Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT05148234 |
Other study ID # |
10000356 |
Secondary ID |
000356-C |
Status |
Active, not recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
November 29, 2022 |
Est. completion date |
July 31, 2025 |
Study information
Verified date |
October 24, 2023 |
Source |
National Institutes of Health Clinical Center (CC) |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Background:
The myelodysplastic syndromes (MDS) are a group of bone marrow neoplasms. MDS mostly affect
elderly people. The drugs used to treat MDS are not always effective, and the only curative
treatment is stem cell transplant. Researchers want to see if a new drug can be used to treat
MDS.
Objective:
To learn if BMS-986253 is a safe and effective treatment for MDS.
Eligibility:
Adults aged 18 and older with MDS.
Design:
Participants will be screened with a medical history, medication review, and physical exam.
They will answer questions about how well they are able to take care of themselves. Their
temperature, blood pressure, breathing rate, and heart rate will be monitored. They will have
an electrocardiogram to see how well their heart is working. They will give blood and urine
samples. They may have a bone marrow biopsy.
Participants will be assigned to a specific group. They will receive either BMS-986253 alone
or in combination with DNA methyltransferase inhibitors (DNMTi).
Treatment will be given in 28-day cycles. Participants will get BMS-986253 as an infusion on
days 1 and 15 of each cycle. Some participants also will take oral DNMTi on days 2-6 of each
cycle. They will receive treatment until their disease gets worse or they have bad side
effects.
At study visits, some screening tests will be repeated. Some of the samples that are
collected will be used for genetic testing.
About 30 days after treatment ends, participants will have a follow-up visit to see how they
are doing. After that, follow up will occur via phone every 3-6 months until the study ends.
NIH will cover the costs for some travel expenses....
Description:
Background:
The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms characterized
by ineffective hematopoiesis, cytopenia, and high risk for transformation to acute myeloid
leukemia (AML).
MDS is primarily a disease of the elderly, with about 80% of participants being older than
65-years of age; with 10,000 new diagnoses per year in the U.S.
The only curative treatment for participants with MDS is allogeneic hematopoietic stem cell
transplantation (HSCT) and only a small portion of participants are eligible. Depending on
risk stratification, the median survival of high- and low-risk MDS participants is 1.5 to 5.9
years, respectively.
DNA methyltransferase inhibitors (DNMTi) are the standard of care therapy for high-risk MDS.
However, less than half of participants respond to DNMTi, and even the best responses are
transient and non-curative. More effective and less toxic therapies are needed.
Interleukin-8 (IL-8) is a proinflammatory chemokine from the CXC family and a potent
chemoattractant of granulocytes and related cells to the site of inflammation. IL-8 is
uniquely upregulated and found at high levels in both the peripheral blood and bone marrow
aspirates of MDS participants. In purified MDS/AML long-term/short term stem cells and
granulocyte-macrophage progenitor cells both IL-8 and the IL-8 receptor, CXCR2, are
overexpressed.
Preclinical data showed that CXCR2 inhibition led to significantly reduce proliferation of
leukemic cell lines. In addition, MDS CD34+ cell cultures treated with neutralizing anti-IL-8
showed improvement in erythroid colony formation.
BMS-986253 is a fully human IgG1 neutralizing antibody that showed a favorable safety profile
in participants with advanced solid tumors.
Concomitant treatment with DNMTi and BMS-986253 may improve treatment responses in
participants with MDS by attenuating chemoattraction of myeloid derived suppressor cells to
the bone marrow, indirectly disinhibiting NK- and T-cell responses against MDS stem cells,
reducing neoangiogenesis, and improving cytopenia.
Objectives:
Primary objectives:
Phase I: To determine the optimal biological dose (OBD) and RP2D of BMS-986253 with or
without DNMTi (decitabine and cedazuridine) therapy in MDS participants, and to describe the
safety and tolerability of BMS-986253.
Phase II: To determine ORR to BMS-986253 with or without DNMTi (decitabine and cedazuridine)
therapy in MDS, measured according to the proposed revised IWG 2018 response criteria.
Eligibility:
Participants must have histologically or cytologically confirmed MDS according to 2016 WHO
criteria and
- have higher risk (HR) MDS (R-IPSS >= 3.5) and received a minimum of 2 and maximum of 8
cycles of DNMTi for Phase I (and a maximum of 4 cycles for Phase 2), or
- have lower risk (LR) MDS(R-IPSS <3.5) and at least one cytopenia (for both Phases I and
II).
Age >=18 years
ECOG performance status <=2 (KPS >= 60%)
Design:
This study consists of two phases:
Phase I: safety evaluation with determination of OBD of BMS-986253 with or without DNMTi
(decitabine and cedazuridine), and
Phase II: efficacy evaluation of BMS-986253 with or without DNMTi (decitabine and
cedazuridine)
In both Phase I and II, participants will be enrolled into two cohorts:
A) Higher-risk cohort (HR-MDS), including high-risk and higher intermediate-risk disease,
defined as those with R-IPSS >= 3.5: treatment with BMS-986253 in combination with DNMTi
(decitabine and cedazuridine)
B) Lower-risk cohort (LR-MDS), including low-risk and lower intermediate-risk disease
participants, defined as those with R-IPSS <3.5: treatment with BMS-986253 given as
monotherapy
For Phase I, the safety endpoint will be DLT by D28 with the objective of defining the OBD
and RP2D for BMS-986253. In addition, follow up for safety will be assessed 100 days after
the end of the treatment cycle. For Phase II, the primary endpoint will be overall response
rate after 6 cycles, reported separately by cohort.