1. Event Free Survival (EFS) (Time Frame - 6 months/16 months after inclusion of last patient): 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
2. Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase) (Time Frame - after cycle 1 (maximal day 42)): 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:
1. Overall Survival (OS) (Time Frame - 6 months/16 months/28 months after inclusion of last patient): OS in patients with newly diagnosed AML
2. CR/CRi rate (Time Frame - 2 months): Complete remission (CR/CRi) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRi after induction chemotherapy
3. CR rate (Time Frame - 2 months): Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy
4. Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy (Time Frame - 2 months): 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
5. Relapse-free survival (RFS) in newly diagnosed AML patients (Time Frame - 16 months after inclusion of last patient): 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
6. Cumulative incidence of relapse (CIR) in newly diagnosed AML patients (Time Frame - 16 months after inclusion of last patient): Cumulative incidence of relapse (CIR) in newly diagnosed AML patients
7. Cumulative incidence of death (CID) (Time Frame - 16 months after inclusion of last patient): Cumulative incidence of death (CID) in newly diagnosed AML patients.
8. EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients (Time Frame - 6 months): 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.
9. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients (Time Frame - 6 months): 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.
10. Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients (Time Frame - 6 months): 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).
Venetoclax: 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)
Placebo: 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)
Standard chemotherapy: 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.
Autologous stem cell transplantation: 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.
Allogeneic stem cell transplantation: 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.
Quelle: ClinicalTrials.gov
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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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