Clinical trial NCT03263637: Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
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)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-08-28
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: 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
measure: Dose limiting toxicities
timeFrame: 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
measure: Maximum tolerated dose
timeFrame: After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort
Secondary outcomes:
measure: Maximum observed plasma concentration of AZD4573
timeFrame: 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)
measure: Area under the concentration-time curve for plasma concentrations of AZD4573
timeFrame: 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).
measure: Volume of distribution (Vd).
timeFrame: 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).
measure: Clearance (CL).
timeFrame: 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).
measure: Antitumor activity of AZD4573 in patients by assessing overall response rate (ORR).
timeFrame: From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
measure: Duration of response (DOR)
timeFrame: From time of first dose until disease progression expected to be for up to 12 months
measure: Antitumor activity of AZD4573 in patients by assessing overall survival (OS).
timeFrame: From time of first dose until death or study end whatever is earlier expected to be for up to 12 months
measure: Minimal Residual Disease (MRD)
timeFrame: From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months
measure: Progression free survival (PFS)
timeFrame: From time of first dose until first observation of progression expected to be for up to 12 months
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Research Site
city: Bonn
country: Germany
facility: Research Site
city: Göttingen
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Nieuwegein
country: Netherlands
facility: Research Site
city: Cardiff
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: 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.