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

AstraZeneca44 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Relapsed or Refractory Haematological Malignancies Including Acute Myeloid Leukemia Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia High Risk Myelodysplastic Syndrome

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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.

Locations (12)

Research Site

Aachen, Germany

Research Site

Bonn, Germany

Research Site

Göttingen, Germany

Research Site

Heidelberg, Germany

Research Site

Ulm, Germany

Research Site

Amsterdam, Netherlands

Research Site

Nieuwegein, Netherlands

Research Site

Cardiff, United Kingdom

Research Site

Manchester, United Kingdom

Research Site

Plymouth, United Kingdom

...and 2 more locations

Outcomes

Primary Outcomes

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

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

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).

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

Maximum tolerated dose

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

Secondary Outcomes

Maximum observed plasma concentration of AZD4573

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

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)

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

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).

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.

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

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

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

Time frame: 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).

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

Time frame: 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)

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

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

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

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

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

Overview

Conditions

Interventions

Eligibility

Locations (12)

Outcomes

Primary Outcomes

Secondary Outcomes