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

October 21, 2021 updated by: AstraZeneca

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
44

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Aachen, Germany, 52074
        • Research Site
      • Bonn, Germany, 53127
        • Research Site
      • Göttingen, Germany, 37075
        • Research Site
      • Heidelberg, Germany, 69120
        • Research Site
      • Ulm, Germany, 89081
        • Research Site
  • Netherlands
      • Amsterdam, Netherlands, 1105 AZ
        • Research Site
      • Nieuwegein, Netherlands, 3435 CM
        • Research Site
  • United Kingdom
      • 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
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 126 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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
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
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).
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
Maximum tolerated dose
Time Frame: After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort
After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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).
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)
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
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).
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).
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).
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.
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).
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
From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
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
From time of first dose until disease progression expected to be for up to 12 months
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
From time of first dose until death or study end whatever is earlier expected to be for up to 12 months
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.
From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
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
From time of first dose until first observation of progression expected to be for up to 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
AstraZeneca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 24, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 30, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 30, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 11, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 24, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 28, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 22, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 21, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • D8230C00001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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.

IPD Sharing 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.

IPD Sharing 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.

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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