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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03263637
Recruitment Status : Completed
First Posted : August 28, 2017
Last Update Posted : October 22, 2021
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)
Actual Enrollment : 44 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
Actual Primary Completion Date : September 30, 2021
Actual Study Completion Date : September 30, 2021


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.
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 cohorts 1 and 2, and for a period of 4 weeks for cohort 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 (8/4 weeks) for the maximum dose cohort ]

Secondary Outcome Measures :
  1. Maximum observed plasma concentration of AZD4573 [ Time Frame: For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1) ]
    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: For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). ]
    The Area under the curve of AZD4573 and its metabolites in blood will be determined

  3. Volume of distribution (Vd). [ Time Frame: For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). ]
    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: For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). ]
    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. 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

  6. 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

  7. 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

  8. 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.

  9. 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

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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

Main Inclusion Criteria (cohorts 1, 2, 3):

• Patients with histologically confirmed, relapsed or refractory haematological malignancies. Patients 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.

Main Exclusion Criteria (cohorts 1,2, 3):

  • Treatment with any of the following: 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, any full-dose level anti-coagulation treatment sufficiently prior to treatment that INR is <1.5 (DVT/PE prophylaxis dose is allowed) 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
  • Patients with any of the following: evidence of severe or uncontrolled systemic disease, asecretory myeloma, a known history of infection with human immunodeficiency virus (HIV), serological evidence of active Hepatitis B infection, cardiac abnormalities as mentioned in the protocol, previous allogeneic bone marrow transplant, adrenal gland insufficiency or pancreatitis.
  • History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573.

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


Locations
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Germany
Research Site
Aachen, Germany, 52074
Research Site
Bonn, Germany, 53127
Research Site
Göttingen, Germany, 37075
Research Site
Heidelberg, Germany, 69120
Research Site
Ulm, Germany, 89081
Netherlands
Research Site
Amsterdam, Netherlands, 1105 AZ
Research Site
Nieuwegein, Netherlands, 3435 CM
United Kingdom
Research Site
Cardiff, United Kingdom, CF14 4XW
Research Site
Manchester, United Kingdom, M20 4BX
Research Site
Plymouth, United Kingdom, PL6 8DH
Research Site
Southampton, United Kingdom, S016 6YD
Research Site
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
AstraZeneca
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03263637    
Other Study ID Numbers: D8230C00001
First Posted: August 28, 2017    Key Record Dates
Last Update Posted: October 22, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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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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Lymphoma
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Multiple Myeloma
Neoplasms
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
Hematologic Neoplasms
Myelodysplastic Syndromes
Syndrome
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias