Acute Myeloid Leukemia
Conditions
Keywords
adult patients
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).
Interventions
DRUGVenetoclax
Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
DRUGPlacebo
Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
COMBINATION_PRODUCTStandard 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 1-4, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4 without daunorubicin. Consolidation chemotherapy with 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.
OTHERAllogeneic 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.
Sponsors
University of Ulm
Stichting Hemato-Oncologie voor Volwassenen Nederland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind with open label dose-finding run-in part
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with newly diagnosed acute myeloid leukemia (AML) according to the International Consensus Classification (ICC). 2. Age ≥ 18 and ≤ 75 years. 3. Patients considered eligible for intensive chemotherapy. 4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 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 Principal Investigators or Trial Coordinators of the study * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Principal Investigators or Trial Coordinators. 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 start of study treatment. 9. Patients must not have received a known strong or moderate CYP3A inducer 7 days before start of study treatment. Patients 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 (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening) * Or, if of childbearing potential (not surgically 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\* method of birth control in combination to a barrier method for the duration of the study and for 27 weeks after the final study drug administration \*Highly effective forms of birth control include * Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (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 27 weeks 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 27 weeks 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 27 weeks after the final study drug administration. 13. Able to understand and willing to sign an informed consent form (ICF).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) | 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 |
| Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase) | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 6 months/16 months/28 months after inclusion of last patient | OS in patients with newly diagnosed AML |
| CR/CRi rate | 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 |
| CR rate | 2 months | Complete remission (CR) rates in newly diagnosed AML patients defined as the proportion of AML patients with CR after induction chemotherapy |
| Event Free Survival (EFS) including CRh | 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, CRh or CRi, or start of new therapy due to confirmed molecular relapse whichever occurs first. Treatment failure is defined as not attaining CR, CRh or CRi by end of induction chemotherapy, i.e. if a patient's best response during or at completion of the induction treatment is less than CR/CRh/CRi |
| Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy | 2 months | Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy, defined as the proportion of AML patients achieving CR 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 | 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/CRh/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 | 16 months after inclusion of last patient | Cumulative incidence of relapse (CIR) in newly diagnosed AML patients |
| Cumulative incidence of death (CID) | 16 months after inclusion of last patient | Cumulative incidence of death (CID) in newly diagnosed AML patients. |
| EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients | at study entry, 2 months, 3 months, 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. |
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients | at study entry, 2 months, 3 months, 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. |
| Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients | at study entry, 2 months, 3 months, 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). |
| CR/CRh rate | 2 months | Complete remission (CR/CRh) rate in newly diagnosed AML patients defined as the proportion of AML patients with CR/CRh after induction chemotherapy |
| Rates of complete remission without measurable residual disease (CR/CRh MRD-) after induction therapy | 2 months | Rates of complete remission without measurable residual disease (CR/CRh MRD-) after induction therapy, defined as the proportion of AML patients achieving CR/CRh with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment |
| Rates of complete remission without measurable residual disease (CR/CRi MRD-) after induction therapy | 2 months | Rates of complete remission without measurable residual disease (CR/CRi MRD-) 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 |
Countries
Austria, Belgium, Estonia, Finland, Germany, Lithuania, Netherlands, Norway
Contacts
CONTACTHartmut Doehner, MD
PRINCIPAL_INVESTIGATORHartmut Doehner, MD
University of Ulm
Outcome results
None listed