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

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ClinicalTrials.gov Identifier: NCT03263637
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : September 2, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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

Condition or disease Intervention/treatment Phase
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 Drug: AZD4573 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a multicentre, open-label, first in human, non-randomized, dose-escalation study including an intra-subject ramp-up. The study will consist of two, parallel dose escalation arms
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 24, 2017
Estimated Primary Completion Date : November 13, 2020
Estimated Study Completion Date : November 13, 2020


Arm Intervention/treatment
Experimental: Arm A: (Cohort 1-3)
dose level 1-3 in subjects with relapsed or refractory haematological malignancies excluding AML/ALL/high-risk MDS/CMML/CLL and Richter's syndrome.
Drug: AZD4573
AZD4573 will be administered as a intravenous (IV) infusion.

Experimental: Arm B: (Cohort 1-3)
dose level 1-3 in subjects with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and Richter's syndrome.
Drug: AZD4573
AZD4573 will be administered as a intravenous (IV) infusion.




Primary Outcome Measures :
  1. 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 ]
    Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

  2. Dose limiting toxicities [ Time Frame: from day 1 of first cycle for a period of 8 weeks for dose cohorts 1 and 2, and for a period of 4 weeks for cohorts 3 and for any other subsequent cohort that may be opened ]
    DLTs will be determined from monitoring adverse events (AEs), and abnormal laboratory tests (clinical chemistry, hematology, and urinalysis), physical examinations, vital signs (blood pressure and pulse), and electrocardiogram (ECG).

  3. maximum tolerated dose [ Time Frame: After completion of dose limiting toxicity (DLT) period (4 weeks) for the maximum dose cohort ]

Secondary Outcome Measures :
  1. Maximum observed plasma concentration of AZD4573 [ Time Frame: Cohorts 1/2: Over 28 weeks (from dosing Day1 ramp-up cycleA until Day2 in target dose Cycle 6 (each target dose cycle 1-2 is 28days). Cohort 3: Over 4 weeks (from dosing Day1 ramp-up cycleA until Day1 in target dose Cycle1) ]
    The concentration of AZD4573 and its metabolites in blood will be determined (Cmax will be derived).

  2. Area under the concentration-time curve for plasma concentrations of AZD4573 [ Time Frame: Cohorts 1/2: Over 28 weeks (from dosing Day1 ramp-up cycleA until Day2 in target dose Cycle 6 (each target dose cycle 1-2 is 28days). Cohort 3: Over 4 weeks (from dosing Day1 ramp-up cycleA until Day1 in target dose Cycle1). ]
    The Area under the curve of AZD4573 and its metabolites in blood will be determined

  3. Volume of distribution (Vd). [ Time Frame: Cohorts 1/2: Over 28 weeks (from dosing Day1 ramp-up cycleA until Day2 in target dose Cycle 6 (each target dose cycle 1-2 is 28days). Cohort 3: Over 4 weeks (from dosing Day1 ramp-up cycleA until Day1 in target dose Cycle1). ]
    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).

  4. Clearance (CL). [ Time Frame: Cohorts 1/2: Over 28 weeks (from dosing Day1 ramp-up cycleA until Day2 in target dose Cycle 6 (each target dose cycle 1-2 is 28days). Cohort 3: Over 4 weeks (from dosing Day1 ramp-up cycleA until Day1 in target dose Cycle1). ]
    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.

  5. Urine PK for AZD4573 [ Time Frame: Pre and post dose urine samples will be collected on Day 1 of Cycle 1. ]
    Urine PK parameters will include renal clearance and amount excreted unchanged.

  6. 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 ]
    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

  7. Duration of response (DOR) [ Time Frame: From time of first dose until disease progression expected to be for up to 12 months ]
    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

  8. 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 ]
    Proportion of patients alive at 12 months post treatment start or other defined timepoints

  9. Minimal Residual Disease (MRD) [ Time Frame: From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months ]
    For applicable histologies/disease indications (e.g., CLL) using IWG criteria for response assessment every 4-12 weeks from start of treatment.

  10. Progression free survival (PFS) [ Time Frame: From time of first dose until first observation of progression expected to be for up to 12 months ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (cohorts 1, 2):

  • 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 (cohorts 1,2):

  • 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.

Inclusion Criteria (cohort 3):

Men and women ≥18 years of age -Subjects with histologically confirmed, relapsed or refractory haematological malignancies, with at least one measurable lesion ≥ 1.5cm and where in the opinion of the treating Investigator, a clinical trial is the best option for next treatment based on prior response and/or tolerability to standard of care, e.g., but not limited to:

Arm A:

  • B-cell Non-Hodgkin lymphoma
  • T-cell Non-Hodgkin lymphoma
  • Small lymphocytic lymphoma (SLL)
  • Multiple myeloma (MM)

Arm B:

  • CLL (chronic lymphocytic leukemia)
  • Richter's syndrome
  • AML/secondary AML
  • ALL
  • High-risk myelodysplastic syndrome (MDS) (according to revised International prognostic scoring system IPSS-R)
  • CMML (chronic myelomonocytic leukaemia)

Exclusion criteria (cohort 3):

  1. Treatment with any of the following:

    - Any other chemotherapy, immunotherapy or anticancer agents, including investigational agents, within 2 weeks of the first dose of study treatment

    • Any hematopoietic growth factors (e.g., 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
  2. Subjects with asecretory myeloma
  3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
  4. Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease or spinal cord compression.
  5. History of prior nonhematologic malignancy except for the following:

    - Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician.

    - Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.

    - Adequately treated carcinoma in situ without current evidence of disease.

  6. As judged by the Investigator, any evidence of severe or uncontrolled systemic disease (e.g., 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 (e.g., haemophilia 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.
  7. Known history of infection with human immunodeficiency virus (HIV).
  8. Serological evidence of active Hepatitis B infection
  9. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months:

    • coronary artery bypass graft
    • angioplasty
    • vascular stent - for the purposes of clarification, a subject who has had a cardiac stent or arterial stent currently or in the preceding 6 months will not be eligible for the study. However, a subject who has had a venous stent to prevent life-threatening conditions, currently or in the preceding

6 months, will be eligible for the study.

  • myocardial infarction
  • angina pectoris
  • congestive heart failure (New York Heart Association Class ≥2)
  • ventricular arrhythmias requiring continuous therapy
  • atrial fibrillation, which is uncontrolled
  • haemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding 10 Hyperuricemia >10 mg/dL. 11 Any of the following cardiac criteria:
  • Resting corrected QT interval (QTcF) ≥ 470 msec obtained from a single electrocardiogram (ECG).
  • 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, 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.

12 History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573.

13 Documented confirmation and treatment of adrenal gland insufficiency or pancreatitis.

14 Judgement by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.

15 Chronic use of systemic corticosteroids (prednisone or equivalent) >20mg/day whilst on study. Systemic corticosteroids at any dose, may be used during the screening period for symptom control, but must be tapered down, if necessary, to 20mg/day prior to dosing with AZD4573. Doses of systemic corticosteroid >20mg/day may be used during the study if clinically indicated (e.g., for treatment of an AE/SAE), but again, the dose must be tapered back down to no greater than 20mg/day upon resolution of the event, to avoid chronic use.

In addition, the following is considered a criterion for exclusion from the optional genetic research:

• Previous allogeneic bone marrow transplant


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03263637


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Germany
Research Site Recruiting
Aachen, Germany, 52074
Research Site Recruiting
Bonn, Germany, 53127
Research Site Recruiting
Heidelberg, Germany, 69120
Research Site Recruiting
Ulm, Germany, 89081
Netherlands
Research Site Recruiting
Amsterdam, Netherlands, 1105 AZ
Research Site Recruiting
Nieuwegein, Netherlands, 3435 CM
United Kingdom
Research Site Recruiting
Cardiff, United Kingdom, CF14 4XW
Research Site Withdrawn
Leicester, United Kingdom, LE1 5WW
Research Site Recruiting
Manchester, United Kingdom, M20 4BX
Research Site Recruiting
Plymouth, United Kingdom, PL6 8DH
Research Site Recruiting
Southampton, United Kingdom, S016 6YD
Research Site Recruiting
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
AstraZeneca

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03263637     History of Changes
Other Study ID Numbers: D8230C00001
First Posted: August 28, 2017    Key Record Dates
Last Update Posted: September 2, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AstraZeneca:
Relapsed or refractory haematological malignancies
AZD4573
CDK9i
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)
Additional relevant MeSH terms:
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Hematologic Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Plasma Cell
Hematologic Diseases
Neoplasms by Site
Lymphoma
Leukemia
Leukemia, Myeloid, Acute
Multiple Myeloma
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myelomonocytic, Chronic
Lymphoma, T-Cell
Lymphoma, B-Cell
Leukemia, Myelomonocytic, Juvenile
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Syndrome
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Leukemia, Myeloid
Hemostatic Disorders
Vascular Diseases