This phase I trial studies the side effects and best dose of edetate calcium disodium or succimer in treating patients with acute myeloid leukemia or myelodysplastic syndrome undergoing chemotherapy. Edetate calcium disodium or succimer may help to lower the level of metals found in the bone marrow and blood and may help to control the disease and/or improve response to chemotherapy.
Recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| Edetate Calcium Disodium | C10H12CaN2Na2O8, Calcium disodium edetate, Calcium Disodium Ethylenediaminetetraacetate, Calcium Disodium Versenate, Calcium EDTA, Disodium calcium ethylenediaminetetraacetate, EDTA Calcium | Cohort I (edetate calcium disodium, multivitamin) |
| Succimer | Chemet, DMSA, Meso 2, 3-Dimercaptosuccinic Acid | Cohort II (succimer, multivitamin) |
PRIMARY OBJECTIVES:
I. To establish the maximal tolerated dose (MTD) of Phase 1 in acute myeloid leukemia (AML)
and myelodysplastic syndrome (MDS) patients undergoing therapy combined with succimer (DMSA)
and edetate calcium disodium (Ca-EDTA). (Phase I dose escalation) II. To assess the efficacy
information regarding the combined therapy in terms of the overall response rate (ORR)
including complete remission (CR), CR with partial hematological recovery (CRh), CR with
incomplete count recovery (CRi), morphologic leukemia free state (MLFS), and partial
remission (PR). (Phase I dose escalation)
SECONDARY OBJECTIVES:
I. To assess the complete remission (CR), complete remission with incomplete hematologic
recovery (CRi), complete remission with partial hematological recovery (CRh), partial
remission (PR), hematologic improvement (HI), morphologic leukemia free state (MLFS) rates
and the 1-year overall survival (OS) in AML patients and the CR/marrow CR/hematologic
improvement (HI) rate, partial remission (PR) rate and 1-year overall survival (OS) and 6-
month cytogenetic response in MDS patients undergoing MDS/AML therapy combined with DMSA and
Ca-EDTA.
II.To assess overall survival and event free survival in AML and MDS patients undergoing AML
and MDS therapy combined with DMSA and Ca-EDTA III. To assess remission duration in AML and
MDS patients undergoing AML and MDS therapy combined with DMSA and Ca-EDTA.
IV. To monitor toxic and essential metal levels during AML and MDS therapy combined with DMSA
and Ca-EDTA and to evaluate the reduction in metals in the bone marrow and blood of newly
diagnosed AML and MDS patients undergoing metal detoxification combined with standard AML/MDS
therapy.
V. To evaluate the safety profile in AML and MDS patients undergoing AML and MDS therapy
combined with DMSA and Ca-EDTA.
VI. Correlate metal and copper isotopic abundance ratios of AML and MDS patients with
clinical data, conventional cytogenetics, extensive next generation sequencing (NGS)
(300-gene panel), exposure survey data, and clinical outcome data, and to perform a larger
analysis by pooling this data with metal/genomic/survey/outcome data obtained on 2017-0937
and PA15-0302.
VII. Estimate the progression rate in MDS patients. VIII. To assess other responses of
interest.
EXPLORATORY OBJECTIVES:
I. To correlate the degree of metal chelation with the degree of therapeutic response and
minimal residual disease (MRD).
II. To collect environmental exposure data on the environmental health assessment survey.
III. To assess P53 folding before and after the first dose of Ca-EDTA chelation in MDS and
AML patients.
IV. To study changes in cytogenetic/molecular data during treatment, as well as protein
expression data (by immunohistochemistry and/or proteomics) including for transcription
factors/tumor suppressors (e.g. TP53 and MYC).
V. To perform pre-clinical proof of concept studies of metals and metal chelators in a
variety of AML cells and cell lines including: AML cell lines, primary hematologic malignancy
cells, stromal cell lines, and patient-derived stromal cells.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 cohorts.
COHORT I: During standard of care chemotherapy, patients receive edetate calcium disodium
intravenously (IV) daily over 30 minutes for 4 doses for each cycle. Treatment continues for
up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also
receive up to 12 multivitamin capsules PO daily while on study.
COHORT II: During standard of care chemotherapy, patients receive succimer orally (PO) daily
for 8 or 21 days of each cycle beginning day 1. Treatment continues for up to 6 cycles in the
absence of disease progression or unacceptable toxicity. Patients also receive up to 12
multivitamin capsules PO daily while on study.
After completion of study treatment, patients are followed up every 3-12 months for up to 10
years.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Cohort I (edetate calcium disodium, multivitamin) | Experimental | During standard of care chemotherapy, patients receive edetate calcium disodium IV daily over 30 minutes for 4 doses for each cycle. Treatment continues for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive up to 12 multivitamin capsules PO daily while on study. |
|
| Cohort II (succimer, multivitamin) | Experimental | During standard of care chemotherapy, patients receive succimer PO daily for 8 or 21 days of each cycle beginning day 1. Treatment continues for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive up to 12 multivitamin capsules PO daily while on study. |
|
Inclusion Criteria:
- Understand and voluntarily sign an informed consent form
- Diagnosis of any of the following:
- Newly diagnosed (or untreated) AML with poor-risk cytogenetics, poor-risk
molecular, or secondary AML (i.e. therapy-related or evolved from antecedent
hematologic malignancy
- Newly diagnosed (or untreated) myeloid blast phase of myeloproliferative neoplasm
(MPN) (including myeloid blast phase of chronic myeloid leukemia [CML])
- Newly diagnosed (or untreated) high-risk, very-high risk or secondary MDS
- Newly diagnosed (or untreated) MDS/MPN (regardless of cytogenetic/molecular
status)
- Relapsed and/or refractory AML, MDS, MDS/MPN, myeloid blast phase of MPN
(including myeloid blast phase of CML) who are either salvage 1 or salvage 2
- Patients on non-investigational regimens or on investigational new drug (IND)-exempt
MD Anderson studies (for hematologic malignancies) of approved drugs are also eligible
- Patients on IND studies (for hematologic malignancies) utilizing Food and Drug
Administration (FDA) approved commercially available drugs are eligible
- Investigational agents that are not used for treatment of the leukemia per se (e.g.
anti-infective prophylaxis or therapy) will be allowed. Other supportive care studies
are allowed, even if under an IND
- Newly diagnosed MDS or AML, as well as MDS/MPN, myeloid blast phase of MPN (including
myeloid blast phase of CML), patients can enroll on this study after start of
non-investigational induction therapy, but must be within first 3 cycles of therapy
and benefiting from their front-line therapy. Patients with relapsed and/or refractory
AML, MDS, MDS/MPN, myeloid blast phase of MPN (including myeloid blast phase of CML)
who are either salvage 1 or salvage 2 are eligible for these salvage cohorts if they
are within the first 3 cycles of salvage 1 or salvage 2 therapy
- Transformed and untreated AML transformed from previously treated MDS,
myeloproliferative neoplasm (MPN) or other types of secondary AML are allowed. Myeloid
blast phase of MPN and chronic myeloid leukemia (CML) are allowed
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry
- Serum creatinine =< 1.5 mg/dL (unless due to leukemia or other hematologic malignancy)
- Total bilirubin =< 2.0 x upper limit of normal (ULN), unless the patient has Gilbert's
(unless due to leukemia or other hematologic malignancy)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.0 x ULN (unless due to leukemia or other hematologic malignancy)
- Women of childbearing potential (WCBP) must have a negative urine pregnancy test
within 7 days and must either commit to continued abstinence from heterosexual
intercourse or adopting at least one highly effective method of contraception. These
methods include intra-uterine device, tubal ligation, partner's vasectomy, and
hormonal birth control pills. Men must agree not to father a child and agree to use a
condom if his partner is of child bearing potential
- Extramedullary disease is allowed as long as it can be measured and followed for
response
Exclusion Criteria:
- Nursing and pregnant females. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately
- Uncontrolled inter-current illness including, but not limited to, uncontrolled active
infection, symptomatic congestive heart failure, unstable angina pectoris, or
psychiatric illness/social situations that would limit compliance with study
requirements or which judged by the investigator, places the patient at unacceptable
risk
- Acute Promyelocytic leukemia (APL)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Incidence of adverse events |
| Time Frame: | At 30 days post-treatment |
| Safety Issue: | |
| Description: | Safety data of the patients will be summarized using descriptive statistics such as mean, standard deviation, median and range. Will follow standard reporting guidelines for adverse events. Safety data will be summarized by category, severity and frequency. |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | M.D. Anderson Cancer Center |
July 28, 2021
