Neoplasms

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Hematologic Neoplasms

Hematologic Diseases

Antineoplastic Agents

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Amino Acids

Acalabrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively.

In Part B, participants will receive the RP2D of AZD4573 from Part A.

Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2.

Part B of Module 2 will be determined from the data emerging from Part A.

AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly (as monotherapy for Module 2 only) and in combination with orally administered acalabrutinib twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 weeks, with a dose ramp-up. Subsequent cycles are 21 days (3 weeks) with once weekly dosing of AZD4573 in combination with acalabrutinib twice daily continuously (in Module 1 and Module 2, period 2).

AZD4573

Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.

This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and expansion study including an intra-participants dose ramp up. AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to participants with relapsed/refractory (r/r) haematological malignancies.

In Module 1 Part A (dose-setting), this study module will enrol participants with r/r Diffuse large B-cell lymphoma (DLBCL) or r/r Marginal zone lymphoma (MZL) who have failed prior therapy(ies), are not eligible for curative treatment options, for whom there is no standard therapy available, and will initially explore once weekly administration of AZD4573 at up to three target dose levels in combination with oral acalabrutinib 100 mg twice daily. The primary objective of Part A will be to identify the maximum tolerated dose and/or Recommended Phase II dose (RP2D) for further evaluation in Part B. A 5-week DLT-assessment period will incorporate the whole of Cycle 1 in Part A, including the dose ramp up and the first 3 weeks at the target dose. In Module 1 Part B (expansion), separate expansion cohorts for participants with Germinal Centre B-cell (GCB) and non-GCB DLBCL subtypes will be opened at the RP2D.

In Module 2, this study module will enroll participants with r/r Mantle Cell Lymphoma (MCL) who have failed at least one line of prior therapy, are not eligible for curative treatment options. Module 2, Part A consist of AZD4573 monotherapy (Period 1) followed by AZD4573 + acalabrutinib combination treatment (Period 2). Period 1: AZD4573 will be administered weekly (12 mg, infusion). Period 2: AZD4573 (RP2D from Module 1) will be administered (weekly) in combination with oral acalabrutinib 100 mg twice daily. Cycle 1 of each dosing period has a duration of 5 weeks; subsequent cycles have a duration of 3 weeks. The AZD4573 monotherapy (Period 1) includes an intra-patient ramp up; participants will receive AZD4573 at Cycle 1 Week 1, Cycle 1 Week 2, and Cycle 1 Week 3 in 3 dose escalation manner (6, 9 and 12 mg respectively). Part A, Period 1 of Module 2 aims to confirm the AZD4573 monotherapy RP2D in MCL participants. In Period 2, the safety and tolerability of the RP2D of AZD4573 + acalabrutinib established in Module 1 will be assessed in participants with MCL. The study design of Part B of Module 2 will be determined from the data emerging from Part A.

AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood Cancer

A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced 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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Safety and tolerability, describe the dose limiting toxicity (DLTs), and identify the maximum tolerated dose (MTD) and/or RP2D of AZD4573 in combination with acalabrutinib.

Assess safety and confirm the RP2D of AZD4573 monotherapy in MCL participants and assess the safety and tolerability of AZD4573 in combination with acalabrutinib in participants administered AZD4573 monotherapy.

Overall response rate (ORR), defined as the proportion of participants who have a tumour response (complete response \[CR\] and partial response \[PR\]).

CR is defined as no detectable evidence of tumor, according to the revised response criteria for malignant lymphoma.

DoR, defined as the time from the first objective response of CR or PR to the time of documented disease progression or death due to any cause, whichever occurs first.

TTR, defined as the time from the first dose of study treatment to the first objective response observed for participants who achieved a CR or PR.

PFS, defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first

OS, defined as the time from first dose until the date of death from any cause.

Safety and tolerability of the RP2D of AZD4573 in combination with acalabrutinib.

Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax).

Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t)

Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast).

Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf).

Time to reach peak or maximum observed concentration following drug administration (tmax).

Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2).

Parexel

AstraZeneca

Patients with high risk haematological malignancies

Unrelated single unit intrabone cord blood transplantation

Intrabone Allogeneic Transplant

Roberto Sorasio, Head, MD

Daniele Mattei, MD

Roberto Sorasio, MD

Cord blood (CB) from an unrelated donor is increasingly used an alternative source of hematopoietic stem cells for adults with hematologic malignancies who lack an HLA-matched donor. However, the utilization of single-unit CB for transplantation of adult patients has been impeded by the low number of nucleated cells available from individual CB units. Direct intrabone CB injection (IBCBi) has been recently investigated as a solution to cell dose problem in adults, with the aims of minimizing non-specific loss of progenitors. We set up a phase I-II study to assess the safety and efficacy of CB transplantation by IBCBi in adult patients with advanced or high-risk hematological malignancies

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood Cancer	NCT04630756	Advanced Haemat...	AZD4573 Acalabrutinib	18 Years - 130 Years	AstraZeneca
Intra-bone Cord Blood Transplantation in Patients With Haematological Malignancies	NCT01613066	High Risk Haema... Advanced Haemat...	Intrabone Allog...	18 Years - 65 Years	Ospedale Santa Croce-Carle Cuneo

Spots Global Cancer Trial Database for advanced haematological malignancies