Adult patients (aged 18 years old or more) with a newly diagnosis of relapsed/refractory (R/R) AML associated to the presence a FLT3 gene internal tandem duplication (FLT3-ITD). MedDRA version: 20.0 Level: LLT Classification code 10001941 Term: AML System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Mylotarg®
Product Name: Gemtuzumab ozogamicine
Product Code: NA
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: GEMTUZUMAB OZOGAMICIN
CAS Number: 220578-59-6
Con
Sponsors
Centre Antoine Lacassagne
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Patients aged 18 years old or more • Confirmed diagnosis of R/R AML, defined as: - AML refractory to 1 or 2 intensive chemotherapy courses or a treatment by hypomethylating agents (HMAs) - Or AML in first hematologic relapse or progression after front-line therapy, including intensive chemotherapy or hypomethylating agents (HMAs). - Previous treatments with FLT3 inhibitors (other than gilteritinib) are allowed - R/R AML secondary to a prior chemotherapy or radiotherapy for another cancer (tAML) could be included. • Presence of a FLT3-ITD mutation (allelic ratio =0.05 at last evaluation)* or a FLT3 TKD mutation • ECOG performance status =2 • AST and ALT = 2.5 x upper the limit of normal (ULN) and/or total and direct serum bilirubin = 1.5 x ULN unless considered due to leukemia • Estimated glomerular filtration rate (GFR) = 50 mL/min according to the formula usually used by the investigator • Written informed consent obtained prior to any screening procedures • Eligible for National Health Insurance in France *Allelic ratio should be assessed at screening time but patient with refractory AML could be included if allelic ratio is >0.05 at diagnosis 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 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: • Acute promyelocytic leukemia or AML with BCR-ABL1 gene fusion • Secondary AML (sAML) defined by a history of prior myelodysplastic syndrome (MDS) or myeloproliferative syndrome (MPN) including chronic myelomonocytic leukemia (CMML) • Patient ineligible for an intensive chemotherapy • Proven central nervous system leukemic involvement • Prior allogeneic HSCT within the last 6 months and/or history of acute GVHD of grade >1 • Prior treatment with gemtuzumab ozogamicin within the last 3 months preceding the initiation of the treatment in the present clinical trial • Uncontrolled or active malignant disease within prior 12 months (excluding cutaneous basal cell carcinoma, “in-situ” carcinoma of the cervix or breast, or other local malignancy excised) • Uncontrolled or significant cardiovascular history or symptoms including: - Prior anthracycline exposure equivalent to more than 550 mg/m2 of daunorubicin - History of clinically relevant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation or torsade de pointes) - History of 2° (Mobitz II) or 3° heart block (subjects with pacemakers are allowed if they have no history of clinically relevant arrhythmias with the pacemaker) - History of uncontrolled angina pectoris or MI within 6 months - History of NYHA Class 3 or 4 heart failure - Left ventricular ejection fraction = 50% or less than the institutional lower limit of normal - History of complete left bundle branch block - Unstable angina, New York Heart Association (NYHA) class 3 or 4 congestive heart failure - QTcF > or equal to 450 msec, long QT syndrome (including family history) - Bradycardia < 50 bpm (unless subject has a pacemaker) - Systolic BP = 180 mmHg or diastolic BP = 110 mmHg • Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate treatment) • Active known HBV or HCV hepatitis or positive HIV serology • Concurrent therapy with any other investigational agent or cytotoxic drug, within 28 days before starting treatment. Only hydroxyurea ± dexamethasone is permitted for the control of blood counts • Current use or anticipated requirement for drugs that are known strong inducers of CYP3 A4/5 • Current use or anticipated requirement for drugs that are known as strong inhibitors or inducers of P glycoprotein (P-gp), as mentioned in the appendix 14 of the protocol, with the exception of drugs that are considered absolutely essential for the care of the subject • Current use or anticipated treatment with concomitant drugs that target 5HT1R or 5HT2BR receptors or sigma non-specific receptor, as mentioned in the appendix 15 of the protocol, with exception of drugs that are considered absolutely essential for the care of the subject • Known malabsorption syndrome or other condition that may significantly impair absorption of oral study medications • Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study • Females who are pregnant or breastfeeding. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of study medication or cytarabine, whichever occurs later. • Adults subject to a legal protection order or unable to give their consent • Persons deprived of their freedom by judicial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Stage 1 - Safety of the addition of gilteritinib to the AGORA treatment platform The primary objective of the first stage is to evaluate the safety of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD mutated R/R AML, through occurrence of dose-limiting toxicity (DLT). Stage 2 - Event-free survival (EFS) The primary objective of the second extension stage is to evaluate the efficacy of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD mutated R/R AML through event-free survival (EFS). ;Secondary Objective: Classical clinical objectives •Response rates to the study treatment •Early mortality rates, at day-30 •Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically •Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS) •Subgroup analyses, defined by patient, disease and treatment related factors •Safety (AEs, SAEs, TEAEs and incidence of sinusoidal obstruction syndrome) (SOS)) Patient-reported outcomes (PROs) •AEs •Quality of life (QoL) Sensitivity analyses •EFS comparisons •Alternative EFS definitions ;Primary end point(s): Stage 1 of the study: assessment of safety of the addition of gilteritinib to the AGORA treatment platform Safety of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD mutated R/R AML will be assessed through the identification of dose-limiting toxicities (DLTs) if any. The goal is to ensure that the combination is associated with a probability of dose-limiting toxicities (DLTs) of 20% maximum until the beginning at the next treatment (consolidation or allograft) or documentation of refractory status at D56 at the latest; Dose limiting toxicities will include: i)Death of any cause ; ii)Prolonged neutropenia, defined as a peripheral blood absolute neutrophil count (ANC) less than 500/µL in the absence of documented refractory AML iii) Grade 3 eleva | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Classical clinical endpoints • Response rate, including CR, CRi and CRh*; the overall response rate (ORR) being defined as CR/CRi/CRh rates *: CRi, CR with incomplete hematologic recovery, meaning CR with platelet count 50,000/µL AND absolute neutrophil count >500/µL. • Early mortality rates, at day-30 • Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS) • Subgroup analyses: - Subgroups defined by a patient related factor: age (<65 vs =65y), - Subgroups defined by disease related factors: cytogenetics, mutation profiles (including NPM1 and FLT3-ITD), ELN-risk classification 2017 - Subgroups defined by treatment related factor by the performance of a subsequent allogeneic HSCT • Safety through the occurrence of (AEs), serious adverse events (SAEs), and treatment emergent adverse events (TEAEs) as defined in section 11. Patient reported outcome • AEs using NCI-CTCAE • QoL using the EORTC QLQ-C30 questionnaire ;Timepoint(s) of evaluation of this end point: - Response rate, including CR, CRi and CRh*; the overall response rate (ORR) being defined as CR/CRi/CRh rates : 60 months. - Early mortality rates, at day-30 : 31 months - Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS): 60 months - Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS) : 60 months - Subgroup analyses defined by patient, disease and treatment related factors : 60 months - Safety concerning AEs, SAEs, TEAEs and incidence of sinusoidal obstruction syndrome (SOS) : 60 months | — |
Countries
France
Contacts
Public ContactDr Lauris GASTAUD
Centre Antoine Lacassagne
Outcome results
None listed