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Relapsed or Refractory Haematological Malignancies IncludingPhase 1NCT03263637

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

A Phase 1 study testing AZD4573 in people with Relapsed or Refractory Haematological Malignancies Including and Acute Myeloid Leukemia, run by AstraZeneca at 12 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 130 years
What is being tested?
AZD4573
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
44 participants
Where
12 sitesin 3 countries
Study dates
24 Oct 2017to 30 Sep 2021
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 130 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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.

Trial locations and contacts

12 sites in 3 countries.

12 sites in 3 countries

Germany5 sites

  • Research Site

    Aachen, 52074

  • Research Site

    Bonn, 53127

  • Research Site

    Göttingen, 37075

  • Research Site

    Heidelberg, 69120

  • Research Site

    Ulm, 89081

Other trials in Germany

United Kingdom5 sites

  • Research Site

    Cardiff, CF14 4XW

  • Research Site

    Manchester, M20 4BX

  • Research Site

    Plymouth, PL6 8DH

  • Research Site

    Southampton, S016 6YD

  • Research Site

    Sutton, SM2 5PT

Other trials in United Kingdom

Netherlands2 sites

  • Research Site

    Amsterdam, 1105 AZ

  • Research Site

    Nieuwegein, 3435 CM

Other trials in Netherlands

About this study

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

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.

Being tested
AZD4573
Keywords
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)
Medical subject headings
Recurrence, Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Myelomonocytic, Chronic, Lymphoma, B-Cell, Lymphoma, T-Cell, Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD4573Drug

    AZD4573 will be administered as a intravenous (IV) infusion.

Study groups in NCT03263637
Study groupRoleWhat they receive
Arm A: (Cohort 1-3)Experimentaldose level 1-3 in subjects with relapsed or refractory haematological malignancies excluding AML/ALL/high-risk MDS/CMML/CLL.
Receives: Drug: AZD4573
Arm B: (Cohort 1-3)Experimentaldose level 1-3 in subjects with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and Richter's syndrome.
Receives: Drug: AZD4573

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events

    Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

    Measured: 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

  2. Dose limiting toxicities

    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).

    Measured: 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

  3. Maximum tolerated dose

    Measured: After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort

Secondary outcomes (9)

  1. Maximum observed plasma concentration of AZD4573

    The concentration of AZD4573 and its metabolites in blood will be determined (Cmax will be derived).

    Measured: 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)

  2. Area under the concentration-time curve for plasma concentrations of AZD4573

    The Area under the curve of AZD4573 and its metabolites in blood will be determined

    Measured: 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).

  3. Volume of distribution (Vd).

    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).

    Measured: 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).

  4. Clearance (CL).

    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.

    Measured: 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).

  5. Antitumor activity of AZD4573 in patients by assessing overall response rate (ORR).

    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

    Measured: From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months

  6. Duration of response (DOR)

    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

    Measured: From time of first dose until disease progression expected to be for up to 12 months

  7. Antitumor activity of AZD4573 in patients by assessing overall survival (OS).

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

    Measured: From time of first dose until death or study end whatever is earlier expected to be for up to 12 months

  8. Minimal Residual Disease (MRD)

    For applicable histologies/disease indications (e.g., CLL) using IWG criteria for response assessment every 4-12 weeks from start of treatment.

    Measured: From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months

  9. Progression free survival (PFS)

    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

    Measured: From time of first dose until first observation of progression expected to be for up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Aug 2017
  2. Study start24 Oct 2017
  3. Primary completion30 Sep 2021
  4. Study completion30 Sep 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
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)
Enrolment
44 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03263637
Sponsor's protocol ID
D8230C00001
Status last verified
Oct 2021
First submitted
11 Aug 2017
Last updated
22 Oct 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, Pop-Damkov P, Su N, Roamio Franklin VN, Sekhar Reddy Chilamakuri C, D'Santos CS, Shao W, Saeh JC, Koch R, Weinstock DM, Zinda M, Fawell SE, Drew L. AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clin Cancer Res. 2020 Feb 15;26(4):922-934. doi: 10.1158/1078-0432.CCR-19-1853. Epub 2019 Nov 7.

    PubMed 31699827

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AZD4573 in people with Relapsed or Refractory Haematological Malignancies Including and Acute Myeloid Leukemia, run by AstraZeneca at 12 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in Germany, United Kingdom, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03263637, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2021.

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