Acute Myeloid Leukemia Clinical Trial

Highest Dose of Uproleselan in Combination With Fludarabine and Cytarabine for Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Mixed Phenotype Acute Leukemia Relapsed or Refractory and That Expresses E-selectin Ligand on the Cell Membrane

Summary

This phase I trial tests the safety, side effects, and best dose of uproleselan in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia, myelodysplastic syndrome or mixed phenotype acute leukemia that has come back (relapsed) or does not respond to treatment (refractory) and that expresses E-selectin ligand on the cell membrane. Uproleselan binds to E-selectin expressed on endothelial cells of the bone marrow and prevents their interaction with selectin-E ligand-expressing cancer cells. This may prevent leukemia cells from being sequestered in the bone marrow niche and escaping the effect of chemotherapy. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving uproleselan in combination with fludarabine and cytarabine may enhance their activity.

View Full Description

Full Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose or recommended Phase 2 dose of uproleselan (GMI-1271) administered in combination with fludarabine and cytarabine to patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or mixed phenotype acute leukemia (MPAL) whose blasts express the E-selectin ligand and that are in second or greater relapse or refractory to relapse therapy.

II. To characterize the pharmacokinetics and pharmacodynamics of uproleselan (GMI-1271) in combination with fludarabine and cytarabine in patients with refractory and/or relapsed AML, MDS or MPAL.

III. To define and describe the toxicities of uproleselan (GMI-1271) in combination with fludarabine and cytarabine among patients with relapsed and/or refractory AML, MDS or MPAL.

SECONDARY OBJECTIVES:

I. To describe the expression of E-selectin ligand on the surface of myeloid leukemic blasts at relapse prior to initiation of uproleselan (GMI-1271) in combination with fludarabine and cytarabine and at completion of the cycle.

II. To describe the antileukemic activity of uproleselan (GMI-1271) (complete remission [CR]/CR with partial recover of platelet count [CRp]/CR with incomplete blood count recovery [CRi] and rates of minimal residual disease (MRD) negative response after up to two cycles of therapy) in combination with fludarabine and cytarabine within the limits of a Phase 1 study.

EXPLORATORY OBJECTIVE:

I. To determine the largest relative reduction in myeloid leukemic blast percentage in the bone marrow, calculated from baseline at time of enrollment to up to two cycles of therapy.

OUTLINE: This is a dose escalation study of uproleselan.

Patients receive uproleselan intravenously (IV) once daily (QD) over 20 minutes on day 1 and IV over 20 minutes twice daily (BID) on days 2-8, fludarabine IV QD over 30 minutes on days 2-6, and high dose cytarabine IV QD over 1-3 hours on days 2-6. Patients also receive cytarabine intrathecal therapy (IT) or intrathecal triple therapy (ITT) on day 0. CNS2 and CNS3 patients receive additional cytarabine IT or ITT once weekly starting on day 7-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients (with down syndrome only) receive leucovorin orally (PO) or IV BID on days 1, 8, 15, 22, and 29.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Patient must be enrolled on APAL2020SC (NCT04726241)
Patients must be < 18 years of age at the time of study enrollment

Patients, with or without Down syndrome (DS), and with de novo acute myeloid leukemia, therapy-related acute myeloid leukemia, myelodysplastic syndrome or mixed phenotype acute leukemia that expresses E-selectin ligand on the cell membrane according to APAL2020SC screening results and meet one of the following:

Second or greater relapse or refractory AML as defined below, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular disease
Second or greater relapse or refractory myelodysplastic syndrome (MDS)
Second or greater relapse or refractory mixed phenotype acute leukemia (MPAL)

Bone marrow relapse: (patients must meet one of the following criteria to be defined as having relapse disease)

A single bone marrow sample showing >= 5% leukemic blasts by flow cytometry performed at the central laboratory, fluorescence in situ hybridization (FISH) testing or other molecular method

A single bone marrow with at least two tests showing >= 1% leukemic blasts; examples of tests include:

Flow cytometry showing leukemia >= 1% by multidimensional flow cytometry (MDF) performed at the central laboratory (performed at Hematologics Inc. through the screening study APAL2020SC)
Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
FISH abnormality identical to one present at diagnosis
Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and >= 1%
In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a white blood count [WBC] count >= 10,000/uL with >= 10% blasts or a WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
Extramedullary relapse: Biopsy proven extramedullary disease after documented complete remission
Refractory disease: Following a re-induction cycle after a second relapse, presence of ≥1% leukemic blasts by flow cytometry performed at the central laboratory (performed only at Hematologics through the screening study APAL2020SC), OR there is persistent extramedullary disease
Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age

Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately

Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:

>= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea
NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy
Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (eg. pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)

Stem cell Infusions (with or without total-body irradiation [TBI]):

Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
Autologous stem cell infusion including boost infusion: >= 30 days
Cellular Therapy: >= 30 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer [NK] cells, dendritic cells, etc.)
External beam radiation therapy (XRT)/External Beam Irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
Patients must not have received prior exposure to uproleselan (GMI-1271). NOTE: Prior therapy with fludarabine and/or cytarabine is permitted

For patients with leukemia:

Platelet count >= 25,000/uL (may receive platelet transfusions)

Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a creatinine based on age/gender as follows:

Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male); 0.4 (female)
Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male); 0.5 (female)
Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
Albumin >= 2 g/dL
Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study

Exclusion Criteria:

Patients with any of the following diagnoses

Patients with isolated or refractory central nervous system (CNS) disease or isolated or refractory testicular relapse
Patients with acute promyelocytic leukemia (APL)
Patients with juvenile myelomonocytic leukemia (JMML)
Patients with a known congenital bone marrow failure syndrome
Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study and for 3 months after the last dose of uproleselan (GMI-1271). Abstinence is an acceptable method of birth control
Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
Patients who are currently receiving another investigational drug are not eligible
Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy
Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
Patients who have an uncontrolled infection are not eligible
Patients who have received a prior solid organ transplantation are not eligible
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 1

Estimated Enrollment:

18

Study ID:

NCT05146739

Recruitment Status:

Recruiting

Sponsor:

National Cancer Institute (NCI)

Check Your Eligibility

Let’s see if you might be eligible for this study.

What is your age and gender ?

Submit

There are 19 Locations for this study

See Locations Near You

Children's Hospital of Alabama
Birmingham Alabama, 35233, United States More Info
Site Public Contact
Contact
205-638-9285
[email protected]
Girish Dhall
Principal Investigator
Children's Hospital Los Angeles
Los Angeles California, 90027, United States More Info
Site Public Contact
Contact
323-361-4110
Fariba Navid
Principal Investigator
Children's Hospital of Orange County
Orange California, 92868, United States More Info
Site Public Contact
Contact
714-509-8646
[email protected]
Josephine H. Haduong
Principal Investigator
UCSF Medical Center-Mission Bay
San Francisco California, 94158, United States More Info
Site Public Contact
Contact
877-827-3222
[email protected]
Kieuhoa T. Vo
Principal Investigator
Children's Hospital Colorado
Aurora Colorado, 80045, United States More Info
Site Public Contact
Contact
303-764-5056
[email protected]
Margaret E. Macy
Principal Investigator
Children's National Medical Center
Washington District of Columbia, 20010, United States More Info
Site Public Contact
Contact
202-476-2800
[email protected]
AeRang Kim
Principal Investigator
Children's Healthcare of Atlanta - Egleston
Atlanta Georgia, 30322, United States More Info
Site Public Contact
Contact
404-785-2025
[email protected]
Jason R. Fangusaro
Principal Investigator
Lurie Children's Hospital-Chicago
Chicago Illinois, 60611, United States More Info
Site Public Contact
Contact
773-880-4562
Jenna Rossoff
Principal Investigator
Riley Hospital for Children
Indianapolis Indiana, 46202, United States More Info
Site Public Contact
Contact
800-248-1199
Brian D. Weiss
Principal Investigator
C S Mott Children's Hospital
Ann Arbor Michigan, 48109, United States More Info
Site Public Contact
Contact
800-865-1125
Rajen Mody
Principal Investigator
University of Minnesota/Masonic Cancer Center
Minneapolis Minnesota, 55455, United States More Info
Site Public Contact
Contact
612-624-2620
Emily G. Greengard
Principal Investigator
Washington University School of Medicine
Saint Louis Missouri, 63110, United States More Info
Site Public Contact
Contact
800-600-3606
[email protected]
Shalini Shenoy
Principal Investigator
Memorial Sloan Kettering Cancer Center
New York New York, 10065, United States More Info
Site Public Contact
Contact
212-639-7592
Maria Luisa Sulis
Principal Investigator
Cincinnati Children's Hospital Medical Center
Cincinnati Ohio, 45229, United States More Info
Site Public Contact
Contact
513-636-2799
[email protected]
Joseph G. Pressey
Principal Investigator
Children's Hospital of Philadelphia
Philadelphia Pennsylvania, 19104, United States More Info
Site Public Contact
Contact
267-425-5544
[email protected]
Sarah K. Tasian
Principal Investigator
Children's Hospital of Pittsburgh of UPMC
Pittsburgh Pennsylvania, 15224, United States More Info
Site Public Contact
Contact
412-692-8570
[email protected]
Andrew Bukowinski
Principal Investigator
Saint Jude Children's Research Hospital
Memphis Tennessee, 38105, United States More Info
Site Public Contact
Contact
888-226-4343
[email protected]
Jessica Gartrell
Principal Investigator
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston Texas, 77030, United States More Info
Site Public Contact
Contact
713-798-1354
[email protected]
Jennifer H. Foster
Principal Investigator
Seattle Children's Hospital
Seattle Washington, 98105, United States More Info
Site Public Contact
Contact
866-987-2000
Katherine G. Tarlock
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Acute Myeloid Leukemia

Phase:

Phase 1

Estimated Enrollment:

18

Study ID:

NCT05146739

Recruitment Status:

Recruiting

Sponsor:


National Cancer Institute (NCI)

How clear is this clinincal trial information?

×

Introducing, the Journey Bar

Use this bar to access information about the steps in your cancer journey.