Open Label 2-Arm Study of Venetoclax in Combination with Azacitidine Versus Best Supportive Care after Allogeneic Stem Cell Transplantation in Subjects with Acute Myeloid Leukemia (AML)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Jul 2020 → 23 Sep 2025

Decision date (initial)

2024-01-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-507222-17-00

EudraCT number

2019-002621-30

ClinicalTrials.gov

NCT04161885

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Part I: To determine the recommended Phase 3 dose of venetoclax in combination with azacitidine in AML patients when given as maintenance therapy following allogeneic SCT.
Part II:To evaluate the efficacy of venetoclax in combination with azacitidine to improve OS in AML patients compared to BSC when given as maintenance therapy following allogeneic SCT.

Secondary objectives 5

1. Part 2: To confirm the safety of venetoclax in combination with azacitidine after allogeneic SCT in subjects diagnosed with AML.
2. To determine the efficacy of venetoclax in combination with azacitidine as measured by RFS.
3. To determine the effect of venetoclax in combination with azacitidine on the frequency and severity of GvHD.
4. To determine the effect of venetoclax in combination with azacitidine on Quality of Life (QoL).
5. To determine the effect of venetoclax in combination with azacitidine on minimal residual disease levels.

Conditions and MedDRA coding

Acute Myeloid Leukaemia

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

AbbVie is committed to responsible clinical trial data sharing. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Adult male or female ≥18 years old for Part 1 and, male or female at least 12 years old for Part 2.
2. Subject must be diagnosed with AML by World Health Organization (WHO) criteria (2017) and either be planning for allogeneic stem cell transplantation or have received allogeneic stem cell transplantation within the past 60 days.
3. Blast percentage in bone marrow prior to pre-transplant conditioning must be < 10%. Blast count in peripheral blood must be "0" and malignant Blast percentage in bone marrow must be < 5% after transplant within 7 days prior to Cycle 1 Day 1.
4. Bilirubin ≤3 × ULN* within 7 days prior to Cycle 1 Day 1. For Part 1: ANC ≥1,500/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have granulocyte-colony stimulating factor (G-CSF) treatment for 7 days before first ANC count. For Part 2: ANC ≥1,000/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have granulocyte- colony stimulating factor (G-CSF) treatment for 7 days before first ANC count.
5. Part 1: Platelet count ≥80,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count. Part 2: Platelet count ≥50,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count.
6. Adequate renal function as demonstrated by a creatinine clearance > 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24- hour urine collection.
7. Subjects ≥17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and Subjects 12 to 16 years old must have a Lansky Play- Performance Scale (LPPS) score > 40. Part 2: If a subject is 12 to 16 at the time of screening and turns 17 during the study, the subject will continue with the LPPS.
8. Cycle 1 Day 1 administration of 1st dose of the study drug(s) must occur within 28 to 100 days after transplant. Subjects may enter into Screening upon the first instance of meeting the count recovery criteria without the need for supportive care (e.g., growth factors and/or platelet transfusions) for at least 7 days prior. Upon entering screening, subjects must maintain count thresholds on at least 2 occasions (approximately 48 hours apart) in the absence of supportive care (platelet transfusion/G-CSF within 7 days).
9. If graft failure occurs during the registration period and a subsequent transplant is planned, the subject can be reconsented for the study.
10. (Notes a - b): a) C1D1 must occur within 28 to 100 days of this subsequent transplant date. b) If there is a subsequent (second) graft failure after reconsent during the registration period, the subject will not be permitted to enroll into the study.
11. No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Exclusion criteria 5

1. Subjects with favorable cytogenetic risk per NCCN 2016 criteria and in first complete remission prior to transplant are not eligible to enroll in this study.
2. History of disease progression during prior treatment with venetoclax.
3. History of any other malignancy within 2 years prior to study entry, except for: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; Myelodysplastic Syndrome; Myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation).
4. Known infection with HIV or subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) with high viral titers.
5. Presence of clinical or laboratory symptoms/signs of extramedullary myeloid malignancy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part I: The primary endpoint is the frequency of DLTs of venetoclax in combination with azacitidine
2. Part II: OS defined as the time from randomization to death from any cause

Secondary endpoints 8

1. IRC-assessed morphologic RFS
2. IRC-assessed composite relapse-free survival
3. GvHD-free, relapse free survival (GRFS)
4. GvHD rate at 90 days after randomization (Arm B) or initiation of treatment (Arm A). "Higher grade GvHD" is defined as Grade 2 or higher for aGvHD and moderate or severe for cGvHD as defined by the investigator following National Institutes of Health (NIH) criteria.
5. Change from baseline (Cycle 1 Day 1 [predose]) at 6 months in physical functioning after randomization (Arm B) or initiation of study treatment (Arm A) in adult subjects, as measured by the EORTC QLQ-C30 physical functioning domain
6. Fatigue Change from baseline at 6 months after randomization (Arm B) or initiation of study treatment (Arm A) in adult subjects –defined as Fatigue measured as Patient Reported Outcome (PRO) using Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue SF 7a
7. Measurable residual disease conversion rate –The rate will be calculated only among subjects with MRD ≥10–3 at baseline (Cycle 1 Day 1 [predose]). The MRD conversion rate will be defined as proportion of subjects who convert to MRD < 10–3 after randomization (Arm B) or initiation of treatment (Arm A)
8. Time to deterioration in Global Health Status (GHS)/QoL in adult subjects - defined as time from randomization to death from any cause, or the first-time deterioration of ≥10 points from baseline (Cycle 1 Day 1 [predose]) in GHS/QoL score as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Version 3, whichever occurs first

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Third parties 6

Locations

7 EU/EEA countries · 36 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 69 files

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

Application history

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