Escalation of Doses of Daratumumab in Combination With Chemotherapy (Idarubicin and Cytarabine) in Patients of 60 Years Old or More With Adverse Risk Acute Myeloblastic Leukemia (AML) (DARALAM)

Study Overview
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Brief Summary
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To search for a Maximum Tolerated Dose (MTD) for the combination of daratumumab and induction chemotherapy with Idarubicin and cytarabine in patients with Acute Myeloblastic Leukemia (AML) of poor prognosis

Official Title
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Multicentric Phase 1 Study With Escalation of Doses of Daratumumab in Combination With Chemotherapy (Idarubicin and Cytarabine) in Patients of 60 Years Old or More With Adverse Risk Acute Myeloblastic Leukemia (AML) (DARALAM)

Conditions
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Adult Patients With Adverse Risk Acute Myeloblastic Leukemia

Intervention / Treatment
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* Drug: Darzalex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 60 ans Poor prognosis AML defined according to the following criteria:1. For first-line AML:intermediate or unfavorable risk according to ELN 2017 2.for Relapsed AML:regardless of the ELN risk group ECOG <= 2 Patient eligible for intensive chemotherapy Who provide their written informed consent Liver workup: transaminases < 3x normal, bilirubin < 1.5 X normal Creatinine clearance > 60ml/mn LVEF >= 50%. Exclusion Criteria: Patients with FLT3 ITD or TKD mutation Patients with tuberculosis Patients with documented active infection with COVID 19 Patients with hereditary fructose intolerance (HFI) Uncontrolled infection Active or past infection with Hep B, C or HIV+ Not Affiliated with French social security system or no beneficiary from such system Pregnant women or patients who cannot take contraception ( contraceptive pill, abstinence, unauthorised IUD) in case of fertility. A patient who cannot continue contraception for at least 6 months after the last injection of DARATUMUMAB is not eligible for inclusion. Breastfeeding women Minors Adults under guardianship, curatorship or safeguard of justice Hypersensitivity to any of the active ingredients or excipients Patients with significant cardiovascular pathology including any of the following: myocardial infarction within 6 months prior to study entry, unstabilized coronary artery disease, uncontrolled hypertension, congestive heart failure. Patient with disease requiring systemic immunosuppressive therapy (such as high-dose steroids defined as ≥ 10mg prednisone or equivalent per day) within 4 weeks prior to the 1st scheduled dose of study treatment with the exception of dermocorticoids

Ages Eligible for Study
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Minimum 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
Intervention Model: Single Group Assignment
Interventional Model Description: Continual Reassessment Method for MTD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darzalex<br>DARZALEX® Dose level 1 : 1800 mg Day 1 Dose level 2 : 1800 mg Day 1 and 8 (+/- 2 days) Dose level 3 : 1800 mg à Day 1, 8 (+/- 2 days) and D15 (+/- 2 days) | Drug: Darzalex<br>* DARZALEX® = Daratumumab. Solution for injection, 1800 mg/15 mL, single vial. Sub-cutaneous administration. Dose level 1 : 1800 mg Day 1 Dose level 2 : 1800 mg Day 1 and 8 (+/- 2 days) Dose level 3 : 1800 mg à Day 1, 8 (+/- 2 days) and D15 (+/- 2 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Dose at which no toxic effect is observed, by determination of the LDT (Toxic Limit Dose). A TLD is defined by the occurrence of grade ≥ 3 daratumumab related toxicity that is not reversible after 7 days (except for haematological toxicity) or the absence of emergence from aplasia at D45 of induction (in the absence of treatment failure). Toxicity is assessed according to NCI-CTCAE version 5 criteria. The search for DLT is continued until D45 of induction. | DAY 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response to the induction treatment | calculation of the rate of complete remission (CR) with negative residual disease (CR MRD-), CR, CR with incomplete haematological recovery (CRi), MLFS (morphological leukemia free state), partial response (PR) or treatment failure according to the 2017 NLE definition between D30 and D45. | DAY 45 | 
| Assessment of myelotoxicity | Neutrophil recovery time (>1.0 × 109/L) from D1 - Recovery time of platelets (>100 × 109/L) from D1 | Day 1 | 
| Overall survival (OS) | time from D1 of induction to date of last contact or death | 6 months | 
| Event-free survival (EFS) | time from D1 of induction to date of relapse, death or date of last | 6 months | 
| Relapse incidence |  | 6 months | 
| Flow cytometry (FCM) investigation of myeloid-derived suppressor cells |  | Day 45 | 
| Comparison of MDSC values in CMF |  | Day 45 | 
| research on the level of CD38 expression on blasts |  | Day 1 |