Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, B-cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelomonocytic Leukemia, High Risk Myelodysplastic Syndrome, Multiple Myeloma, Relapsed or Refractory Haematological Malignancies Including, Richter's Syndrome, Small Lymphocytic Lymphoma, T-cell Non-Hodgkin Lymphoma
Conditions
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)
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.
Interventions
DRUGAZD4573
AZD4573 will be administered as a intravenous (IV) infusion.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | 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 |
| Dose limiting toxicities | 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). |
| Maximum tolerated dose | After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clearance (CL). | 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. |
| Antitumor activity of AZD4573 in patients by assessing overall response rate (ORR). | 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 |
| Duration of response (DOR) | 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 |
| Maximum observed plasma concentration of AZD4573 | 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). |
| Minimal Residual Disease (MRD) | 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. |
| Progression free survival (PFS) | 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 |
| Antitumor activity of AZD4573 in patients by assessing overall survival (OS). | 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 |
| Area under the concentration-time curve for plasma concentrations of AZD4573 | 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 |
| Volume of distribution (Vd). | 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). |
Countries
Germany, Netherlands, United Kingdom
Outcome results
None listed