Study of safety and efficacy of Venetoclax in combination with Vidaza (Azacitidine) in higher-risk Chronic Myelomonocytic Leukemia (CMML)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Groupe Francophone Des Myelodysplasies

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

4 Oct 2023 → ongoing

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie

External identifiers

EU CT number

2024-514878-53-00

EudraCT number

2021-002007-35

ClinicalTrials.gov

NCT05768711

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To determine the safety of venetoclax + azacitidine in the study population during the run-in phase and the overall response rate in the phase II portion of the study

Secondary objectives 2

1. Description of efficacy in terms of complete response rate, duration of response and survival and description of safety
2. Exploratory objectives aim at nominating potential biomarkers of the AZA-VEN combination

Conditions and MedDRA coding

HMA-naïve, higher-risk (HR, defined as CPSS-mol risk intermediate-2 or high) CMML patients

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age 18 and older
2. CMML diagnosis according to ICC 2022 criteria
3. Intermediate-2 or high risk according to the molecular CMML Prognostic Scoring System (CPSS-mol, Elena Blood 2016)
4. No prior treatment with HMAs. Prior treatment with Erythropoiesis Stimulating Agents (ESA) is allowed with a > 15 days washout from ESAs. Prior treatment with hydroxurea (HY) is acceptable.
5. ECOG Performance status 0-2
6. Adequate organ function: total bilirubin < 2 times upper limit of normal (ULN), ALT and AST < 3 times ULN, creatinine clearance > 30 mL/min.
7. Signed Informed Consent Form
8. Negative pregnancy and adequate contraception (including in male patients) if relevant
9. Affiliation to a health insurance system

Exclusion criteria 14

1. Myeloproliferative / myelodysplastic syndrome other than CMML
2. Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%
3. CMML with t(5;12) or PDGFRß rearrangement that may be treated with imatinib
4. Unavailable CPSS-mol at inclusion (WBC prior to HY used to compute CPSS-mol at inclusion in HY-exposed patients) or with a CPSS-mol low or intermediate-1 at study entry
5. Pregnant or breastfeeding
6. Serious concomitant systemic disorder, including auto-immune or auto-inflammatory disease requiring > 20 mg/d prednisone equivalent, active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.
7. Medical condition requiring therapies with CYP3A strong or moderate inducing or inhibiting activity at screening
8. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years)
9. Known positive test for human immunodeficiency virus (HIV)
10. Malabsorption syndrome or other condition that precludes an enteral route of administration
11. Previous therapy with a hypomethylating agent for CMML or any antecedent condition
12. Previous therapy with a BH3 mimetic
13. Antecedent allogeneic stem cell transplantation (HSCT) for CMML or an antecedent of hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.
14. Subjects referred to in Articles L1121-5 to L1121-8-1 and L1122-1-2 of the Public Health Code

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety run-in: dose-limiting toxicity occurring within the first two cycles of treatment
2. Phase II: Overall response rate (ORR) after 3 and 6 cycles according to protocol-defined criteria modified from MDS/MPN IWG criteria (Savona Blood. 2015 Mar 19; 125(12): 1857–1865). Overall response includes complete remission (CR), partial remission (PR), marrow response (MR) and clinical benefit (CB).

Secondary endpoints 15

1. CR rate after 3 and 6 cycles according to modified MDS/MPN IWG criteria
2. ORR at best response according to modified MDS/MPN IWG criteria
3. ORR after 3 and 6 cycles, and at best response according to DACOTA response criteria (ie modified MDS IWG 2006 criteria, Braun Blood 2011)
4. Duration of Response (according to modified MDS/MPN IWG criteria)
5. Safety profile (both hematological and non-hematological) of venetoclax in combination with azacitidine
6. Overall Survival (OS)
7. AML-free survival (AMLFS)
8. Progression-free survival (PFS)
9. Event-free survival (EFS)
10. Cumulative incidence of AML and cumulative risk of death without AML
11. Cumulative incidence of progressive disease (or AML transformation) and cumulative risk of death without progression or AML transformation
12. Rate of HSCT and post-HSCT OS and AMLFS
13. OS, AMLFS and PFS censoring at HSCT
14. Rate and description of subsequent therapy
15. OS, AMLFS and PFS censoring at subsequent therapy

Investigational products

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

Test 3

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Groupe Francophone Des Myelodysplasies

Sponsor organisation

Groupe Francophone Des Myelodysplasies

Address

Opital St Louis Hemato Seniors T4, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Raphaël ITZYKSON

Public contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Raphaël ITZYKSON

Locations

1 EU/EEA country · 24 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 6 files

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

Application history

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