STUDY AGORA-1 / ALFA 2100: Phase 2 on the combinaison of Gemtuzumab Ozogamicin witk gilteritinib in adult patients with acute myeloid leukemia (AML) with a relapsed or refractory FLT3 mutation.
- Conditions
- Acute Myeloid Leukemia
- Registration Number
- 2023-504176-25-00
- Lead Sponsor
- Centre Antoine Lacassagne
- Brief Summary
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 and/or FLT3-TKD 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 and/or FLT3-TKD mutated R/R AML through event-free survival (EFS).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 50
Patients aged 18 years old or more
Confirmed diagnosis of R/R AML positive for CD33 antigen as determined locally by immunophenotyping according to routine practice, 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
Patient with no contraindication to gemtuzumab ozogamicin (GO), cytarabine and gilteritinib
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
Acute promyelocytic leukemia or AML with BCR-ABL1 gene fusion
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
Patient currently receiving one or more inadvisable or prohibited treatments described in section 6.4.2 of the protocol.
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.
Patient with contraindications to the administration of gemtuzumab ozogamicin (GO), cytarabine and gilteritinib. Refer to the SPCs of the molecules mentioned concerning the contraindications, special warnings, precautions for use, dose modifications in the event of toxicity, contraception and monitoring of patients and drugs prohibited or to be used with caution.
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method 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 and/or FLT3-TKD mutated R/R AML will be assessed through the identification of dose-limiting toxicities (DLTs) if any. 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 and/or FLT3-TKD mutated R/R AML will be assessed through the identification of dose-limiting toxicities (DLTs) if any.
Stage 2 of the study: assessment of efficacy of gilteritinib-combined to GO/cytarabine AGORA platform through EFS. The definition of EFS will be adapted to the current real-life setting, including the increasing number of experimental options. Actually, the decision to switch toward another therapy may be influenced by other events than hematologic relapse, like suboptimal tolerance or MRD monitoring or simply availability of new promising options. Stage 2 of the study: assessment of efficacy of gilteritinib-combined to GO/cytarabine AGORA platform through EFS. The definition of EFS will be adapted to the current real-life setting, including the increasing number of experimental options. Actually, the decision to switch toward another therapy may be influenced by other events than hematologic relapse, like suboptimal tolerance or MRD monitoring or simply availability of new promising options.
- Secondary Outcome Measures
Name Time Method 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 <100,000/µL or absolute neutrophil count <1000/µL; CRh, CR with partial hematologic recovery, meaning CR not fulfilling CR or CRi criteria but with platelet count >50,000/µL AND absolute neutrophil count >500/µL. 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 <100,000/µL or absolute neutrophil count <1000/µL; CRh, CR with partial hematologic recovery, meaning CR not fulfilling CR or CRi criteria but with platelet count >50,000/µL AND absolute neutrophil count >500/µL.
Early mortality rates, at day-30 Early mortality rates, at day-30
Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically
Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS) 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 2022 Subgroups defined by treatment related factor by the performance of a subsequent allogeneic HSCT 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 2022 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) Safety through the occurrence of (AEs), serious adverse events (SAEs), and treatment emergent adverse events (TEAEs)
Patient reported outcome Patient reported outcome
Trial Locations
- Locations (28)
Hopital Necker Enfants Malades
🇫🇷Paris, France
Grand Hopital De L Est Francilien
🇫🇷Meaux, France
Centre Hospitalier Universitaire D Orleans
🇫🇷Orleans Cedex 2, France
Centre Hospitalier Victor Dupouy
🇫🇷Argenteuil Cedex, France
CHRU Tours Hopital Bretonneau
🇫🇷Tours, France
Hopital NOVO
🇫🇷Pontoise, France
Hopital Saint Louis
🇫🇷Paris, France
Hopital D'Instruction Des Armees Percy
🇫🇷Clamart, France
Centre Hospitalier Universitaire De Caen Normandie
🇫🇷Caen Cedex 9, France
University Of Bordeaux
🇫🇷Talence Cedex, France
Scroll for more (18 remaining)Hopital Necker Enfants Malades🇫🇷Paris, FranceAmbroise MARCAISSite contact0033144495663ambroise.marcais@aphp.frMadalina UZUNOVSite contact+33142162824madalina.uzunov@aphp.fr