Oral Arsenic (ATO) in Low-risk Myelodysplastic Syndromes (MDS)

Official title

Phase I Study With Dose-escalation and Expansion Evaluating the Safety and Efficacy of Oral Arsenic (ATO) in Low-risk Myelodysplastic Syndromes Failing Erythropoiesis Stimulating Agents and Luspatercept (or Ineligible for the Latter)

Overview

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).

Detailed description

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.

Interventions

• Drug Arsenic Trioxide (ATO)
  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 contin

Primary outcome measures

• To determine the dose-limiting toxicity (DLT) of oral Arsenic (ATO) [Time frame: At the end of cycle 1 (each cycle is 28 days)]

Secondary outcome measures (8)

• To determine safety profile [Time frame: Through study completion, an average of 2 years]
• Pharmacokinetics [Time frame: At the end of cycle 1 (each cycle is 28 days)]
• Pharmacokinetics [Time frame: At the end of cycle 1 (each cycle is 28 days)]
• Pharmacokinetics [Time frame: At the end of cycle 1 (each cycle is 28 days)]
• Efficacy [Time frame: At the end of cycle 3 (each cycle is 28 days)]
• Response duration [Time frame: Through study completion, an average of 2 years]
• Progression-free survival [Time frame: Through study completion, an average of 2 years]
• Overall survival [Time frame: Through study completion, an average of 2 years]

Eligibility criteria

Inclusion criteria

Patients must meet all the following criteria to participate in the study:

• Myelodysplastic syndrome according to WHO (World Health Organization) 2022 classification
• Age ≥ 18 years
• Patient with low-risk Myelodysplastic Syndromes according to Revised International Prognostic Scoring System (IPSS-R) classification (very low, low, intermediate):

• non-sideroblastic who failed to achieved a response or who subsequently relapse after Erythropoiesis Stimulating Agents (ESA) (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) without disease progression or ineligible to ESA (defined by Erythopoietine (EPO) > 500UI/L)
• sideroblastic who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) or ineligible for ESA (defined by EPO >500UI/L) and who failed to achieved a response or who subsequently relapse after Luspatercept
• del (5q) who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000IU or equivalent over at least 12 weeks) and who failed to achieved a response or who subsequently relapse after Lenalidomide
• Transfusion dependence (at least 3 RBC (Red Blood Cell) within a 16-week period and at least 2 transfusion episodes during this period)
• Patient not eligible for another clinical trial
• Adequate renal function defined by creatinine level less than 1.5 times the upper limit of normal and creatinine clearance ≥ 40mL/min (according to MDRD (Modification of Diet in Renal Disease) formula)
• Adequate liver function defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal
• Patient not refractory to platelet transfusions
• Written consent
• Patient must understand and voluntarily sign informed consent form
• Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
• Performance status 0-2 at the time of screening
• A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

A FCBP participating in the study must:

• Have had 2 negative pregnancy tests as verified by the investigator prior to starting IP (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after end of treatment.
• If sexually active, agreed to have used, and been able to comply with, highly effective contraception\*\* without interruption, 5 weeks prior to starting treatment, during treatment (including dose interruptions), and for 24 weeks after discontinuation of treatment.

• Highly effective contraception was defined in this protocol as the following (information also appeared in the Informed Consent Form): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy.
• Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 24 weeks following treatment discontinuation, even if he had undergone a successful vasectomy.

Exclusion criteria

Any patient meeting one of the following criteria cannot be included in the study:

• Severe infection or any uncontrolled severe condition
• Uncontrolled hypertension
• Significant cardiac disease - NYHA (New York Heart Association) Class III or IV or having suffered a myocardial infarction in the last 6 months
• QTcF (Fridericia's corrected QT interval) > 460ms
• Use of investigational agents within 30 days or any anticancer therapy (including IMiD (Immunomodulatory treatments)) within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy. However, patients may have received Lenalidomide, hypomethylating agent, or anti-lymphocytic serum (ALS) (but not within 4 weeks before the study entry and, for ALS, within 16 weeks before the study entry).
• Use of EPO within 4 weeks before the study entry
• Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast
• Patient already enrolled in another therapeutic trial of an investigational drug
• Known Human Immunodeficiency Virus infection or active hepatitis B or C
• Women who are or could become pregnant or who are currently breastfeeding
• Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
• Patient eligible for allogeneic stem cell transplantation
• No affiliation to a health insurance system

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 3 centers

• CHU de Nice - Hôpital l'Archet - Service d'hématologie clinique — Nice
• Hôpital Saint Louis - Service Hématologie séniors — Paris
• Institut Gustave Roussy - Service d'hématologie — Villejuif

Identifiers

NCT: NCT06670222 · ATOMYELO · 2024-515311-22-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗