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

NCT05580861 | Recruiting Phase 1 DMC

• 1 other identifier: APHP211176
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 13

Brief Summary

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

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (25)

• Adverse events

  Month 12

• Peak plasma concentration (Cmax) of Sulfazalazine

  Day 1, 4 and 15

• Time of peak plasma concentration (Tmax) of Sulfazalazine

  Day 1, 4 and 15

• Area under the plasma concentration versus time curve (AUC) for Sulfazalazine

  Day 1, 4 and 15

• Clearance (Cl) of Sulfazalazine

  Day 1, 4 and 15

Study Arms (1)

Cohort : Patients with acute myeloid leukemia

EXPERIMENTAL

Drug: Sulfasalazine

Interventions

Sulfasalazine DRUG

Sulfazalazine 500mg-tablets ; 7 dose levels explored in the phase I part of the trial.

Cohort : Patients with acute myeloid leukemia

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (13)

CHU Amiens

Amiens, France

NOT YET RECRUITING

Hôpital Avicenne

Bobigny, France

NOT YET RECRUITING

CHU Caen

Caen, France

NOT YET RECRUITING

CHU Henri Mondor

Créteil, France

RECRUITING

Centre Hospitalier Lyon Sud, Lyon

Lyon, France

RECRUITING

Hôpital de la Conception, AP-HM

Marseille, France

NOT YET RECRUITING

CHU Nice

Nice, France

RECRUITING

AP-HP Hôpital Saint Louis

Paris, 75010, France

RECRUITING

AP-HP Hôpital Cochin

Paris, 75014, France

RECRUITING

Centre Henri Becquerel

Rouen, France

NOT YET RECRUITING

CHU Tours

Tours, France

RECRUITING

CH Mignot

Versailles, France

RECRUITING

Gustave Roussy

Villejuif, France

NOT YET RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Sulfasalazine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Central Study Contacts

Raphaël Itzykson, Pr

CONTACT

1 42 49 96 43; raphael.itzykson@aphp.fr

Jérôme Lambert, Pr

CONTACT

142499742; jerome.lambert@u-paris.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I dose-finding design unsing the continueal reassessment method, followed by a dose expansion cohort using a Simon's phase II design.

Study Record Dates

• First Submitted: September 26, 2022
• First Posted: October 14, 2022
• Study Start: May 17, 2023
• Primary Completion: November 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: May 29, 2024

Record last verified: 2024-05

Locations

FR (13)