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

NCT04630756 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: D8230C000022020-001642-18
• Study Type: interventional
• Target: 40
• Locations: 9 countries
• Sites: 17

Brief Summary

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.

Conditions

Advanced Haematological Malignancies

Keywords

AZD4573; Anti-cancer Agents; Sequential dose-setting and expansion treatment

Outcome Measures

Primary Outcomes (3)

• Module 1: Number of Participants With Adverse Events

  Safety and tolerability of AZD4573 in combination with acalabrutinib was assessed.

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 2: Number of Participants With Adverse Events

  Assessed safety and confirmed the RP2D of AZD4573 monotherapy in MCL participants and assessed the safety and tolerability of AZD4573 in combination with acalabrutinib in participants administered AZD4573 monotherapy.

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 1: Overall Response Rate (ORR) of AZD4573 in Combination With Acalabrutinib

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

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

Secondary Outcomes (19)

• Module 1: Complete Response (CR) Rate

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 1: Duration of Response (DoR)

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 1: Progression Free Survival (PFS)

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 1: Overall Survival (OS)

  From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)

• Module 1: Cmax of AZD4573

  Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1

Study Arms (2)

Module 1: Part A and Part B

EXPERIMENTAL

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.

Drug: AZD4573; Drug: Acalabrutinib

Module 2: Part A and Part B

EXPERIMENTAL

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.

Drug: AZD4573; Drug: Acalabrutinib

Interventions

AZD4573 DRUG

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).

Also known as: AZ13810325

Module 1: Part A and Part B; Module 2: Part A and Part B

Acalabrutinib DRUG

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

Also known as: ACP-196 /Calquence

Module 1: Part A and Part B; Module 2: Part A and Part B

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant must be ≥ 18 years of age at the time of signing the informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Must have received at least one prior line of therapy for the treatment of current disease and a clinical study is the best option for next treatment based on prior response and/or tolerability.
• Documented active disease requiring treatment that is r/r defined as: Recurrence of disease after response to at least one prior line(s) of therapy or Progressive disease after completion of or on the treatment regimen preceding entry into the study or Disease that did not achieve an objective response (overall response of CR or PR).
• Adequate haematological function.
• Adequate organ function at Screening.
• Uric acid level \< upper limit of normal (ULN).
• \- Participants with histologically confirmed, r/r DLBCL, or r/r MZL, for whom a clinical study is the best option for next treatment based on response and/or tolerability to prior lines of therapy.
• PART A
• Participants with r/r DLBCL, including subtypes such as DLBCL not otherwise specified \[NOS\], high-grade B cell lymphoma \[HGBCL\], primary mediastinal large B-cell lymphoma \[PMBCL\], or large B cell lymphoma transformed from indolent B-cell lymphomas (including but not limited to Richter Syndrome, transformed Follicular Lymphoma, transformed MZL), or r/r MZL: participants with r/r MZL are eligible as well. In case fresh tumor biopsy is not available, archival tumor samples are acceptable, if done with 24 months
• PART B • Participants with r/r de novo r/r DLBCL only, fresh tumor biopsy, done at screening or within 60 days before planned 1st dosing, unless there was any anticancer treatment given after tumor biopsy, but prior initiated study treatment.
• Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy.
• Participants must have failed at least two prior therapies for the treatment of current disease. Participants shall not be eligible for curative treatment options, and have no standard therapy available (including CAR-T cell therapy).
• Adequate haematologic function at screening: No growth factor support within 14 days prior to the date of the screening laboratory assessment; No transfusions within 7 days prior to the date of the screening laboratory assessment.
• Optional tumour biopsy on study: Participants are also encouraged to consent to and undergo an optional tumour biopsy at disease progression to support correlative biomarker studies.

You may not qualify if:

• Participants with non-secretory myeloma.
• With the exception of alopecia, any unresolved non-haematological toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment.
• Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease, or spinal cord compression.
• History of prior non-haematological malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease for \>1 year before Screening and felt to be at low risk for recurrence by treating physician; Adequately treated lentigo maligna melanoma without evidence of disease or adequately controlled non-melanomatous skin cancer; Adequately treated carcinoma in situ without current evidence of disease.
• Any evidence of severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial lung disease), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses or uncontrolled active systemic fungal, bacterial, viral, or other infection, or IV anti infective treatment within two weeks before first dose of study drug.
• Known history of infection with human immunodeficiency virus (HIV).
• Serologic status reflecting active hepatitis B or C infection.
• Any of the following cardiac criteria: Resting QT interval corrected using Fridericia's formula (QTcF) ≥ 470 msec obtained from a single electrocardiogram (ECG); any clinically important abnormalities in rhythm (except for participants with a pacemaker in place), conduction or morphology of resting ECG); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study drug and through the DLT-assessment period (Part A) or during the scheduled ECG assessments.
• History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of study treatment.
• Documented confirmation and ongoing treatment of adrenal gland insufficiency or pancreatitis.
• History, within the previous 6 months prior to first dose, of: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure (New York Heart Association Class ≥ 2); ventricular arrhythmias requiring continuous therapy; atrial fibrillation, which is judged as uncontrolled by the treating physician; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.
• Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, bowel obstruction, or gastric restrictions and bariatric surgery.
• Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
• Requires treatment with strong CYP3A inhibitors or inducers.
• Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (17)

Research Site

Duarte, California, 91010, United States

Location

Research Site

La Jolla, California, 92093-0052, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Salt Lake City, Utah, 84112, United States

Location

Research Site

Clayton, 3168, Australia

Location

Research Site

Nedlands, 6009, Australia

Location

Research Site

Québec, Quebec, G1R 2J6, Canada

Location

Research Site

Lille, 59037, France

Location

Research Site

Dublin, D08 NHY1, Ireland

Location

Research Site

Galway, H91 YR71, Ireland

Location

Research Site

Krakow, 30-510, Poland

Location

Research Site

Seoul, 03080, South Korea

Location

Research Site

Seoul, 05505, South Korea

Location

Research Site

Seoul, 06351, South Korea

Location

Research Site

Barcelona, 08035, Spain

Location

Research Site

Palma de Mallorca, 07120, Spain

Location

Research Site

Plymouth, PL6 8DH, United Kingdom

Location

Related Links

• D8230C00002\_CSP\_redacted
• D8230C00002\_CSR Synopsis\_redacted
• D8230C00002\_Statistical Analysis Plan\_redacted

MeSH Terms

Interventions

acalabrutinib

Limitations and Caveats

Due to the overall AZD4573 development programme being discontinued as part of a strategic portfolio decision, available data analyzed for this study is limited.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2020
• First Posted: November 16, 2020
• Study Start: February 17, 2021
• Primary Completion: September 8, 2023
• Study Completion: February 27, 2025
• Last Updated: April 9, 2025
• Results First Posted: February 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

KR (3); GB (1); CA (1); AU (2); IE (2); US (4); FR (1); ES (2); PL (1)