Phase I study with dose-escalation and expansion evaluating the safety and efficacy of oral Arsenic (ATO) in low-risk Myelodysplastic Syndromes having failed to Erythropoiesis Stimulating Agents and Luspatercept (or ineligible for the latter).
Dose escalation cohort to determine the dose limiting toxicity according to a BOIN (Bayesian optimal interval) scheme. Patients will receive one dose of study treatment (oral Arsenic (ATO)) 5d/7 for 21 days over a 28-day cycle. Three doses of ATO will be tested (0.10 mg/kg, 0.15 mg/kg and 0.20 mg/kg), and 9 patients will be treated at each dose. An expansion cohort at the selected dose based on DSMB recommendations will be conducted with 6 patients, for a maximum of 15 patients included at this dose level. Tolerability will be assessed after one treatment cycle. Response will be assessed after 3 cycles of treatment. Responders may continue study treatment until progression or limiting toxicity. Limiting toxicity is defined as any grade III/IV extra-hematological toxicity or grade IV hematological toxicity lasting more than 25 days. If there is no response, patients will stop treatment and enter the follow-up phase of the study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Study treatment: oral Arsenic 5d/7 for 21 days over a 28-day cycle, three doses tested (0.10 mg/kg, 0.15 mg/kg and 0.20 mg/kg). Dose escalation cohort to determine the dose limiting toxicity according to a BOIN (Bayesian optimal interval) scheme, 9 patients will be treated at each dose. An expansion cohort at the selected dose will be conducted with 6 patients. Tolerability will be assessed after one treatment cycle. Response will be assessed after 3 cycles of treatment. Responders may continue study treatment until progression or limiting toxicity. Limiting toxicity is defined as any grade III/IV extra-hematological toxicity or grade IV hematological toxicity lasting more than 25 days.
CHU de Nice - Hôpital l'Archet - Service d'hématologie clinique
Nice, France
NOT_YET_RECRUITINGHôpital Saint Louis - Service Hématologie séniors
Paris, France
RECRUITINGInstitut Gustave Roussy - Service d'hématologie
Villejuif, France
NOT_YET_RECRUITINGTo determine the dose-limiting toxicity (DLT) of oral Arsenic (ATO)
Dose-limiting toxicity will be defined by the occurrence during the first treatment cycle of any of the following toxicities related to the trial drug (oral ATO): * Non-hematological toxicity of grade ≥ 3 * Hematological toxicity of grade ≥ 4 corresponding to a decrease of 50% or more of absolute neutrophil count (ANC) or platelet count from baseline or lower limit (if baseline was above normal), without recovery at D42 of the first cycle.
Time frame: At the end of cycle 1 (each cycle is 28 days)
To determine safety profile
Toxicities measured according to CTCAE (Common Terminology Criteria for Adverse Events)
Time frame: Through study completion, an average of 2 years
Pharmacokinetics
Measurement of the peak plasma concentration (Cmax) of oral ATO
Time frame: At the end of cycle 1 (each cycle is 28 days)
Pharmacokinetics
Measurement of area under the plasma concentration versus time curve (AUC) for oral ATO
Time frame: At the end of cycle 1 (each cycle is 28 days)
Pharmacokinetics
Measurement of the residual concentration (Cmin) of oral ATO
Time frame: At the end of cycle 1 (each cycle is 28 days)
Efficacy
Response rate (Complete Response + Partial Response + stable disease with hematological improvement according to IWG (International Working Group) 2018 criteria)
Time frame: At the end of cycle 3 (each cycle is 28 days)
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Response duration
Response duration measured from date of objective response to date of relapse or progression (or date of last news in absence of event)
Time frame: Through study completion, an average of 2 years
Progression-free survival
Rate and time to transformation to high-risk myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML)
Time frame: Through study completion, an average of 2 years
Overall survival
Overall survival from date of inclusion to death or date of last news
Time frame: Through study completion, an average of 2 years