VEX-AZA: Treating VEXAS Syndrome with Azacitidine. A Single-Arm, Multicenter Phase II Study on the Efficacy and Safety of Azacitidine in Patients with VEXAS Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

26 Sep 2024 → ongoing

Decision date (initial)

2024-05-07

Transition trial

No

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

This trial's primary goal is to evaluate the effectiveness of Azacitidine therapy in reducing the UBA1 Variant Allele Frequency (VAF) in patients.

Secondary objectives 7

1. A. To determine the safety of Azacitidine for treating VEXAS Syndrome, based on occurrence of serious adverse events (SAEs) (AEs , grade 3-5), rate of dose modifications and discontinuation rate and the need for Granulocyte colony-stimulating factor (G-CSF) and/or antibiotic, antifungal or antiviral prophylaxis.
2. B. To determine clinical efficacy of Azacitidine, by measuring dose modifications (including discontinuation) of systemic corticosteroids, anti-IL6R treatment, changes in symptoms, changes in blood chemistry values including hemoglobin level, and required blood transfusions.
3. C. To determine the potential of Azacitidine for improving patient-reported outcome measures (PROs) including health-related quality of life (HRQoL) and symptoms, based on the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
4. D. To further assess the molecular response rate and depth.
5. E. In patients who responded to Azacitidine, assess clinical response duration and relapse frequency, evaluated by a VEXAS expert council.
6. F. Describe the mortality rate in responders and non-responders.
7. G. Examine correlation for correlations between UBA1 VAF, changes clinician reported VEXAS organ involvement, and PROs.

Conditions and MedDRA coding

VEXAS

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Participants must possess one of the currently described UBA1 mutations with a VAF > 10%. The currently described UBA1 mutations are: p.Met41Leu (c.121A.C), p.Met41Val (c.121A.G), p.Met41Thr (c.122T.C), p.Ser56Phe (c.167C>T), p.(splice)(c.118-1G>C) or intronic deletions like (c.118-9_118-2del) affecting the splice site
2. Participants must meet one of the following conditions: (1) Present with any degree of cytopenia, or (2) Exhibit inflammatory symptoms of VEXAS with/without cytopenia.
3. Participants must be at least 18 years old and possess the cognitive capacity to provide informed consent.
4. It is mandatory that male participants, who engage in sex with pre-menopausal (i.e. fertile) women, are willing to use barrier contraceptives (i.e condoms), during treatment with Azacitidine, and until three months after the last treatment. Additionally, it is highly recommended that their fertile partner also uses highly effective contraceptives during and for three months after the participants last treatment. Fertile female participants must exhibit a negative result on a pregnancy test before inclusion, demonstrate a commitment to monthly pregnancy testing and employment of safe contraceptive measures during treatment with Azacitidine, and until three months after the last treatment.

Exclusion criteria 8

1. Patients having received Prior therapy with hypomethylating agents (i.e., Azacitidine, Decitabine).
2. Patients having received or is planned to receive alloHSCT.
3. Patients with active cancer requiring treatment are excluded from participation in this study. Active cancer is defined as a diagnosis of cancer for which the patient is currently receiving treatment, such as chemotherapy, radiation therapy, immunotherapy, targeted therapy, or any other curative or disease-controlling intervention.
4. Concomitant treatment with Disease modifying antirheumatic drugs (DMARDs), Chemotherapy/Cytostatic agents, Immunosuppressives, Radiotherapy any novel biological response modifying agents, is not allowed in the trials regardless of the underlying condition for which they are used. These treatments must be discontinued at least 14 days prior to inclusion.
5. Failure to obtain bone marrow examination maximum 8 weeks prior to initiating Azacitidine treatment.
6. Patients who are diagnosed with severe comorbidities including decompensated cirrhosis, end-stage kidney disease requiring dialysis, Severe cardiac disease (LVEF <30%), Severe pulmonary disease (FEV1 < 50% of predicted or DLCO < 40%), or a severe immunodeficiency including a diagnosis of HIV. If any of these conditions are suspected but undiagnosed, relevant tests will be ordered prior to screening based on clinical suspicion. However, diagnostic tests for all potential severe comorbidities will not be conducted systematically for every candidate; clinical suspicion will guide the decision to investigate further.
7. Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status > 2
8. Patients who have a condition where Azacitidine is contraindicated, including hypersensitivity to Azacitidine, advanced malignant hepatic tumors, pregnancy, and breastfeeding individuals.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint: to assess the number and percentage of patients who experience a 50% relative reduction in VAF after completing six cycles of Azacitidine treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Jakob Werner Hansen

Public contact point

Organisation

Rigshospitalet

Contact name

Jakob Werner Hansen

Third parties 3

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications