Clinical trial NCT06156579: Combination Salvage Therapy With Venetoclax and Decitabine in Relapsed/Refractory AML
Official title: Phase II Study of (Early) Combination Salvage Therapy With Venetoclax and Intensified Decitabine in Relapsed/Refractory AML
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: AML
MDS
Keywords: Venetoclax
Decitabine
salvage therapy
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2023-12-05
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single center, one arm, open label clinical trial
Primary purpose: TREATMENT

Brief summary: The goal of this prospective, phase II single center, one arm, open label clinical trial is to test the efficacy and feasibility of a combination salvage therapy with Venetoclax and intensified Decitabine in patients with newly diagnosed AML (acute myeloid leukemia) and primary induction failure and patients with relapse of AML/MDS IB2 (myelodysplastic neoplasm with increased blasts 2) after chemotherapy. The primary endpoint is hematologic remission after treatment with Decitabine and Venetoclax. Participants eligible for the trial will receive a treatment of ten days of Decitabine and twenty-eight days of Venetoclax for one or two cycles, after which hematological remission will be assessed. Follow up will include the first one hundred days after end of treatment.

Detailed description: This is a prospective, phase II single center one arm, open label clinical trial testing the efficacy and feasibility of a combination salvage therapy with Venetoclax and intensified Decitabine in relapsed or refractory AML and MDS IB2. Enrolled will be twenty-seven patients with newly diagnosed AML and primary induction failure to conventional anthracycline-based induction chemotherapy, as well as patients with a relapse of AML oder MDS IB2 after chemotherapy. Patients will receive a combination therapy of ten days of Decitabine and twenty-eigt days of Venetoclax. If hematologic remission is not achieved after one cycle of treatment, patients receive a second cycle. After treatment, a follow-up period of 100 days will ensue. The main aim of the trial is the assessment of hematologic remission after combining Venetoclax with a time-dense immediate application of the hypomethylating agent Decitabine after failure of a chemotherapy approach, thus additionally altering backbone treatment modalities from chemotherapy to epigenetic and anti-BCL2 (B-cell lymphoma 2) treatment. A first assessment of safety and feasibility will take place after the treatment of three patients and a second assessment for safety, feasibility and efficacy/futility after nine patients.

Eligibility criteria: Inclusion Criteria

1. Diagnosis of AML according to WHO criteria regardless of subtype, including de novo and transformed MPN and transformed MDS 2. A. Refractory to induction chemotherapy consisting of Daunorubicin+Cytarabin ("3+7") based chemotherapy, including CPX351, including combinations with GemtuzumabOzogamicin 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. Must be ≥ 18 years at the time of signing the informed consent. 4. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. 5. Able to adhere to the study visit schedule and other protocol requirements. 6. Patient is fit for aggressive induction chemotherapy and transplantation by assessment of an experienced hematologist 7. 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% 8. 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 ofvulation, 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.

1. A FCBP is defined as any female who does not meet the criteria of non-childbearing potential. These are as follows:

   * documented hysterectomy, bilateral oophorectomy (ovarectomy), or bilateral tubal ligation
   * post-menopausal (a practical definition accepts menopause ≥ 1 year without menses with an appropriate clinical profile, e.g. age \> 45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicle stimulating hormone (FSH) value \> 40 mIU/ml and an estradiol value \< 40pg/ml.
2. Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success
3. In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 9. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment. 10. All subjects must agree not to share medication.

   * in bone marrow aspiration cytomorphology, or bone marrow pathology, if aspiration morphology not available or not representative \*\*\* time frame of tolerance from day 13 to day 20 \*\*\*\*time frame of tolerance from day 21 to day 42

Exclusion Criteria

1. APL (AML with t (15;17))
2. Not consenting to chemotherapy in general
3. Previous Treatment with allogeneic stem cell transplantation
4. ECOG \>3
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. Relapsed FLT3-ITD- or FLT3-TKD-mutated patients, who previously responded (CR, CRi, CRh or MLFS) to a regimen containing a FLT3-inhibitor.
7. Women during pregnancy and lactation.
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.
9. Severe obstructive or restrictive ventilation disorder
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)
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 CYP3A4 inducer is allowed.
12. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
13. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
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.
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).

Primary outcomes:
measure: Rate of hematological remissions
timeFrame: measured after the first and second cycle (each cycle is 28 days)
Secondary outcomes:
measure: Rate of CTCAEs ≥ Grade 3
timeFrame: observed during the first and second cycle (each cycle is 28 days) and until day 30 after therapy application
measure: Time to hematopoietic recovery in days
timeFrame: after each chemotherapy treatment cycle (28 days), defined as the time from the start of the cycle until recovery
measure: Rate of MRD-negativity (measurable residual disease)
timeFrame: measured at each remission assessment (C1D15, C1D28, C2D28, Follow Up)
measure: Rate of infectious complications CTCAEs ≥ grade 3
timeFrame: measured during the first and second cycle and the first 30 days after end of treatment (each cycle is 28 days)
measure: Time to transplant in days
timeFrame: until day 100 after end of treatment
measure: Progression-free survival
timeFrame: day 100 after end of treatment
measure: Overall survival
timeFrame: day 100 after end of treatment
measure: Early Mortality
timeFrame: day 30 after start of treatment
measure: Quality of Life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30))
timeFrame: at screening and at the end of cycle one and two (one cycle is 28 days) and at follow up (day 100 after end of treatment)
measure: Hospitalisation days
timeFrame: Day 1 of therapy until day 30 after end of treatment
measure: ECOG prior to start of conditioning for transplant
timeFrame: between end of treatment and follow up
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University Hospital
state: Baden-Wuerttemberg
Study officials:
affiliation: University Hospital Tuebingen
name: Claudia Lengerke, Prof.
role: PRINCIPAL_INVESTIGATOR
References: