Phase Ii Study of Azacitidine in Combination with Low Dose Intensity Venetoclax in Patients with Acute Myeloid Leukemia with Integration of Explorative Multi-Omics and Ex Vivo Drug Screening Data

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

28 Aug 2024 → ongoing

Decision date (initial)

2024-08-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-510415-19-00

EudraCT number

2020-005461-14

ClinicalTrials.gov

NCT05431257

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy

To assess the efficacy of azacitidine in combination with low dose venetoclax in patients with AML (ORR = CR+ CRh + CRi + MLFS rate, composite CR/CRh/CRi rate, PR rate).

Secondary objectives 2

1. To assess overall survival (OS), duration of response (DOR), progression free survival (PFS) in patients with AML.
2. To assess the safety of azacitidine in combination with low dose venetoclax in patients with AML.

Conditions and MedDRA coding

Acute Myeloid Leukemia

Regulatory references

Scientific advice from competent authorities

Frederiksberg Hospital

Plan to share IPD

Yes

IPD plan description

Exchange of patient data will take place in pseudonymized form and in accordance with local data protection law and the EU General Data Protection Regulation (GDPR). Encoded (pseudonymized) electronic data transferred from the national exploratory protocols to the LD-VenEx protocol will be shared with collaborating Nordic countries of the LD-VexEx trial in accordance with local data protection law and in compliance with EU General Data Protection Regulation (GDPR). Data will be shared with the objective to integrate analyses of research data from the national exploratory protocols with clinical data from the LD-VenEx protocol from all participating countries. These data will also be compared with data from the Finnish VenEx trial. Agreements with data transfer regulation for transfer of encoded (pseudonymized) electronic data from the LD-VenEx and VenEx protocol have been established. Oral and written information about data transfer will be given to the patients prior to signing inform

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Written informed consent.
2. Patients who present with one of the following (except acute promyelocytic leukemia) a. De novo or secondary AML unfit for standard induction therapy (see inclusion criterion 8). b. Relapsed/refractory AML1 (2022 ELN response criteria) after 1-3 lines of prior therapy (see inclusion criterion 9).
3. Written informed consent to participate in an exploratory research protocol including biobanking, comprehensive AML profiling (genomics, transcriptomics, proteomics, etc.) and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities. (Not applicable for patients enrolled in Sweden).a. All patients are treated with azacytidine + venetoclax irrespective of the ex vivo screening results.
4. ECOG Performance Status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age
5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.
6. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
7. Adequate liver function as demonstrated by a. alanine aminotransferase (ALT) ≤ 4.0 × ULN. b. bilirubin ≤ 1.5 × ULN.
8. Specific inclusion criteria for elderly/unfit AML patients: a. ≥ 70 years of age OR b. ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the following criteria:  Clinically significant comorbidities, as reflected by at least 1 of the following criteria: o Left ventricular ejection fraction (LVEF) < 50%. o Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected. o Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected. o Chronic stable angina or congestive heart failure controlled with medication. o Alanine aminotransferase (ALT) 3.0-4.0 × ULN.  Other contraindication(s) to anthracycline therapy (must be documented).  Adverse risk genetics (2022 ELN risk classification criteria) associated with poor outcome with standard chemotherapy.  Patient declines intensive chemotherapy.  Secondary AML after previous disease modifying treatment (i.e., HMA/induction chemotherapy and/or allogeneic stem cell transplantation) of clonal myeloid diseases such as MDS, MDS/MPN, or MPN.
9. Specific inclusion criteria for relapsed AML patients: a. ≥ 55 years of age with non-CBF AML relapse OR b. ≥ 18 of age and meeting at least one of the following criteria:  Not candidate for intensive chemotherapy (see criterion 8).  Relapse after chemotherapy, or monotherapy with HMA, or allogeneic stem cell transplantation (note: patients with 4th or higher relapse are excluded).  Patient declines intensive chemotherapy.
10. Specific inclusion criteria for refractory AML patients: Patients who fail to achieve a complete or partial remission after previous monotherapy with HMA or induction chemotherapy (at least 1 cycle of chemotherapy containing cytarabine or clofarabine, in combination with a topoisomerase II inhibitor (e.g., anthracycline or mitoxantrone).

Exclusion criteria 13

1. Acute promyelocytic leukemia (APL).
2. Patients with 4th or higher AML relapse.
3. Blast percentage in peripheral blood < 10% (only applicable for patients in whom DSRT during screening is performed on blood).
4. ECOG Performance Status >3 (see also inclusion criteria 4).
5. Prior venetoclax treatment for myeloid malignancy.
6. AML patients with CNS involvement (note: cerebrospinal fluid or radiological investigations are not required without clinical suspicion).
7. HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with antiviral medication with the definition hereof at the discretion of the investigator.
8. Cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
9. Evidence of clinically significant condition(s), which at the investigator's discretion would adversely affect the patient’s participation in this study (including but not limited to): a. Chronic respiratory disease that requires continuous oxygen use. b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal). c. Malabsorption syndrome or other condition that precludes enteral route of administration. d. Uncontrolled GVHD.
10. Previous non-myeloid malignancies with the exception of previous malignancy treated successfully with curative intent or indolent/smoldering malignancies (defined at the investigator's discretion).
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment).
12. Fertile men or women of childbearing potential unless: a. Surgically sterile or ≥ 2 years after the onset of menopause. Willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 3months after the end of study treatment.
13. Known hypersensitivity to venetoclax or azacitidine or excipients of any of the drugs.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR (including CR/CRh/CRi/MLFS rate, composite CR/CRh/CRi rate, PR rate).

Secondary endpoints 2

1. Overall survival (OS), duration of response (DOR), progression free survival (PFS).
2. Frequency and severity of adverse events (hematologic toxicities-AE grade 3+4, febrile neutropenia, days until neutrophil recovery ≥ 0.5 x 10E9/l and platelet recovery ≥ 50 x 10E9/l, severe AE grade 3+4).

Investigational products

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

Test 2

Auxiliary 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

Sponsoring Principal Investigator

Public contact point

Organisation

Rigshospitalet

Contact name

Sponsoring Principal Investigator

Third parties 1

Locations

4 EU/EEA countries · 16 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 29 files

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

Application history

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