Clinical trial NCT05148234: BMS-986253 in Myelodysplastic Syndromes
Official title: A Phase I/II Trial of BMS-986253 in Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: heterogenous clonal diseases neoplasms
Interleukin-8
DNA methyltransferase inhibitors
cytopenias
Allogeneic Hematopoietic Stem Cell Transplantation
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2021-12-08
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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 HuMax-interleukin 8 (IL-8) 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 deoxyribonucleic acid (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.

National Institutes of Health (NIH) will cover the costs for some travel expenses....

Detailed 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 United States (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.

Deoxyribonucleic acid (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 chemokine (C-X-C motif) 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/Acute myeloid leukemia (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 cluster of differentiation 34 (CD34+) cell cultures treated with neutralizing anti-IL-8 showed improvement in erythroid colony formation.

BMS-986253 is a fully human Immunoglobulin G1 (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 natural killer (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 recommended phase 2 dose (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 overall response rate (ORR) to BMS-986253 with or without DNMTi (decitabine and cedazuridine) therapy in MDS, measured according to the proposed revised International Working Group (IWG) 2018 response criteria.

Eligibility:

Participants must have histologically or cytologically confirmed MDS according to 2016 World Health Organization (WHO) criteria and

* have higher risk (HR) MDS Revised International Prognostic Scoring System (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

Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (KPS \>= 60%)

Design:

This study consists of two phases:

Phase I: safety evaluation with determination of optimal biological dose (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 dose limiting-toxicity (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.

Eligibility criteria: * INCLUSION CRITERIA:
* Participants must have histologically or cytologically confirmed myelodysplastic syndromes (MDS) according to 2016 World Health Organization (WHO) criteria
* And:

  * have higher-risk myelodysplastic syndrome (HR-MDS) Revised International Prognostic Scoring System (R-IPSS \>= 3.5) and received a minimum of 2 and maximum of 8 prior cycles for phase I and 4 for phase II of deoxyribonucleic acid (DNA) methyltransferase inhibitors (DNMTi) therapy, or
  * have lower-risk myelodysplastic syndrome (LR-MDS) (R-IPSS \<3.5),

    * and, at least one cytopenia:

      * granulocytes \< 1.0 x 10\^9/L and/or
      * hemoglobin \< 110 g/L with signs/symptoms of symptomatic anemia or transfusion-dependency
      * platelets \< 100 x 10\^9/L
* Age \>=18 years

  --Because no dosing or adverse event data are currently available on the use of HuMax-interleukin 8 (IL-8) BMS-986253 as monotherapy or in combination with DNMTi in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (Karnofsky \>=60%).
* Life expectancy greater than 6 months.
* Participants must have adequate organ function as defined below:

  --total bilirubin \<=1.5 X institutional upper limit of normal OR \<=3 X institutional upper limit of normal in participants with Gilbert's syndrome (\*except for participants with increased bilirubin levels attributed to intramedullary hemolysis, which will be allowable)
* Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT)/Alanine transaminase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) \<=3 X institutional upper limit of normal OR \<=5 X institutional upper limit of normal if related to disease specific cause
* creatinine clearance (by Cockcroft-Gault) \>=60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal.
* The effects of BMS-986253 on the developing human fetus are unknown. For this reason and because DNMTi as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and up to 6 months after study completion and last dose of DNMTi.
* Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* For phase I: Participants with HR-MDS (R-IPSS \>=3.5) that have not yet received or received less than 2 cycles of DNMTi therapy.
* Participants with LR-MDS (R-IPSS \<3.5) with the following characteristics that have not yet received or are still deriving benefit from the following standard of care therapies:

  * Hemoglobin (Hgb) \<10 g/dL, Epo level \<500 mU/mL: Erythropoietin-stimulating agents (ESAs)
  * MDS with del5q: Lenalidomide
  * MDS with ringed sideroblasts (MDS-RS) with splicing factor 3b subunit 1 (SF3B1) mutation: Luspatercept
* Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10K/mcL with transfusions or those with ongoing or uncontrolled hemorrhagic complications.
* Participants with clinically significant neutropenia, absolute neutrophil count (ANC)\<100, with frequent hospitalizations for infection (average \>1 hospitalization per month in past 6 months)
* Participants who are receiving or have received any other investigational agents within 28 days before start of study

treatment.

* History of allergic reactions attributed to compounds of similar chemical or biologic composition to DNMTi or other agents used in study.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women or women presently breast-feeding their children are excluded due to unknown risks to a developing fetus or infant.
* Any significant disease that, in the opinion of the investigator, may impair the participant s tolerance of study treatment.
* Active or uncontrolled autoimmune diseases requiring treatment.
* Chronic hepatitis B or C infection, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy.
* Human immunodeficiency virus (HIV)-positive participants are ineligible because of the potential for decreased immune response.
* Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, or stable chronic cancers on hormone or targeted therapy) for which participant received systemic anticancer treatment within 24 months prior to enrollment.
* Prior history of allogeneic hematopoietic stem cell transplantation.

Primary outcomes:
measure: Phase I: Optimal Biological Dose (OBD) for Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253)
timeFrame: First 28 days (C1D28) on up to 30 days.
measure: Phase I: Recommended Phase 2 Dose (RP2D) of Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253)
timeFrame: First 28 days (C1D28)
measure: Phase II: Overall Response Rate
timeFrame: 6 months
measure: Phase I: Number of Grades 1-5 Serious and/or Non-serious Adverse Events Related to Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253) and Deoxyribonucleic Acid (DNA) Methyltransferase Inhibitors (DNMTi)
timeFrame: First 28 days and follow up after the end of the treatment cycle; approximately 2 months.
measure: Phase II: Fraction of Participants With Clinical Response
timeFrame: Study treatment until occurrence of disease progression, death, or unacceptable toxicity or until response assessment on Cycle 7 day 1 (C7D1), a maximum of 6 cycles
Secondary outcomes:
measure: Phase I: Area Under the Concentration Time Curve (AUC 0-24h) of Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253) in Myelodysplastic Syndromes (MDS) With and Without Deoxyribonucleic Acid (DNA) Methyltransferase Inhibitors (DNMTi)
timeFrame: Before infusion, within 30 minutes, start of infusion, 1, 4, 12, and 24 hours after end of infusion.
measure: Phase I: Half-life of Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253) With and Without Deoxyribonucleic Acid (DNA) Methyltransferase Inhibitors (DNMTi)
timeFrame: Before infusion, within 30 minutes, start of infusion, 1, 4, 12, and 24 hours after end of infusion.
measure: Phase I: Concentration of Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253) at Steady State With and Without Deoxyribonucleic Acid (DNA) Methyltransferase Inhibitors (DNMTi)
timeFrame: Before infusion, within 30 minutes, start of infusion, 1, 4, 12, and 24 hours after end of infusion.
measure: Phase II: Number of Grades 1-5 Serious and/or Non-serious Adverse Events Related to Human Humax (HuMax)-Interleukin 8 (IL-8) (BMS-986253) and Deoxyribonucleic Acid (DNA) Methyltransferase Inhibitors (DNMTi)
timeFrame: 1 year
measure: Phase II: Cytogenetic Response Rate
timeFrame: Study treatment until occurrence of disease progression, death, or unacceptable toxicity or until response assessment on Cycle 7 day 1 (C7D1), a maximum of 6 cycles
measure: Phase II: Time to Best Response (Complete Remission (CR), Partial Remission (PR), Marrow CR + Hematologic Improvement (HI), HI)
timeFrame: Time to best response
measure: Phase II: Disease Free Survival (DFS)
timeFrame: Until study closure
measure: Phase II: Progression Free Survival (PFS)
timeFrame: Until study closure
measure: Phase II: Leukemia Free Survival (LFS)
timeFrame: Until study closure
measure: Phase II: Overall Survival (OS)
timeFrame: Until study closure
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
timeFrame: From first study intervention, study day 1, through study day 100 after the end of the treatment cycle; approximately 7 months.
measure: Phase I: Proportion of Participants With Dose-limiting Toxicities (DLT)
timeFrame: First 28 days
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Alain Mina, M.D.
role: PRINCIPAL_INVESTIGATOR
References: