Sulfasalazine in AML Treated by Intensive Chemotherapy: Elderly Patients-first Line Treatment

Study Overview
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Brief Summary
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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

Official Title
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Phase I/II Clinical Trial Assessing the Combination of Sulfasalazine With Standard of Care Induction Therapy in Newly Diagnosed Acute Myeloid Leukemias (AML) Patients 60 Years or Older- the SALMA Study

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Sulfasalazine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 60 years or older With newly diagnosed acute myeloid leukemia (AML) (short course treatment with hydroxyurea and or steroids is acceptable). Patients with AML secondary to an antecedent Myelodysplastic Syndromes (MDS) or Myeloproliferative Neoplasms (MPN) are eligible, as those with therapy-related AML. Eligible for intensive chemotherapy in the investigator's opinion Leukaemia-associated immunophenotypes (LAIP) detected at screening allowing flow cytometry (FCM)-based Minimal Residual Disease monitoring (Phase II only). Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Aspartate transaminase (AST) and Alanine transaminanse (ALT) ≤ 3.0 times upper the limit of normal (ULN) and 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 MDRD equation Written informed consent obtained prior to any screening procedures Eligible for National Health Insurance in France Exclusion Criteria: Myeloid Sarcoma with < 20% bone marrow blasts Patient who has received a vaccine injection with live-attenuated virus in the last three weeks Proven central nervous system leukemic involvement Favorable risk cytogenetics: t(15;17), t(8;21), inv(16) or t(16;16) or presence of PML-RARA, RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcript. Presence of FLT3-ITD or TKD mandating treatment with midostaurin. Concurrent therapy with any cytotoxic drug within 3 weeks before the first study dose. Only hydroxyurea for the control of blood counts is permitted. Patients planned to received CPX-351 for myelodysplasia-related changes or therapy-related AML. Previous treatment with sulfasalazine in the last 5 years or ongoing treatment with sulfasalazine or 5-aminosalicylic acid (5-ASA) for ulcerative colitis or inflammatory rheumatisms. History of allergy SSZ, one of its metabolites (5-aminosalicylic acid, 5-ASA) or mesalazine, other sulfonylarylamines sulfonamides or salicylates, or sulfasalazine excipients History of allergic reaction to idarubicin or idarubicin excipients History of allergic reaction to cytarabine or cytarabine excipients Known glucose 6-phosphate dehydrogenase deficiency. Known acute intermittent porphyria or porphyria variegata. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate treatment). Other uncontrolled or active malignant disease within prior 12 months (excluding myelodysplastic syndrome; cutaneous basal cell carcinoma, in-situ carcinoma of the cervix or breast, or other local malignancy excised). Known human immunodeficiency virus (HIV) infection or HIV-related malignancy. Clinically active hepatitis B or hepatitis C infection. Inability to swallow. Known malabsorption syndrome or other condition that may significantly impair absorption of oral study medications. Participation in another therapeutic interventional clinical study within 30 days of enrolment. Administration of any therapy considered investigational (i.e., used for non-approved indications(s) or in the context of a research investigation) within 5 drug half-lives (whichever is longer) prior to the first dose of study drug. Previous treatment by anthracyclines Any contraindication to use anthracyclines including uncontrolled coronary disease, severe renal failure, severe hepatic failure, recent myocardial infarction, symptomatic congestive heart failure, severe cardiomyopathy, significant arrhythmia as estimated by the investigator or left-ventricule ejection fraction (LVEF) <53% as assessed by echocardiography or Multigated Acquisition Scan (MUGA), anterior treatment by idarubicin and/or anthracyclines and anthracènediones beyond the maximum cumulative dose. Any contraindication to use cytarabine including degenerative and toxic encephalopathy. Any condition requiring treatment with digoxin. Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study. Females who are pregnant or breastfeeding. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use a highly effective contraceptive method for the entire treatment period and for at least 6 months after completion of protocol treatment. Highly effective contraception methods include: combined (estrogen and progestogen containing) hormonal methods associated with inhibition of ovulation, intra-uterine device; surgical sterilization (including bilateral tubal occlusion, partner's vasectomy) or sexual abstinence if this is the preferred and usual lifestyle of the patient. Male patients must not freeze or donate sperm starting at screening and throughout the treatment period and 3 months after the administration of the final dose of study medication. - In a heterosexually active woman of childbearing potential, unwillingness or inability to use a highly effective contraceptive method (as described above) for the entire treatment period and for at least 6 months after the administration of the final dose of study medication. Women are not regarded as of childbearing potential if they are post-menopausal (at least 2 years without menses) or are surgically sterile (at least 1 month before enrollment). Female patients must not donate or retrieve, for their own use, ova from the time of screening and throughout the treatment period, and for 12 weeks after the administration of the final dose of study medication. Female patients must agree not to breastfeed from the time of screening and throughout the protocol period, and for (5 half-lives) days after the administration of the final dose of study medication. Adults subjects to a legal protection order or unable to give their consent - Persons deprived of their freedom by judicial or administrative decision, person hospitalized without their consent by virtues of French Public Health Code articles L 3212-1 and L3213-1 and who are not subject to the provisions of article L 1121-8.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I dose-finding design unsing the continueal reassessment method, followed by a dose expansion cohort using a Simon's phase II design.
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Sulfasalazine|Sulfazalazine 500mg-tablets ; 7 dose levels explored in the phase I part of the trial.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Day 28 to 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | Day 1, 4 and 15 | 
| Plasma levels of malondialdehyde | Pharmacodynamics with plasma levels of malondialdehyde (MDA) | Day 1, 2 | 
| Plasma levels of glutathione | Pharmacodynamics with plasma levels of glutathione (reduced/oxidized) | 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 | Day 1, 2 | 
| Response | Response at end of induction assessment (day 28-42) as per European LeukemiaNet (ELN) Criteria. | 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 | End of induction treatment - day 28 to 42 | 
| Next-generation sequencing (NGS)-based Minimal Residual Disease (MRD) | NGS-based MRD in all patients | 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 | 12 months | 
| Duration of response (DOR) | Duration of response (DOR) | 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 | 12 months | 
| Overall survival | Overall survival (OS), defined as the time between inclusion and death | 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 | 12 months | 
| Targeted gene sequencing | Targeted sequencing of a panel of genes recurrently mutated in AML, on bone marrow and peripheral blood samples | 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 | 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 | Inclusion and end of induction (day 28 to 42) | 
| NAT2 genotype | NAT2 genotype (NAT2*4, NAT2*5B, NAT2*6A, NAT2*7B), in consenting patients | 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) | 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) | 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 | Inclusion and end of induction (day 28 to 42) |