Phase I/II Evaluation of Sulfasalazine, Idarubicin, and Cytarabine in Newly Diagnosed Non-Favorable Acute Myeloid Leukemia Patients Aged 60 and Above
- Trial ID
- 2024-513084-38-00
- Protocol
- APHP211176
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and characterize the dose-limiting toxicities (DLTs) of the combination of Sulfasalazine (SSZ) with Idarubicin (IDA) and Cytarabine (AraC) in patients with newly diagnosed non-favorable Acute Myeloid Leukemia (AML). The study aims to identify the maximal tolerated dose (MTD) and the recommended phase II dose (RP2D) of this combination. The clinical relevance of this objective lies in determining a safe and effective dosage regimen that minimizes the probability of DLTs, which should not exceed 33% by the end of the induction cycle (up to Day 42).
Secondary objectives include: - Characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of SSZ, IDA, and AraC when administered in combination during phase I, and confirming the PD during phase II. - Describing the response of leukemia to the treatment and the survival of patients up to 12 months after the end of induction (EOI) visit during phase I. - Documenting the safety profile further and confirming the recommended phase II dose of the IDA, AraC, and SSZ combination during phase II.
Participants
The clinical trial involves participants diagnosed with **recently diagnosed non-favorable Acute Myeloid Leukemias**. The study population includes both male and female subjects aged 60 years or older. Participants are required to have a newly diagnosed case of AML, with allowances for those with AML secondary to antecedent Myelodysplastic Syndromes or Myeloproliferative Neoplasms, as well as therapy-related AML. The trial does not include a vulnerable population. Participants must be eligible for intensive chemotherapy and have an ECOG performance status of 2 or less. They should have AST and ALT levels not exceeding three times the upper limit of normal, and total and direct serum bilirubin levels not exceeding 1.5 times the upper limit unless attributed to leukemia. An estimated glomerular filtration rate of at least 50 mL/min is required. Written informed consent is mandatory, and participants must be eligible for National Health Insurance in France. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the safety and efficacy of combining **sulfasalazine** with standard induction therapy in patients aged 60 years or older with newly diagnosed non-favorable **acute myeloid leukemia** (AML). This is a Phase I/II, open-label, multicenter trial with two sequential phases. Phase I involves dose-escalation using a survival continual reassessment method to identify the maximal tolerated dose (MTD) and the recommended Phase II dose (RP2D). Phase II extends at the MTD or RP2D, as determined by the data and safety monitoring board (DSMB), to confirm the safety and preliminarily document the clinical efficacy of the RP2D. The trial is expected to run from May 17, 2023, to May 17, 2026.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and health status. The inclusion criteria require patients to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, specific liver and kidney function parameters, and eligibility for intensive chemotherapy. Following the screening, participants will be enrolled in the trial and receive treatment according to the assigned phase. Regular follow-up visits will be conducted to monitor safety, assess dose-limiting toxicities, and evaluate pharmacokinetics and pharmacodynamics. The primary endpoint for Phase I is the documentation of dose-limiting toxicity, while Phase II focuses on achieving a minimal residual disease (MRD)-negative complete response by the end of induction (EOI) period, assessed between days 28 and 42.
The expected duration of participant involvement varies depending on the phase and individual response to treatment, with the possibility of early termination due to adverse events, withdrawal of consent, or non-compliance with study procedures. Safety assessments will be ongoing throughout the trial, including monitoring of electrocardiograms (ECGs), clinical laboratory values, and adverse events, evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. The trial aims to provide preliminary data on the anti-leukemia efficacy of the treatment combination, with secondary endpoints including survival assessment at 12 months and response evaluation at the EOI.
Treatment
The clinical trial involves the administration of **Idarubicin Hydrochloride**, a chemical compound used as part of the experimental treatment regimen. This medication is provided in the form of a **solution for injection** and is administered via **intravenous administration**. The specific dosage and frequency of administration are determined based on the trial protocol, with the aim of assessing safety and identifying the maximal tolerated dose (MTD) and recommended phase II dose (RP2D) in patients with newly diagnosed non-favorable acute myeloid leukemia (AML).
**Sulfasalazine** is another component of the experimental treatment regimen. It is administered in the form of a **tablet** and taken **orally**. The role of Sulfasalazine in this trial is to be combined with standard induction therapy to evaluate its safety and efficacy in conjunction with other medications. The dosing schedule is designed to ensure optimal therapeutic outcomes while monitoring for any dose-limiting toxicities (DLTs).
**Cytarabine** is also included in the treatment protocol as a **solution for injection**. Similar to Idarubicin Hydrochloride, Cytarabine is administered through **intravenous administration**. The combination of Cytarabine with Idarubicin and Sulfasalazine is intended to enhance the anti-leukemia efficacy of the treatment regimen. The administration schedule is carefully monitored to assess the preliminary anti-leukemia efficacy and to ensure participant safety throughout the trial.
Participant compliance with the dosing schedules is monitored closely to ensure adherence to the treatment protocol. The trial aims to maintain a probability of dose-limiting toxicities not exceeding 33% at the end of the induction cycle, which extends up to Day 42 of the treatment regimen. The study does not involve any pediatric formulations, and all substances used are of chemical origin.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase I, the primary endpoints include the documentation of dose-limiting toxicity (DLT) during dose escalation and the identification of the maximal tolerated dose (MTD), which is anticipated to be the recommended phase II dose (RP2D). The MTD is defined by a target DLT rate of 33%, assessed during the dose escalation phase using a continual reassessment method. The RP2D is anticipated to be the MTD, but it could be one dose level lower, determined in interaction with the Data and Safety Monitoring Board (DSMB) and validated by pharmacokinetic/pharmacodynamic (PK/PD) studies and preliminary efficacy data.
In Phase II, the primary endpoint is the **MRD-negative Complete Response** at the end of induction (EOI), assessed between days 28 to 42, according to the European LeukemiaNet (ELN) 2022 Criteria. Secondary endpoints include continuous safety assessments throughout the study, with monitoring of ECGs and clinical laboratory values. Adverse events (AEs), treatment-emergent adverse events (TEAEs), and treatment-related TEAEs will be evaluated according to the NCI CTCAE version 5.0. Pharmacokinetic assessments will be conducted to evaluate Sulfasalazine (SSZ) and its metabolites, Idarubicin (IDA) and its metabolite, and Cytarabine (AraC), to establish a PK model for SSZ and confirm the lack of interaction with IDA or AraC. Pharmacodynamic assays will aim to demonstrate reactive oxygen species (ROS) induction upon SSZ exposure relative to pre-treatment levels. Additionally, antileukemia activity will be assessed at EOI (days 28-42) per ELN 2022 Criteria and through survival assessment at 12 months.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients aged 60 years or older
- With newly diagnosed 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
- Multiparameter Flow Cytometry detected at screening allowing and / or compatible with MFCM-based MRD monitoring defined according to ELN criteria (Phase II only)
- ECOG performance status ≤2
- AST and ALT ≤3.0 x 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 LVEF <53% as assessed by echocardiography or 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 1/2 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 articles L 3212-1 and L3213-1 and who are not subject to the provisions of article L 1121
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 17 May 2023 | 64 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CYTARABINE | Other | — | INTRAVENOUS ADMINISTRATION | — | — | SUB06880MIG |
SULFASALAZINE | Test | — | ORAL | — | — | SUB10727MIG |
IDARUBICIN HYDROCHLORIDE | Other | — | INTRAVENOUS ADMINISTRATION | — | — | SUB02635MIG |