetoclax in Subjects With Relapsed or Refractory Haematologic Malignancies

Brief Summary

      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. Closed November 2020 Part 2 of the study
      is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL),
      AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM). Closed November 2020 Part 3
      is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in
      subjects with relapsed/refractory AML
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Incidence of Adverse Events

Secondary Outcome

 Maximum observed plasma concentration of AZD5991 monotherapy and AZD5991+venetoclax

Condition

Relapsed or Refractory Acute Myeloid Leukemia (AML)

Intervention

AZD5991

Study Arms / Comparison Groups

 Monotherapy AZD5991
Description:  Dose escalation - multiple dose levels

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

144

Start Date

August 14, 2017

Completion Date

March 1, 2023

Primary Completion Date

March 1, 2023

Eligibility Criteria

        Inclusion Criteria (AZD5991 + venetoclax):

          -  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 AML and histologically proven based on criteria established by the World
             Health Organisation (WHO) as documented by medical records. Must have a measurable
             blast infiltration in bone marrow which will serve as a response parameter

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

          -  Must have received at least 1 prior line of therapy and there must be 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 ≤10,000 cells/mm3 (10 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.

          -  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 (AZD5991 + venetoclax):

          -  Treatment with any of the following:

               -  Any investigational agents from a previous clinical study within 4 half-lives or
                  14 days, whichever is the greater, 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.

          -  AML with known active central nervous system involvement.

          -  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.

          -  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

          -  Undergone any of the following procedures or experienced any of the following
             conditions currently or in the preceding 6 months:

               -  angina pectoris

               -  supraventricular arrhythmias, including atrial fibrillation, which are
                  uncontrolled

               -  Myocarditis

               -  heart failure NYHA Class I or above

          -  Experienced any of the following conditions currently or at any previous timepoint

               -  Myocardial infarction (MI)

               -  coronary artery bypass graft

               -  angioplasty

               -  vascular stent

               -  Heart failure NYHA Class ≥ 2

               -  Ventricular arrhythmias requiring continuous therapy

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTcF) ≥ 450 msec applicable to both genders
                  obtained from 3 electrocardiograms (ECGs) (averaged)

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG eg, complete left bundle branch block, second to third degree AV
                  block, sinus node dysfunction with clinically significant sinus pause

               -  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.

               -  ST-wave depression and T-wave changes (e.g. inversion or flattened) in recent or
                  screening ECG

               -  CPK assay reading ≥ ULN at screening

               -  Subjects with any troponin assay reading of ≥ULN during screening

               -  Left ventricular ejection fraction [LVEF] <55% with echocardiogram (ECHO) or
                  multi-gated acquisition scan (MUGA). 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.
      

Gender

All

Ages

18 Years - 85 Years

Accepts Healthy Volunteers

No

Contacts

, 1-877-240-9479, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03218683

Organization ID

D6910C00001


Responsible Party

Sponsor

Study Sponsor

AstraZeneca


Study Sponsor

, , 


Verification Date

June 2021