A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
Status:
Not yet recruiting
Trial end date:
2025-01-31
Target enrollment:
Participant gender:
Summary
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 humanized 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, for Phase I: received a minimum of 2 and maximum of 8 cycles of DNMTi
have higher-risk (HR) MDS (R-IPSS >= 3.5) or
have lower risk (LR) MDS (R-IPSS <3.5), at least one cytopenia and are either ineligible or
relapsed/refractory to other standard of care therapies
And, for Phase II: received a minimum of 2 and maximum of 4 cycles of DNMTi
have HR-MDS (R-IPSS >= 3.5) or
have LR-MDS (R-IPSS <3.5), at least one cytopenia and are either ineligible or
relapsed/refractory to other standard of care therapies
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 30 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.