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dose level 1-3 in subjects with relapsed or refractory haematological malignancies excluding AML/ALL/high-risk MDS/CMML/CLL.

dose level 1-3 in subjects with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and Richter's syndrome.

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

AZD4573

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.

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

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

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

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.

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

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).

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

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

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).

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.

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

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

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

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

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

AstraZeneca

CD8+ T-cell depleted donor lymphocyte infusion

Chien-Shing Chen, MD

Primary Objectives:

This a pilot project to determine the feasibility of the preemptive CD8+ depleted T-cell donor lymphocyte infusion (DLI) in:

* Reducing the incidence of graft versus host disease (GVHD) based on standard classification of acute and chronic GVHD
* Improving hte disease remission rate in comparison with our previous study results.

Secondary Objectives:

* To investigate the impact of CD8+ depleted T-cell DLI in hematopoietic chimerism, and immunologic recovery of transplant patients.

The scientific investigation in this study protocol:

1. Define the role of preemptive and specific DLI in preserving the GVL effect in the setting of NMT. The ability of selecting components of T cells for transplant and DLI will allow us to test the hypothesis of distinctive roles in subsets of T cells. It was found that CD8-depleted DLI was administered to prevent relapse after TCD (T-cell depleted) BMT (bone marrow as the stem cell source) or CD34-selected PBSC.

   Whether preemptive CD8-depleted DLI can perform this function after nonmyeloablative transplantation (NMT) needs to be established, as proposed in our study. If there turns out to be a role for DLI in these circumstances, a CD8-depleted lymphocyte product that can limit GVHD would be a very attractive option. We would also define the relationship of the level of donor chimerism and disease control.
2. Investigate the impact of CD8-depleted DLI in NMT at specific doses and time points for the reduction of GVHD. The GVHD pattern may vary between different ethnic populations as suggested by our earlier NMT study. Our current proposed study will further shed light on the optimal GVHD prophylaxis regimen in the Singapore patient population.

T-cell Depleted Donor Lymphocyte Infusion (DLI)for Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

Preemptive CD8+ T-cell Depleted Donor Lymphocyte Infusion (DLI) Following Nonmyeloablative Stem Cell Transplantation (NMT) for Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies	NCT03263637	Relapsed or Ref... Acute Myeloid L... Acute Lymphocyt... Chronic Lymphoc... High Risk Myelo... Chronic Myelomo... Richter's Syndr... B-cell Non-Hodg... T-cell Non-Hodg... Small Lymphocyt... Multiple Myelom...	AZD4573	18 Years - 130 Years	AstraZeneca
T-cell Depleted Donor Lymphocyte Infusion (DLI)for Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)	NCT00242515	Acute Myeloid L... Myelodysplastic...	CD8+ T-cell dep...	21 Years - 90 Years	National University Hospital, Singapore
T-cell Depleted Donor Lymphocyte Infusion (DLI)for Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)	NCT00242515	Acute Myeloid L... Myelodysplastic...	CD8+ T-cell dep...	21 Years - 90 Years	National University Hospital, Singapore

Spots Global Cancer Trial Database for high risk myelodysplastic syndrome (mds)