## Protocol Section
### Identification Module
**NCT ID:** NCT06156579

**Acronym:** VenSwitch

**Brief Title:** Combination Salvage Therapy With Venetoclax and Decitabine in Relapsed/Refractory AML

**Official Title:** Phase II Study of (Early) Combination Salvage Therapy With Venetoclax and in Intensified Decitabine in Relapsed/Refractory AML

#### Organization Study ID Info
**ID:** VenSwitch
#### Organization
**Class:** OTHER
**Full Name:** University Hospital Tuebingen
### Status Module
#### Completion Date
**Date:** 2025-03-04

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-12-05

**Type:** ACTUAL

**Last Update Submit Date:** 2023-11-30

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2024-12-04

**Type:** ESTIMATED

#### Start Date
**Date:** 2023-11-04

**Type:** ACTUAL

**Status Verified Date:** 2023-11

#### Study First Post Date
**Date:** 2023-12-05
**Type:** ACTUAL
**Study First Submit Date:** 2023-11-13
**Study First Submit QC Date:** 2023-11-30
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University Hospital Tuebingen

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**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.

### Conditions Module

**Conditions:**

- AML

- MDS

**Keywords:**

- Venetoclax

- Decitabine

- salvage therapy

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

**Intervention Model Description:** single center, one arm, open label clinical trial

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 27

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Salvage therapy with Venetoclax and intensified Decitabine

**Intervention Names:**

- Drug: Decitabine

- Drug: Venetoclax

**Label:** Treatment

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Treatment

**Description:** Decitabine 20 mg/m\^2, i.v., once daily, 10 days

**Name:** Decitabine

**Other Names:**

- Dacogen

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Treatment

**Description:** Venetoclax, 400 mg, p.o., once daily, 28 days

**Name:** Venetoclax

**Other Names:**

- Venclyxto

- Venclexta

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** defined as best response in bone marrow aspiration cytology with \<5% residual bone marrow blasts

**Measure:** Rate of hematological remissions

**Time Frame:** measured after the first and second cycle (each cycle is 28 days)

#### Secondary Outcomes

**Description:** evaluated by the incidence of CTCAEs ≥ grade 3

**Measure:** Rate of CTCAEs ≥ grade 3

**Time Frame:** observed during the first and second cycle (each cycle is 28 days)

**Description:** hematopoietic recovery defined as absolute neutrophil counts ≥0.5 and ≥1.0 x 109/L; platelets ≥50 and ≥100 x 109/L)

**Measure:** Time to hematopoietic recovery in days

**Time Frame:** after he first and second cycle (each cycle is 28 days) and the first 100 days after end of treatment

**Description:** cytogenetic MRD is evaluated after each cycle of Decitabine/ Venetoclax in those patients with an established MRD-marker

**Measure:** Rate of MRD-negativity (measurable residual disease)

**Time Frame:** measured after the first and second cycle (each cycle is 28 days)

**Description:** evaluated by the incidence of infections requiring i.v. antibiotic treatment (CTCAEs ≥ grade 3)

**Measure:** Rate of infectious complications

**Time Frame:** measured during the first and second cycle and the first 28 days after end of treatment (each cycle is 28 days)

**Description:** defined as days from diagnosis of primary induction failure or relapse to infusion of allogeneic hematopoietic stem cells

**Measure:** Time to transplant in days

**Time Frame:** until day 100 after end of treatment

**Description:** defined as rate of patients alive without hematological progression at day 100 after end of treatment

**Measure:** Progression-free survival

**Time Frame:** day 100 after end of treatment

**Description:** defined as rate of patients alive at day 100 after end of treatment

**Measure:** Overall survival

**Time Frame:** day 100 after end of treatment

**Description:** Defined patients non longer alive at day 30 after start of treatment

**Measure:** Early Mortality

**Time Frame:** day 30 after start of treatment

**Description:** evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) at screening, and at the end of cycle one and two, as well as at follow up; scale scores ranging from 0 to 100 with higher scores indicating better outcomes

**Measure:** Quality of Life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30))

**Time Frame:** 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)

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Diagnosis of AML according to WHO (world health organization) criteria regardless of subtype a. Including de novo and transformed MPN (myeloproliferative neoplasm) and transformed MDS
2. Refractory to induction chemotherapy consisting of Daunorubicin+Cytarabine ("3+7") based chemotherapy, including CPX351, including combination with the FLT3- inhibitor (fms-like tyrosine kinase) Midostaurin or Mylotarg, defined as

   1. ≥5% medullary blasts in bone marrow assessments after first cycle of induction chemotherapy
3. Relapse of AML/MDS IB2 after chemotherapy (≥5% medullary blasts in bone marrow assessment)
4. Must be ≥ 18 years at the time of signing the informed consent.
5. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
6. Able to adhere to the study visit schedule and other protocol requirements.
7. Patient is fit for aggressive induction chemotherapy and transplantation by assessment of an experienced hematologist
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% (Forced expiratory volume in one second/ forced vital capacity)
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 partner, sexual abstinence). 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 (ovariectomy), 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.

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. All subjects must agree not to share medication.

Exclusion Criteria:

1. Acute Promyelocytic Leukemia (AML with t (15;17))
2. Not consenting to chemotherapy in general
3. Previous Treatment with allogeneic stem cell transplantation
4. ECOG \>3 (Eastern Cooperative Oncology Group)
5. Medical History of hypersensitivity to to the active substances of Venetoclax and Decitabine or to any of the excipients listed in the respective SmPCs (summary of product characteristics)
6. Women during pregnancy and lactation.
7. 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.
8. Severe obstructive or restrictive ventilation disorder
9. 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)
10. 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 (cytochrome P450) inducer is allowed.
11. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
12. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
13. 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
14. 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).

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** lucas.mix@med.uni-tuebingen.de

**Name:** Lucas Mix, Dr.

**Phone:** (+49)70712961781

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Tuebingen

**Contacts:**

***Contact 1:***

- **Email:** lucas.mix@med.uni-tuebingen.de

- **Name:** Lucas Mix, Dr.

- **Phone:** (+49)70712961781

- **Role:** CONTACT

***Contact 2:***

- **Name:** Claudia Lengerke, Prof.

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 3:***

- **Name:** Wolfgang Bethge, Prof.

- **Role:** SUB_INVESTIGATOR

***Contact 4:***

- **Name:** Wichard Vogel, Prof.

- **Role:** SUB_INVESTIGATOR

***Contact 5:***

- **Name:** Lucas Mix, Dr.

- **Role:** SUB_INVESTIGATOR

**Country:** Germany

**Facility:** University Hospital

**State:** Baden-Wuerttemberg

**Status:** RECRUITING

**Zip:** 72076

#### Overall Officials

**Official 1:**

**Affiliation:** University Hospital Tuebingen

**Name:** Claudia Lengerke, Prof.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Intervention Browse Module - Ancestors

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000000964

- Term: Antimetabolites, Antineoplastic

- ID: D000000963

- Term: Antimetabolites

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000004791

- Term: Enzyme Inhibitors

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M1697

- Name: Decitabine

- Relevance: HIGH

- As Found: Above

- ID: M249656

- Name: Venetoclax

- Relevance: HIGH

- As Found: Third

- ID: M4281

- Name: Antimetabolites

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000579720

- Term: Venetoclax

- ID: D000077209

- Term: Decitabine

### Misc Info Module

- Version Holder: 2024-05-24
