SALMA Study - Phase I/II Clinical Trial Assessing the Combination of Sulfasalazine with Standard of Care Induction Therapy in Newly Diagnosed Non-Favorable Acute Myeloid Leukemias (AML) Patients 60 years or older
Overview
- Phase
- Phase 1/2
- Intervention
- Not specified
- Conditions
- Not specified
- Sponsor
- Assistance Publique Hopitaux De Paris
- Enrollment
- 64
- Locations
- 10
- Primary Endpoint
- Phase I : Documentation during the dose escalation of dose limiting toxicity (DLT)
- Status
- Recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
Phase I To assess the safety, characterize the dose-limiting toxicities (DLTs), and identify the maximal tolerated dose (MTD), and recommended phase II dose (RP2D) of the combination of Sulfasalazine (SSZ) with Idarubicin (IDA) and Cytarabine (AraC) in patients with newly diagnosed non-favorable AML. Probability of DLT should not exceed 33% at the end of the induction cycle (EOI) of IDA-AraC + SSZ treatment (up to Day 42). Phase II To assess preliminarily the anti-leukemia efficacy of the combination of IDA-AraC + SSZ, mainly in phase II, in newly diagnosed non-favorable AML with reference from historical data on complete remission rate, and MRD.
Investigators
Raphael Itzykson
Scientific
Assistance Publique Hopitaux De Paris
Eligibility 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
- •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
Outcomes
Primary Outcomes
Phase I : Documentation during the dose escalation of dose limiting toxicity (DLT)
Phase I : Documentation during the dose escalation of dose limiting toxicity (DLT)
Phase I : Identification of a maximal tolerated dose (MTD) anticipated to be the recommended phase II dose (RP2D) - MTD is defined by a target DLT rate of 33%, assessed during the dose escalation phase by a continual reassessment method - RP2D is anticipated to be the MTD. However, it could be equal to one dose level lower than the MTD. It will be determined in interaction with the DSMB, insofar that this dose level is validated by PK/PD studies and efficacy preliminary data.
Phase I : Identification of a maximal tolerated dose (MTD) anticipated to be the recommended phase II dose (RP2D) - MTD is defined by a target DLT rate of 33%, assessed during the dose escalation phase by a continual reassessment method - RP2D is anticipated to be the MTD. However, it could be equal to one dose level lower than the MTD. It will be determined in interaction with the DSMB, insofar that this dose level is validated by PK/PD studies and efficacy preliminary data.
Phase II : MRD-negative Complete Response at EOI (day 28-42) per ELN 2022 Criteria
Phase II : MRD-negative Complete Response at EOI (day 28-42) per ELN 2022 Criteria
Secondary Outcomes
- Assessment of safety - Safety outcome measures will be assessed continuously during the study. Monitoring of ECGs and clinical laboratory values are integral to safety assessment. Adverse events (AE), treatment emergent adverse events (TEAE) and treatment-related TEAEs will be evaluated according to the NCI CTCAE version 5.0.
- Pharmacokinetics - To assess SSZ and its metabolites, IDA (and its metabolite) and AraC. This will allow to determine a PK model for SSZ at an early and late time point and confirm the lack of interaction between SSZ and IDA or AraC.
- Pharmacodynamics - Pharmacodynamic assays aim at demonstrating ROS induction upon SSZ exposure relative to pre-treatment levels.
- Antileukemia activity - Response at EOI assessment (day 28-42) per ELN 2022 Criteria.
- Antileukemia activity - Survival assessment at 12 months