Acute myeloid leukemia (AML) is a heterogeneous clonal myeloid neoplasm where abnormal proliferation and impaired differentiation of hematopoietic stem and myeloid progenitor cells impedes normal hematopoiesis. Sulfasalazine (SSZ) is a broadly available, well tolerated anti-inflammatory medicine approved for the treatment of ulcerative colitis and rheumatoid arthritis. Intact SSZ, but not its metabolites 5-aminosalicylic acid and sulfapyridine, competitively inhibits xCT.21 SSZ is thus an ideal candidate for drug repurposing in AML.The purpose of this phase I study is to evaluate the safety and feasibility of such strategy, provide preliminary signals of efficacy, and identify potential biomarkers
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
64
Sulfazalazine 500mg-tablets ; 7 dose levels explored in the phase I part of the trial.
CHU Amiens
Amiens, France
NOT_YET_RECRUITINGHôpital Avicenne
Bobigny, France
NOT_YET_RECRUITINGCHU Caen
Caen, France
NOT_YET_RECRUITINGCHU Henri Mondor
Créteil, France
RECRUITINGCentre Hospitalier Lyon Sud, Lyon
Lyon, France
RECRUITINGHôpital de la Conception, AP-HM
Marseille, France
NOT_YET_RECRUITINGCHU Nice
Nice, France
RECRUITINGAP-HP Hôpital Saint Louis
Paris, France
RECRUITINGAP-HP Hôpital Cochin
Paris, France
RECRUITINGCentre Henri Becquerel
Rouen, France
NOT_YET_RECRUITING...and 3 more locations
Dose Limiting Toxicity (for phase I part of the trial)
Defined as any of the following events: * Prolonged myelosuppression defined as Grade ≥ 3 Neutropenia or Thrombocytopenia on Day 42 from start of therapy or later without evidence of leukemia (assessed by bone marrow aspiration and/or biopsy) * Grade ≥3 hemorrhages until day 42. * Grade ≥3 non- hematological toxicity until day 42 with the exception of: Grade 3 infection, grade 3 fever with neutropenia (NB. grade 4 infections and grade 4 fever with neutropenia are considered as DLTs), Grade ≥3 nausea, vomiting or diarrhea that can be managed to ≤ Grade 2 within 72 hours of symptomatic treatment, Grade ≥3 asymptomatic liver enzymes elevation that improves to ≤ Grade 2 within 72 hours of onset, Grade ≥3 tumor lysis syndrome that resolves within 72 hours of onset with medical treatment
Time frame: 42 days
Minimal Residual Disease (MRD)-negative Complete Response (for phase II part of the trial)
Defined as: * Complete Remission CR or CRi (CR with incomplete hematologic recovery, meaning CR with platelet count \<100,000/μL or absolute neutrophil count \<1000/μL) and CRh (CR with partial hematologic recovery, meaning CR not fulfilling CR or CRi peripheral blood count criteria but with platelet count \>50,000/μL AND absolute neutrophil count \>500/μL). * MRD-negativity is defined as an 8-color bone marrow FCM MRD \< 0.1% at EOI. * Of note, NPM1 (nucleoplasmin)-transcript based MRD in the Bone Marrow and Peripheral Blood will be carried as exploratory endpoint in NPM1-mutated patients.
Time frame: Day 28 to 42
Adverse events
Adverse events (AE), treatment emergent adverse events (TEAE) and treatment-related TEAEs will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: Month 12
Peak plasma concentration (Cmax) of Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of Peak Plasma Concentration (Cmax), in the phase I part of the study
Time frame: Day 1, 4 and 15
Time of peak plasma concentration (Tmax) of Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of Time of peak plasma concentration (Tmax) of Sulfazalazine, in the phase I part of the study
Time frame: Day 1, 4 and 15
Area under the plasma concentration versus time curve (AUC) for Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of area under the plasma concentration versus time curve (AUC), in the phase I part of the study
Time frame: Day 1, 4 and 15
Clearance (Cl) of Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of clearance (Cl), in the phase I part of the study
Time frame: Day 1, 4 and 15
Mean residence time (MRT) of Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of mean residence time (MRT), in the phase I part of the study
Time frame: Day 1, 4 and 15
Distribution volume (Vd/F) of Sulfazalazine
Pharmacokinetics of Sulfazalazine in terms of distribution volume (Vd/F), in the phase I part of the study
Time frame: Day 1, 4 and 15
Plasma levels of malondialdehyde
Pharmacodynamics with plasma levels of malondialdehyde (MDA)
Time frame: Day 1, 2
Plasma levels of glutathione
Pharmacodynamics with plasma levels of glutathione (reduced/oxidized)
Time frame: Day 1, 2
Reactive Oxygen Species (ROS) levels of peripheral blood mononuclear cells
In patients with circulating leukemic cells, ROS levels of peripheral blood mononuclear cells by flow cytometry
Time frame: Day 1, 2
Response
Response at end of induction assessment (day 28-42) as per European LeukemiaNet (ELN) Criteria.
Time frame: End of induction treatment - day 28 to 42
Nucleophosmin (NPM1)-transcript based Minimal Residual Disease (MRD)
NPM1-transcript based MRD in the bone marrow and peripheral blood in NPM1-mutated patients
Time frame: End of induction treatment - day 28 to 42
Next-generation sequencing (NGS)-based Minimal Residual Disease (MRD)
NGS-based MRD in all patients
Time frame: End of induction treatment - day 28 to 42
Event-free survival
Event-free survival (EFS) defined as the time between inclusion and the first of the following events: * Non achievement of hematologic response (including complete response (CR), CR with incomplete hematologic recovery (CRi), CR with partial hematologic recovery (CRh)) * Hematologic relapse or progressive disease * Initiation of any subsequent anti-leukemic therapy (excluding hydroxyurea) * Death
Time frame: 12 months
Duration of response (DOR)
Duration of response (DOR)
Time frame: 12 months
Relapse-free survival
Relapse-free survival (RFS) defined as the time between inclusion and the first of the following events: * Hematologic relapse or progressive disease * Death
Time frame: 12 months
Overall survival
Overall survival (OS), defined as the time between inclusion and death
Time frame: 12 months
Incidence of subsequent allogeneic hematopoietic stem cell transplant
Incidence of subsequent allogeneic hematopoietic stem cell transplant (HSCT), overall and in responding patients specifically
Time frame: 12 months
Targeted gene sequencing
Targeted sequencing of a panel of genes recurrently mutated in AML, on bone marrow and peripheral blood samples
Time frame: Inclusion and end of induction (day 28 to 42)
SLC7A11 expression
SLC7A11 expression by flow cytometry (FCM) and/or western blot (WB), on bone marrow and peripheral blood samples
Time frame: Inclusion and end of induction (day 28 to 42)
Genotyping of ABCG2 rs2231142 polymorphisms
Genotyping of ABCG2 rs2231142 polymorphisms, on bone marrow and peripheral blood samples, in consenting patients
Time frame: Inclusion and end of induction (day 28 to 42)
NAT2 genotype
NAT2 genotype (NAT2\*4, NAT2\*5B, NAT2\*6A, NAT2\*7B), in consenting patients
Time frame: Inclusion and end of induction (day 28 to 42)
RNA-based antioxidogram
RNA-based expression patterns of major enzymes involved in the antioxidant cellular response (as described in Picou et al, Blood Advances 2019)
Time frame: Inclusion and end of induction (day 28 to 42)
Antioxidant score
Antioxidant score is a summary measure of expression patterns of major enzymes involved in the antioxidant cellular response (as described in Picou et al, Blood Advances 2019)
Time frame: Inclusion and end of induction (day 28 to 42)
Expression of NRF2 target genes
Expression of NRF2 target genes (NRF2 score) on bone marrow samples
Time frame: Inclusion and end of induction (day 28 to 42)
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