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Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndromes

Status
Recruiting
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Venetoclax
Placebo
Standard chemotherapy
Autologous stem cell transplantation
Allogeneic stem cell transplantation
Sponsored by
University of Ulm
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring adult patients

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients with newly diagnosed acute myeloid leukemia (AML), or myelodysplastic syndrome with excess blasts-2 (MDS-EB2) according to World Health Organization (WHO) classification.
  2. Age ≥ 18 years, no upper age limit.
  3. Patient considered eligible for intensive chemotherapy.
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at randomization.
  5. Molecular analysis centrally performed in AMLSG and HOVON laboratories.
  6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
  7. Adequate hepatic function as evidenced by:

    • Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert's disease, or leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator
  8. No prior chemotherapy for AML except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 25x109/L); patients may have had previous treatment with erythroid stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS; ESA and HMAs have to be stopped at least four weeks before enrolment.
  9. Subjects must not have received a known strong or moderate CYP3A inducer 7 days before enrolment. Subjects must have no known medical conditions requiring chronic therapy with moderate or strong CYP3A inducers.
  10. Female patient must either:

    • Be of nonchildbearing potential:

      • Postmenopausal (defined as at least 1 year without any menses)
      • Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
    • Or, if of childbearing potential (not surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) and not postmenopausal)

      • Not planning to become pregnant during the study and for 6 months after the final study drug administration
      • And have a negative urine or serum pregnancy test at screening
      • And, if heterosexually active, agree to consistently apply one highly effective* in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration

        *Highly effective forms of birth control include

      • Consistent and correct usage of established hormonal contraceptives that inhibit ovulation (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used.
      • Established intrauterine device (IUD) or intrauterine system (IUS)
      • Bilateral tubal occlusion
      • Vasectomy - a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
      • Male is sterile due to a bilateral orchiectomy.
      • Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.

        *List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.

      • Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
      • Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
  11. Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control.
  12. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.
  13. Able to understand and willing to sign an informed consent form (ICF).

Exclusion Criteria:

  1. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes.
  2. AML with BCR-ABL1; or myeloid blast crisis of CML.
  3. Patients with AML and activating FLT3 mutations who have access (including reimbursement) to treatment with a FLT3 inhibitor approved for first-line therapy of AML.
  4. Prior treatment of MDS with intensive chemotherapy or allogeneic hematopoietic cell transplantation (HCT) with a curative intent.
  5. 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
  6. Severe obstructive or restrictive ventilation disorder.
  7. Co-administration of moderate/strong CYP inhibitors during the DLT observation period for subjects in the dose-finding part of the study.
  8. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening.
  9. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled at randomization and may interfere with the study objectives or which could expose the subject 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.
  10. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation.
  11. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
  12. 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, subjects 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.
  13. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: subjects, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy).
  14. Severe neurological or psychiatric disorder interfering with ability to give an informed consent.
  15. Known or suspected hypersensitivity to any of the chemotherapeutic agents used.
  16. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation.
  17. No consent for biobanking of patient's biological specimens.
  18. Participation in other prospective studies with anti-leukemic and/or investigational agents.
  19. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.

Sites / Locations

  • Charité Berlin - Campus MitteRecruiting
  • Charité Berlin - Campus Benjamin FranklinRecruiting
  • Charité Berlin - Campus Virchow KlinikumRecruiting
  • Knappschaftskrankenhaus Bochum-LangendreerRecruiting
  • Uniklinikum BonnRecruiting
  • Staedtisches Klinikum BraunschweigRecruiting
  • Universitätsklinikum Hamburg-EppendorfRecruiting
  • Medizinische Hochschule HannoverRecruiting
  • Städtisches Klinikum KarlsruheRecruiting
  • Diakonie Klinikum StuttgartRecruiting
  • Uniklinikum TübingenRecruiting
  • University Hospital UlmRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

standard chemotherapy in combination with venetoclax

standard chemotherapy in combination with placebo

Outcomes

Primary Outcome Measures

Event Free Survival (EFS)
EFS in adult patients with newly diagnosed AML, defined as the time from randomization to treatment failure, death from any cause, or relapse after achieving CR or CRi, or start of new therapy due to confirmed molecular relapse whichever occurs first. Treatment failure is defined as not attaining CR or CRi after induction chemotherapy, and EFS event time for treatment failure is Day 1 of post-randomization
Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase)
Frequency of dose-limiting toxicities (DLTs) during the observation period (from start of cycle 1 up to a maximum of day 42, or until the start of cycle 2)

Secondary Outcome Measures

Overall Survival (OS)
OS in patients with newly diagnosed AML
CR/CRi rate
Complete remission (CR/CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi after induction chemotherapy
CR rate
Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy, defined as the proportion of AML patients achieving CR/CRi with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment
Relapse-free survival (RFS) in newly diagnosed AML patients
Relapse-free survival (RFS) in newly diagnosed AML patients, defined as the time from achievement of a remission (CR/CRi) following curative therapy (induction and consolidation), to relapse, or start of new therapy due to confirmed molecular relapse or death from any cause
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Cumulative incidence of death (CID)
Cumulative incidence of death (CID) in newly diagnosed AML patients.
EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients
Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated using a 5 level (5L) scale from 1 (minimum) to 5 (maximum). Higher score values mean a worse outcome.
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients
All sub scales and single items have values from 1 (minimum) to 100 (maximum) points. A higher point value represents a better condition in terms of the functional scales and quality of life. In the symptomal sub scales a higher point value represents a worse condition.
Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients
The 7-item PROMIS Cancer Fatigue Short Form assesses the frequency of fatigue in the past seven days (7). Table 2 presents a list of the items. Items are measured on a five point scale (1 = never; 5 = always) and summed, after reverse scoring item 7, with higher scores indicating greater fatigue (worse condition).

Full Information

First Posted
November 3, 2020
Last Updated
June 6, 2023
Sponsor
University of Ulm
Collaborators
Stichting Hemato-Oncologie voor Volwassenen Nederland
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1. Study Identification

Unique Protocol Identification Number
NCT04628026
Brief Title
Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2
Official Title
A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 13, 2022 (Actual)
Primary Completion Date
February 1, 2025 (Anticipated)
Study Completion Date
February 1, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Ulm
Collaborators
Stichting Hemato-Oncologie voor Volwassenen Nederland

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2
Detailed Description
Prospective, multicenter, double-blind, randomized, placebo-controlled phase 3 clinical study. The randomized phase of the study will be preceded by a feasibility run-in dose-escalation phase in patients with AML in which the venetoclax dose for the phase 3 part will be established. After the feasibility run-in phase, eligible patients will be randomized to intensive chemotherapy with venetoclax or placebo. Patients will receive two cycles of induction chemotherapy; patients achieving CR or CRi after two cycles will continue with consolidation treatment according to initial randomization, and according to Cooperative Group-specific consolidation regimens or investigator choice. Patients achieving morphologic leukemia-free state (MLFS) only, may also continue consolidation treatment on protocol. Assignment to either allogeneic hematopoietic cell transplantation (HCT), conventional chemotherapy or autologous HCT will be done according to institutional standards, and based on (prognostic) disease characteristics, individual patient assessment, and established comorbidity risk scores (e.g., HCT-CI score).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Myelodysplastic Syndromes
Keywords
adult patients

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
double-blind with open label dose-finding run-in part
Allocation
Randomized
Enrollment
650 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
standard chemotherapy in combination with venetoclax
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
standard chemotherapy in combination with placebo
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
Induction cycle 1: Venetoclax will be administered orally QD, daily dose: 100mg/200mg/300mg, days 1-12 (after a 1/2/3 day ramp-up phase) (as determined during run-in phase) Induction cycle 2: Venetoclax will be administered orally QD, daily dose: 100mg/200mg/300mg, patients not in CR/CRi: days 1-12 (after a 1/2/3 day ramp-up phase) or patients in CR/CRi: days 1-14 (without ramp-up) (as determined during run-in phase) Consolidation phase: Venetoclax will be administered orally QD, daily dose: 100mg/200mg/300mg, days 1-14 (as determined during run-in phase)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Induction cycle 1: Placebo will be administered orally QD, daily dose: 100mg/200mg/300mg, days 1-12 (after a 1/2/3 day ramp-up phase) (as determined during run-in phase) Induction cycle 2: Placebo will be administered orally QD, daily dose: 100mg/200mg/300mg, patients not in CR/CRi: days 1-12 (after a 1/2/3 day ramp-up phase) or patients in CR/CRi: days 1-14 (without ramp-up) (as determined during run-in phase) Consolidation phase: Placebo will be administered orally QD, daily dose: 100mg/200mg/300mg, days 1-14 (as determined during run-in phase)
Intervention Type
Combination Product
Intervention Name(s)
Standard chemotherapy
Intervention Description
Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6, and daunorubicin 60 mg/m2 IV (days 1-3). Patients >60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6 without daunorubicin. Consolidation chemotherapy option 1 consists of one cycle of mitoxantrone (10mg/m2 IV) and etoposide (100mg/m2 IV) (ME) days 1-5 (patients ≤60 yrs) or days 1-3 (patients >60 yrs). Consolidation chemotherapy option 2 consists of intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are >60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients >60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.
Intervention Type
Other
Intervention Name(s)
Autologous stem cell transplantation
Intervention Description
Busulfan/Cyclophosphamide will be administered as conditioning regime. Patients may proceed to autologous HCT when they have reached CR/CRi/MLFS after at least two cycles of chemotherapy and performance status permits continuation with high-dose chemotherapy. Venetoclax will not be added to or given after the conditioning regimen.
Intervention Type
Other
Intervention Name(s)
Allogeneic stem cell transplantation
Intervention Description
Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.
Primary Outcome Measure Information:
Title
Event Free Survival (EFS)
Description
EFS in adult patients with newly diagnosed AML, defined as the time from randomization to treatment failure, death from any cause, or relapse after achieving CR or CRi, or start of new therapy due to confirmed molecular relapse whichever occurs first. Treatment failure is defined as not attaining CR or CRi after induction chemotherapy, and EFS event time for treatment failure is Day 1 of post-randomization
Time Frame
6 months/16 months after inclusion of last patient
Title
Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase)
Description
Frequency of dose-limiting toxicities (DLTs) during the observation period (from start of cycle 1 up to a maximum of day 42, or until the start of cycle 2)
Time Frame
after cycle 1 (maximal day 42)
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
OS in patients with newly diagnosed AML
Time Frame
6 months/16 months/28 months after inclusion of last patient
Title
CR/CRi rate
Description
Complete remission (CR/CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi after induction chemotherapy
Time Frame
2 months
Title
CR rate
Description
Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy
Time Frame
2 months
Title
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy
Description
Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy, defined as the proportion of AML patients achieving CR/CRi with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment
Time Frame
2 months
Title
Relapse-free survival (RFS) in newly diagnosed AML patients
Description
Relapse-free survival (RFS) in newly diagnosed AML patients, defined as the time from achievement of a remission (CR/CRi) following curative therapy (induction and consolidation), to relapse, or start of new therapy due to confirmed molecular relapse or death from any cause
Time Frame
16 months after inclusion of last patient
Title
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Description
Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
Time Frame
16 months after inclusion of last patient
Title
Cumulative incidence of death (CID)
Description
Cumulative incidence of death (CID) in newly diagnosed AML patients.
Time Frame
16 months after inclusion of last patient
Title
EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients
Description
Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated using a 5 level (5L) scale from 1 (minimum) to 5 (maximum). Higher score values mean a worse outcome.
Time Frame
6 months
Title
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients
Description
All sub scales and single items have values from 1 (minimum) to 100 (maximum) points. A higher point value represents a better condition in terms of the functional scales and quality of life. In the symptomal sub scales a higher point value represents a worse condition.
Time Frame
6 months
Title
Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients
Description
The 7-item PROMIS Cancer Fatigue Short Form assesses the frequency of fatigue in the past seven days (7). Table 2 presents a list of the items. Items are measured on a five point scale (1 = never; 5 = always) and summed, after reverse scoring item 7, with higher scores indicating greater fatigue (worse condition).
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Rates of CR+CRi in newly diagnosed AML patients after induction 1
Description
Rates of CR+CRi in newly diagnosed AML patients defined as proportion of AML patients achieving CR/CRi after first course of induction
Time Frame
1 month
Title
Rates of CR in newly diagnosed AML patients after induction 1
Description
Rates of CR in newly diagnosed AML patients defined as proportion of AML patients achieving CR after first course of induction
Time Frame
1 month
Title
EFS in newly diagnosed AML patients across different patient subgroups
Description
EFS in newly diagnosed AML patients across different groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
6 months/16 months after inclusion of last patient
Title
OS in newly diagnosed AML patients across different patient subgroups
Description
OS in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
6 months/16 months/28 months after inclusion of last patient
Title
CR/CRi rates in newly diagnosed AML patients across different patient subgroups
Description
CR/CRi rates in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
1 month
Title
CR rates in newly diagnosed AML patients across different patient subgroups
Description
CR rates in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
1 month
Title
RFS in newly diagnosed AML patients across different patient subgroups
Description
RFS in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
16 months after inclusion of last patient
Title
CIR in newly diagnosed AML patients across different patient subgroups
Description
CIR in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
16 months after inclusion of last patient
Title
CID in newly diagnosed AML patients across different patient subgroups
Description
CID in newly diagnosed AML patients across different patient subgroups, where the groups are defined based on prognostic characteristics including age at registration , risk category according to ELN 2017 recommendations, as well as specific AML genotypes
Time Frame
16 months after inclusion of last patient
Title
Frequency and severity of AE
Description
Frequency and severity of AE according to CTCAE version 5.0 in newly diagnosed AML patients and MDS-EB2 patients
Time Frame
6 months
Title
Times to hematopoietic recovery
Description
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 among AML patients am MDS-EB2 patients
Time Frame
6 months
Title
Frequency and severity of adverse events (AEs) (Secondary Safety endpoint during dose-finding phase)
Description
Frequency and severity of adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0, see protocol Section 12.1 for definitions
Time Frame
6 months
Title
EFS rates in MDS-EB2 patients
Description
EFS rates in MDS-EB2 patients
Time Frame
6 months/16 months after inclusion of last patient
Title
OS rates in MDS-EB2 patients
Description
OS rates in MDS-EB2 patients
Time Frame
6 months/16 months/28 months after inclusion of last patient
Title
CR/CRi rates after induction chemotherapy in MDS-EB2 patients
Description
CR/CRi rates after induction chemotherapy in MDS-EB2 patients
Time Frame
2 months
Title
CR rates after induction chemotherapy in MDS-EB2 patients
Description
CR rates after induction chemotherapy in MDS-EB2 patients
Time Frame
2 months
Title
RFS rates in MDS-EB2 patients
Description
RFS rates in MDS-EB2 patients
Time Frame
16 months after inclusion of last patient
Title
CIR rates in MDS-EB2 patients
Description
CIR rates in MDS-EB2 patients
Time Frame
16 months after inclusion of last patient
Title
CID rates in MDS-EB2 patients
Description
CID rates in MDS-EB2 patients
Time Frame
16 months after inclusion of last patient
Title
EQ-5D-5L questionnaire of the EuroQoL group, among MDS-EB2 patients
Description
Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated using a 5 level (5L) scale from 1 (minimum) to 5 (maximum). Higher score values mean a worse outcome.
Time Frame
6 months
Title
European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC-QLQ-C30) among MDS-EB2 patients
Description
All sub scales and single items have values from 1 (minimum) to 100 (maximum) points. A higher point value represents a better condition in terms of the functional scales and quality of life. In the symptomal sub scales a higher point value represents a worse condition.
Time Frame
6 months
Title
Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among MDS-EB2 patients
Description
The 7-item PROMIS Cancer Fatigue Short Form assesses the frequency of fatigue in the past seven days (7). Table 2 presents a list of the items. Items are measured on a five point scale (1 = never; 5 = always) and summed, after reverse scoring item 7, with higher scores indicating greater fatigue (worse condition).
Time Frame
6 months
Title
EFS with modified definition
Description
To evaluate the impact of venetoclax on EFS in newly diagnosed AML patients and MDS-EB2 patients using modified endpoint definitions: o Modified EFS includes treatment failure defined as not achieving CR after induction chemotherapy assessed by investigator. The date of treatment failure is Day 1 post-randomization. Patients achieving CRi are counted as events.
Time Frame
6 months/16 months after inclusion of last patient
Title
RFS with modified definition
Description
To evaluate the impact of venetoclax on RFS in newly diagnosed AML patients and MDS-EB2 patients using modified endpoint definitions: o Modified RFS includes only subjects achieving CR
Time Frame
16 months after inclusion of last patient

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with newly diagnosed acute myeloid leukemia (AML), or myelodysplastic syndrome with excess blasts-2 (MDS-EB2) according to World Health Organization (WHO) classification. Age ≥ 18 years, no upper age limit. Patient considered eligible for intensive chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at randomization. Molecular analysis centrally performed in AMLSG and HOVON laboratories. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR). Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert's disease, or leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Coordinating Investigator or Trial Coordinator No prior chemotherapy for AML except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 25x109/L); patients may have had previous treatment with erythroid stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS; ESA and HMAs have to be stopped at least four weeks before enrolment. Subjects must not have received a known strong or moderate CYP3A inducer 7 days before enrolment. Subjects must have no known medical conditions requiring chronic therapy with moderate or strong CYP3A inducers. Female patient must either: Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses) Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening) Or, if of childbearing potential (not surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) and not postmenopausal) Not planning to become pregnant during the study and for 6 months after the final study drug administration And have a negative urine or serum pregnancy test at screening And, if heterosexually active, agree to consistently apply one highly effective* in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration *Highly effective forms of birth control include Consistent and correct usage of established hormonal contraceptives that inhibit ovulation (hormonal contraception is only a highly effective method of birth control, if a combined [estrogen and progestogen containing] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used. Established intrauterine device (IUD) or intrauterine system (IUS) Bilateral tubal occlusion Vasectomy - a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Male is sterile due to a bilateral orchiectomy. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. *List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period. Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration. Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration. Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration. Able to understand and willing to sign an informed consent form (ICF). Exclusion Criteria: Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations / fusion genes. AML with BCR-ABL1; or myeloid blast crisis of CML. Patients with AML and activating FLT3 mutations who have access (including reimbursement) to treatment with a FLT3 inhibitor approved for first-line therapy of AML. Prior treatment of MDS with intensive chemotherapy or allogeneic hematopoietic cell transplantation (HCT) with a curative intent. 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 Severe obstructive or restrictive ventilation disorder. Co-administration of moderate/strong CYP inhibitors during the DLT observation period for subjects in the dose-finding part of the study. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening. Active infection, including hepatitis B or hepatitis C or Human Immunodeficiency Virus (HIV) infection, that is uncontrolled at randomization and may interfere with the study objectives or which could expose the subject 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. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation. Conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs. 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, subjects 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. Receipt of live, attenuated vaccine within 30 days prior to the study inclusion (NOTE: subjects, if enrolled, should not receive live vaccine during the study and until 6 months after the therapy). Severe neurological or psychiatric disorder interfering with ability to give an informed consent. Known or suspected hypersensitivity to any of the chemotherapeutic agents used. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation. No consent for biobanking of patient's biological specimens. Participation in other prospective studies with anti-leukemic and/or investigational agents. The patient is a pregnant or lactating woman, or plans to become pregnant during the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hartmut Doehner, MD
Phone
004973150045501
Email
harmut.doehner@uniklinik-ulm.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hartmut Doehner, MD
Organizational Affiliation
University of Ulm
Official's Role
Principal Investigator
Facility Information:
Facility Name
Charité Berlin - Campus Mitte
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Kroenke, Prof.
Facility Name
Charité Berlin - Campus Benjamin Franklin
City
Berlin
ZIP/Postal Code
12200
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Kroenke, Porf.
Facility Name
Charité Berlin - Campus Virchow Klinikum
City
Berlin
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Kroenke, Prof.
Facility Name
Knappschaftskrankenhaus Bochum-Langendreer
City
Bochum
ZIP/Postal Code
44892
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roland Schroers, Prof.
Facility Name
Uniklinikum Bonn
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lino Teichmann, Dr.
Facility Name
Staedtisches Klinikum Braunschweig
City
Braunschweig
ZIP/Postal Code
38114
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jürgen Krauter, Prof.
Facility Name
Universitätsklinikum Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Walter Fiedler, Prof.
Facility Name
Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Heuser, Prof.
Facility Name
Städtisches Klinikum Karlsruhe
City
Karlsruhe
ZIP/Postal Code
76133
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark Ringhoffer, Prof.
Facility Name
Diakonie Klinikum Stuttgart
City
Stuttgart
ZIP/Postal Code
70176
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jochen Greiner, Prof
Facility Name
Uniklinikum Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Claudia Lengerke, Prof. Dr.
Facility Name
University Hospital Ulm
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hartmut Döhner, Prof. Dr.
First Name & Middle Initial & Last Name & Degree
Gaidzik Verena, PD Dr.

12. IPD Sharing Statement

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Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2

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