Newly diagnosed acute myeloid leukemia patients aged equal or more than 60 years old MedDRA version: 20.0 Level: HLT Classification code 10024291 Term: Leukaemias acute myeloid System Organ Class: 100000004851
Conditions
Interventions
Trade Name: Venetoclax
Product Name: Venetoclax
Pharmaceutical Form: Tablet
INN or Proposed INN: VENETOCLAX
CAS Number: Venetoclax
Concentration unit: mg milligram(s)
Concentration type: up to
Concent
Sponsors
Fundación Pethema
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Newly diagnosed AML. 2. Morphological diagnosis of AML (WHO criteria 2008). 3. Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. = 71 years of age; 3.2. = 60 to 70 years of age with at least one of the following co-morbidities: - ECOG Performance Status of 2 or 3; - Cardiac history of CHF requiring treatment or Ejection Fraction = 55% or chronic stable angina; - DLCO = 65% or FEV1 = 65% or significant history of chronic pulmonary obstructive; - Creatinine clearance = 30 mL/min to 1.5 to = 3.0 × ULN - Non active/controlled prior neoplastic disease - Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Trial coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics) 4. ECOG performance status = 3. 5. Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception (see Section 7.8). 6. Female subjects must be either postmenopausal for at least 1 year before screening OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding. 7. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 54
Exclusion criteria
Exclusion criteria: 1. Age 3 times the upper normal limit (unless it is attributable to AML activity). 7. WBC> 50 x 109/L. Subject should have white blood cell count 450 msec; c) Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome); d) Systolic blood pressure =180 mmHg or diastolic blood pressure =110 mmHg; e) History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes); f) History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker); g) History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening; h) History of New York Heart Association Class 3 or 4 heart failure; i) Known history of left ventricular ejection fraction (LVEF) =45% or less than the institutional lower limit of normal; j) Complete left bundle branch block; 13. Prior therapy for AML (except hydroxiurea). 14. Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose. 15. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax. 16. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion; 17. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C) 18. Known
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Timepoint for Phase 1 would be evaluated after end of Phase I (aproximately 6 months after FPFV) Timepoint for Phase 2 would be evaluated after LPLV (aproximately 3 years after FPFV) Patients will receive 4 consecutive cycles of treatment (approximately every 28 days). After the first 4 cycles, depending on the response and tolerance to treatment, the patient will continue receiving treatment in maintenance cycles until one of these situations occurs: disease progression, lack of clinical benefit, hematological relapse, unacceptable toxicity.;Main Objective: - For the phase I: to establish the RP2D of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules. - For the phase II: to assess and to compare the CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.;Secondary Objective: - To evaluate the CR/CRi rate after 1 and 4 cycles of both triple combination - To compare the median OS between both triple combination - To evaluate the safety and tolerability of both triple combination - To estimate 1, 2 and 3 years event-free, disease-free, and relapse-free survival, as well as on the cumulative incidence of relapse - To evaluate the impact on the quality of life, using the EQ5D and the EORTC Quality of Life Questionnaire-Core 30 forms of both triple combination - To evaluate the impact on the use of medical resources during treatment phase - To evaluate the quality of CR - To evaluate the CRh rate in both triple combination - To evaluate early mortality - Separate analyses in secondary AML, CBF, FLT3-ITD, NPM1, P53, and IDH1/IDH2 subsets. - Exploration of biomarkers predictive of drug activity and duration of response may be performed;Primary end point(s): - Phase I: Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules - Phase II: CR/CRi rate of AZA based and LDAC based triple | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - CR/CRi rate after 1, and 4 cycles - Overall survival (OS) - Safety and tolerability of the AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules (overall hematologic and non-hematologic toxicity) - Event-free survival (EFS) - Disease-free survival (DFS) - Relapse-free survival (RFS) - Quality of life (from the EuroQoL Group EQ-5D-5L and the EORTC QLQ-C30 instruments) - Medical resources during treatment phase - Minimal residual disease (MRD) - CRh rate (Bone marrow blasts <5% with partial hematologic recovery defined as ANC =0.5 × 109/L and platelet count =50 × 109/L, with no evidence of extramedullary leukemia and cannot be classified as CR) - Early mortality (first 30 and 60 days) - Separate analyses in secondary AML, CBF, FLT3-ITD, NPM1, P53, and IDH1/IDH2 subsets. - Exploration of biomarkers predictive of drug activity and duration of response. Potential analyses may include: . To evaluate the MRD negativity rate in the BM using MPFC and NGS . Immune recovery . Exhaustive biomarker plan including baseline and relapse molecular characterization by NGS;Timepoint(s) of evaluation of this end point: Timepoint after LPLV and EFS, DFS and RFS after 1,2 and 3 years of LPFV. Patients will receive 4 consecutive cycles of treatment (approximately every 28 days). After the first 4 cycles, depending on the response and tolerance to treatment, the patient will continue receiving treatment in maintenance cycles until one of these situations occurs: disease progression, lack of clinical benefit, hematological relapse, unacceptable toxicity. | — |
Countries
Spain
Contacts
Public ContactDr. Juan José Lahuerta Palacios
Fundación Pethema
Outcome results
None listed