Phase II study of (early) combination salvage therapy with Venetoclax and intensified Decitabine in Relapsed/Refractory AML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen

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 Oct 2023 → ongoing

Decision date (initial)

2023-05-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2022-502665-15-00

ClinicalTrials.gov

NCT06156579

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Hematologic remission (best response in bone marrow aspiration cytomorphology, hematologic remission defined as <5% residual bone marrow blasts) after one or two cycles of Decitabine/Venetoclax

Secondary objectives 8

1.  Safety and feasibility of combining Venetoclax with a time-dense immediate application of the hypomethylating agent Decitabine evaluated by the incidence of CTCAEs ≥ grade 3 and times to hematopoietic recovery (absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery
2.  MRD assessment (cytogenetics, molecular genetics or by flow cytometry) after each cycle of Decitabine/Venetoclax and prior to potential allogeneic transplantation
3.  Infectious complications requiring i.v. antibiotics
4.  Time-to-transplant for salvage therapies defined as time from diagnosis of primary induction failure to infusion of allogeneic stem cells
5.  ECOG prior to start of potential conditioning for transplant
6.  PFS and OS 3 months after EOT
7.  Mortality at 30 days post start of salvage therapy/Hospitalisation days
8.  Quality of life assessment at screening (additional at the end of each cycle Venetoclax/Decitabine) and at the end of the trial (follow up)

Conditions and MedDRA coding

acute myeloid leukemia (AML)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Diagnosis of AML according to WHO criteria regardless of subtype. Including de novo and transformed MPN and transformed MDS
2. 2.A. Refractory to induction chemotherapy consisting of Daunorubicin+Cytarabin (“3+7”) based chemotherapy, including CPX351, including combinations with Gemtuzumab-Ozogamicin or with the FLT3-inhibitors Midostaurin or Quizartinib. This trial defines refractory disease as one of the following: i. ≥20% bone marrow blasts** at day 15*** first cycle of intensive induction chemotherapy ii. ≥5-20% bone marrow blasts** at day 15*** of first cycle of intensive induction chemotherapy in patients, in whom relative blast count reduction as compared to initial diagnosis is ≤50% iii. c) ≥5% bone marrow blasts** at day 28**** of first cycle of induction chemotherapy, or at any point during a second cycle of induction chemotherapy OR 2. B. Relapse of AML/MDS IB2 after chemotherapy (≥5% medullary blasts in bone marrow assessment**)
3. 3. Relapse of AML/MDS EB2 after chemotherapy (≥5% medullary blasts in bone marrow assessment)
4. 4. Must be ≥ 18 years at the time of signing the informed consent
5. 5. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
6. 6. Able to adhere to the study visit schedule and other protocol requirements
7. 7. Patient is fit for aggressive induction chemotherapy and transplantation by assessment of an experienced hematologist
8. 8. No known history of chronic pulmonary disease and absence of dyspnea. Otherwise, documented diffusion lung capacity for carbon monoxide (DLCO) >40% (adjusted for hemoglobin, if available) and FEV1/FVC >50%
9. Subject (male or female (FCBP))1 is willing to use highly effective birth control methods during treatment and for 3 months (male) and 6 months (female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system bilateral tubal occlusion, vasectomized partner2 sexual abstinence3). Female subjects who use hormonal contraceptives should also use a barrier method.
10. 10. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
11. 11. All subjects must agree not to share medication

Exclusion criteria 15

1. 1. APL (AML with t(15;17))
2. 10. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia.(Note: Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening)
3. 11. Active infection, including hepatitis B or hepatitis C antibody or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or which could expose the patient to undue risk through the participation in the clinical trial; an infection controlled with an approved antibiotic/ antiviral/ antifungal treatment that is not a strong or moderate CYP3A inducer is allowed
4. 12. Immediate life‐threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminatwed intravascular coagulation
5. 5. Medical History of hypersensitivity to to the active substances of Venetoclax and Decitabin or to any of the excipients listed in the respective SmPCs
6. 7. Women during pregnancy and lactation.
7. 13. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
8. 14. Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at <30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:• Basal or squamous cell carcinoma of the skin;• Carcinoma in situ of the cervix;• Carcinoma in situ of the breast;• Incidental histologic finding of prostate cancer.
9. 15. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: patients, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
10. 2. Not consenting to chemotherapy in general
11. 3. Previous Treatment with allogeneic stem cell transplantation
12. 4. ECOG >3
13. 8. Significant active cardiac disease within 6 months prior to the start of study treatment, including:• New York Heart Association (NYHA) class III or IV congestive heart failure;• Myocardial infarction;• Unstable angina and/or stroke;• Severe cardiac arrhythmias• Left ventricular ejection fraction (LVEF) <40% by ultrasound obtained within 28 days prior to the start of study treatment.
14. 9. Severe obstructive or restrictive ventilation disorder
15. 6. Relapsed FLT3-ITD- or FLT3-TKD-mutated patients, who previously responded (CR, CRi, CRh or MLFS) to a regimen containing a FLT3-inhibitor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1.  Hematologic remission (defined as morphologically leukemia-free state (MLFS), complete remission (CR), complete remission with incomplete hematological recovery (CRi) or complete remission with partial hematological recovery (CRh)) as best response in bone marrow aspiration cytomorphology*) after one or two cycles of Decitabine/Venetoclax.

Secondary endpoints 9

1. Safety and feasibility of combining Venetoclax with a timedense immediate application of the hypomethylating agent Decitabine evaluated by the incidence of CTCAEs ≥ grade 3 until day 30 after therapy application and times to hematopoietic recovery (absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery
2. MRD assessment (MRD including qPCR for established MRD markers and NGS for exploratory MRD markers) at each remission assessment
3. Infectious complications CTCAEs >=grade 3
4. Time-to-transplant from diagnosis of primary induction failure to infusion of allogeneic stem cells
5. ECOG prior to start of potential conditioning for transplant
6. PFS and OS at Follow-up Visit (100 days after EOT) and time dependent
7. Mortality at 30 days post start of salvage therapy
8. Quality of life assessment at screening (additional at the end of each cycle Venetoclax/Decitabine) and at the end of the trial (follow up)
9. Hospitalisation days, defined as days in hospital from day 1 of therapy until day 30 after EOT

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen

Sponsor organisation

Universitaetsklinikum Tuebingen

Address

Geissweg 3, Innenstadt Innenstadt

City

Tübingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen

Contact name

Claudia Lengerke

Public contact point

Organisation

Universitaetsklinikum Tuebingen

Contact name

Claudia Lengerke

Locations

1 EU/EEA country · 1 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 8 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