Gemtuzumab Chemotherapy MRD Levels; Glasdegib Post-transplant, Adult Untreated, de Novo, Fav Interm Risk AML

Study Overview
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Brief Summary
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MRD driven study. Addition of gemtuzumab to conventional chemotherapy to reduce MRD of patients with favorable/intermediate-risk AML. Post-consolidation assessment of MRD. Role of a post-SCT maintenance with glasdegib.

Detailed Description
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Setting up a multicenter, MRD (Minimal Residual Disease)-driven study that relies on addition of gemtuzumab ozogamicin to conventional chemotherapy to reduce the pre-transplant levels of MRD of patients with favorable/intermediate-risk (according to ELN 2017) AML. Post-consolidation assessment of MRD will be exploited to establish the final risk assignment and to verify whether the delivery of a post remission therapy intensity (AuSCT, Autologous Stem Cell Transplant, vs ASCT, Allogeneic Stem Cell Transplant) of which is MRD-driven will improve the outcome in terms of anti-leukemic efficacy. Finally, the role of a post-SCT maintenance with glasdegib will be explored.

Official Title
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Phase 3 Study to Assess Gemtuzumab, in Combination With Standard Chemotherapy, on MRD Levels, and the Role of Glasdegib as a Post-transplant Maintenance, in Adult, 18-60 Years, With Previously Untreated de Novo Fav-interm Risk AML

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Glasdegib
* Drug: Gemtuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent according to ICH/EU/GCP and national/local laws Patients aged between 18 and 60 years Patients previously untreated for their AML by other chemotherapeutic agents (except for no more than 7 days HU) or radiotherapy Unequivocal diagnosis of de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), other than acute promyelocytic leukemia, documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of ≥ 6 months duration) Patients with favorable-intermediate AML according to ELN 2017 (except for FLT3-ITD/TKD positive AML) WHO performance status 0-3 Adequate renal (serum creatinine ≤ 2 x the institutional ULN) and liver (total serum bilirubin ≤ 2 x ULN; serum ALT and AST ≤ 2.5 x ULN) function, unless considered due to organ leukemic involvement Left Ventricular Ejection Fraction (LVEF) ≥ 50%, as determined by echocardiogram Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule. Exclusion Criteria: Patients already treated for their AML by other chemotherapeutic agents (except for no more than 7 days HU) or radiotherapy Acute promyelocytic leukemia Blast crisis of chronic myeloid leukemia FLT3-ITD/TKD positive AML AML supervening after other myeloproliferative disease ≥ 6 months duration AML supervening after antecedent myelodysplastic syndromes Therapy-related AML Other active or progressive malignant diseases. Inadequate renal or liver function (metabolic abnormalities > 2-2.5 times the normal upper limit) Severe heart failure requiring diuretics Ejection fraction < 50% Uncontrolled infections Severe concomitant neurological or psychiatric diseases Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of chemotherapy. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for at least 6 months following discontinuation of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>Induction: Gemtuzumab 3 mg/m2 day 1,4,7 Daunorubicin 60 mg/m2 day 1-3 Cytosine arabinoside 200 mg/m2 day 1-7 Consolidation: Gemtuzumab 3 mg/m2 day 1 Daunorubicin 50 mg/m2 day 4-6 Cytosine arabinoside 500 mg/m2 twice a day, day 1-6 Allogeneic transplantation or Autologous transplantation according to MRD level Maintenance with glasdegib 100 mg daily for one year or until toxicity/relapse | Drug: Glasdegib<br>* After randomization patients in both arms will be randomized to maintenance with glasdegib vs clinical observation<br>Drug: Gemtuzumab Ozogamicin<br>* Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine<br>|
| Active Comparator: Standard arm<br>Induction: Gemtuzumab 3 mg/m2 day 1,4,7 Daunorubicin 60 mg/m2 day 1-3 Cytosine arabinoside 200 mg/m2 day 1-7 Consolidation: Gemtuzumab 3 mg/m2 day 1 Daunorubicin 50 mg/m2 day 4-6 Cytosine arabinoside 500 mg/m2 twice a day, day 1-6 Allogeneic transplantation or Autologous transplantation according to MRD level clinical observation | Drug: Gemtuzumab Ozogamicin<br>* Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activity of GO in combination with chemotherapy in terms of MRD negativity achievement | Percentage of MRD negativity after consolidation in patients treated in induction and consolidation with GO | 2 months | 
| Efficacy of Glasdegib maintenance vs clinical observation | Disease Free Survival (DFS) in patients randomized to glasdegib maintenance or clinical observation | 2,5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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De-novo, Favorable risk, Intermediate risk, Gemtuzumab ozogamicin, Glasdegib, Acute Myeloid Leukemia