What side effects are associated with this type of intervention?

Common treatments for blood cancers, such as azacitidine, decitabine, bortezomib, and hydroxyurea, have a range of side effects. Azacitidine and decitabine can cause cytopenias, gastrointestinal symptoms, and fatigue. Bortezomib is associated with peripheral neuropathy, gastrointestinal disturbances, and hematologic toxicities. Hydroxyurea can lead to cytopenias, mucocutaneous ulcers, and potential teratogenicity. These side effects highlight the importance of monitoring and managing adverse effects during treatment.

What prior FDA approvals exist?

FDA-approved treatments for blood cancers include a variety of targeted therapies and combination regimens. For example, venetoclax, a BCL2 inhibitor, is approved for use in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults who are 75 years or older or have comorbidities precluding intensive induction chemotherapy. Bortezomib, a proteasome inhibitor, is approved for multiple myeloma and mantle cell lymphoma. Additionally, tyrosine kinase inhibitors like imatinib, dasatinib, and ponatinib are approved for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). These treatments, often used in combination with other agents, aim to improve response rates and survival outcomes in patients with relapsed or refractory blood cancers.

What other types of research exist?

Promising novel alternatives to AZD4573 for blood cancer patients in 2024 include: 1) Acalabrutinib, a Bruton tyrosine kinase inhibitor, which has shown efficacy in relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia. 2) Lenalidomide, an immunomodulatory drug, which has demonstrated high response rates in relapsed/refractory mantle cell lymphoma. 3) KTE-X19 CAR T-Cell Therapy, which has shown durable responses in relapsed/refractory mantle cell lymphoma. 4) Selinexor, a selective inhibitor of nuclear export, which has been effective in combination with bortezomib and dexamethasone for relapsed multiple myeloma. 5) Polatuzumab vedotin, an anti-CD79B antibody-drug conjugate, which has shown activity in relapsed/refractory B-cell non-Hodgkin lymphoma.

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Epigenetic Modulator

AZD4573 + Acalabrutinib for Blood Cancer

Phase 1 & 2

Waitlist Available

Research Sponsored by AstraZeneca

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participant must be ≥ 18 years of age at the time of signing the informed consent.

Diagnosis must be confirmed by biopsy and be immunohistologically characterised.

Must not have

History of or ongoing confirmed progressive multifocal leukoencephalopathy

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.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 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

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a new drug, AZD4573, combined with another drug, acalabrutinib, for patients with certain blood cancers who haven't responded to other treatments. The drugs work together to kill cancer cells and block their growth. Acalabrutinib is more selective and has fewer side effects compared to an older drug.

Who is the study for?

This trial is for adults with advanced blood cancers who have tried at least two prior treatments without a cure in sight. They should not be eligible for curative therapies like CAR-T cell therapy and must have specific types of relapsed/refractory (r/r) blood cancers, such as DLBCL or MZL. Participants need to show active disease requiring treatment, adequate organ and bone marrow function, no recent transfusions or growth factor support, and an ECOG status ≤ 2.

What is being tested?

The study tests AZD4573 combined with other anti-cancer agents in patients with advanced blood cancer. It's an open-label Phase I/II trial where the drug is given intravenously. The goal is to find the right dose and see how well it works when paired with different cancer medications.

What are the potential side effects?

Potential side effects may include reactions related to the immune system due to infusion of drugs, changes in blood counts leading to increased risk of infections or bleeding, fatigue from treatment-related anemia, digestive issues due to impact on gastrointestinal tract functions, and possible liver or kidney function alterations.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My diagnosis was confirmed through a biopsy and detailed lab tests.

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I can take care of myself but might not be able to do heavy physical work.

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My tumor tissue can be sent to AstraZeneca for testing.

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My disease has come back or worsened after treatment.

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My cancer can be seen on scans and involves lymph nodes or tissues.

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I haven't had blood transfusions or growth factor support in the last 2 weeks.

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I have relapsed or refractory DLBCL or MZL and can provide a recent or archival tumor sample.

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I have tried at least two treatments for my current illness without success and cannot be cured with available treatments.

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My cancer can be seen on scans and involves lymph nodes or tissues.

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I have relapsed or refractory mantle cell lymphoma.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been diagnosed with or currently have progressive multifocal leukoencephalopathy.

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I have a heart condition or take medication that affects my heart's rhythm.

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I have been diagnosed with HIV.

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I need medication that strongly affects liver enzymes.

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I am on blood thinners like warfarin.

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I do not have any severe illnesses or infections that are not under control.

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I am currently being treated for adrenal gland insufficiency or pancreatitis.

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My myeloma does not produce detectable levels of M protein.

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I have or had brain lymphoma, leptomeningeal disease, or spinal cord compression.

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I have not had major heart or stroke issues in the last 6 months.

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I have severe stomach or bowel problems that affect how I digest food.

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I am currently taking both antiplatelet and anticoagulant medications.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 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

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~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

This trial's timeline: 3 weeks for screening, Varies for treatment, and 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 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Module 1 Part A : Number of participants with serious and non-serious adverse events

Module 1 Part B: Overall response rate (ORR) of AZD4573 in combination with acalabrutinib

Module 2 Part A : Number of participants with serious and non-serious adverse events

Secondary study objectives

Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUC0-t) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination

Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUCinf) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination

Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUClast) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination

+9 more

Side effects data

From 2024 Phase 2 trial • 52 Patients • NCT05140382

68%

Neutropenia

58%

Alanine aminotransferase increased

58%

Aspartate aminotransferase increased

53%

Anaemia

47%

Nausea

37%

Diarrhoea

32%

Fatigue

26%

Blood bilirubin increased

26%

Constipation

21%

Hypokalaemia

21%

Thrombocytopenia

21%

Headache

21%

Cough

21%

Gamma-glutamyltransferase increased

16%

Dyspnoea

16%

Dizziness

16%

Upper respiratory tract infection

16%

Pyrexia

16%

Pruritus

16%

Febrile neutropenia

11%

Amylase increased

11%

Rash

11%

Hypotension

11%

Hypophosphataemia

11%

Fibrin D dimer increased

11%

Transaminases increased

11%

Serum sickness

11%

Blood alkaline phosphatase increased

11%

Alopecia

11%

Hyperkalaemia

11%

Blood phosphorus increased

11%

Back pain

11%

Vomiting

11%

Decreased appetite

Cancer pain

Urinary tract infection

Tendon rupture

Anxiety

Erythema

Chills

Enterococcal infection

Influenza like illness

Blood cholesterol increased

Muscle spasms

Arthralgia

Vulvovaginal dryness

Hypertriglyceridaemia

Rash maculo-papular

Dry eye

Tachypnoea

Hypervolaemia

White blood cell count decreased

Influenza

Catheter site infection

Lipase increased

Pain in extremity

Cholestasis

Leukopenia

Liver function test increased

Bacteraemia

Hyperphosphataemia

Serum ferritin increased

Tachycardia

Activated partial thromboplastin time prolonged

Herpes zoster

Pulmonary embolism

Enterobacter bacteraemia

Pneumonia

Lymph node pain

Hypocalcaemia

Eye pain

Stomatitis

Mucosal inflammation

Oedema peripheral

Blood fibrinogen increased

C-reactive protein increased

COVID-19

Vascular device infection

Vision blurred

Palpitations

Blood calcium decreased

Blood creatinine increased

Blood lactate dehydrogenase increased

Hyponatraemia

Syncope

Herpes zoster disseminated

Vascular access complication

Tumour lysis syndrome

Hiccups

Skin weeping

Pelvic pain

Blood urea increased

Streptococcal sepsis

Mouth ulceration

Acute kidney injury

Streptococcal infection

100%

80%

60%

40%

20%

Study treatment Arm

Cohort 3 cHL

Cohort 1 Non-NK PTCL

Cohort 2 NK PTCL

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Module 2: Part A and Part BExperimental Treatment2 Interventions

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.

Group II: Module 1: Part A and Part BExperimental Treatment2 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Acalabrutinib

2020

Completed Phase 2

~2080

AZD4573

2017

Completed Phase 2

~100

0 / 23Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for blood cancers include targeted therapies, chemotherapy, and immunotherapy. Targeted therapies, such as CDK9 inhibitors like AZD4573, work by specifically inhibiting proteins essential for cancer cell survival and proliferation, thereby inducing cancer cell death. Chemotherapy uses cytotoxic drugs to kill rapidly dividing cells, including cancer cells, but can also affect normal cells. Immunotherapy boosts the body's immune system to recognize and destroy cancer cells. These mechanisms are crucial for blood cancer patients as they offer more precise and potentially less toxic treatment options compared to traditional chemotherapy, improving outcomes and quality of life.

[The Onco-hematology clinical research unit at the Geneva University Hospital: example of a fruitful public-private partners].