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

M
Melissa Bear, MD

Primary Investigator

Overview

This phase I trial tests the safety, side effects, and best dose of uproleselan inbination with fludarabine and cytarabine in treating patients with acute myeloid leukemia,yelodysplastic 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 cellbrane. Uproleselan binds to E-selectin expressed on endothelial cells of the bone marrowd prevents their interaction with selectin-E ligand-expressing cancer cells. This mayvent leukemia cells from being sequestered in the bone marrow niche and escaping thehemotherapy. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stoppinghem from dividing, or by stopping them from spreading. Giving uproleselan in combination with fludarabine and cytarabine may enhance their activity.

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 acuteyeloid 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 relapsey to relapse therapy.
II. To characterize the pharmacokinetics and pharmacodynamics of uproleselan (GMI-1271) inbination with fludarabine and cytarabine in patients with refractory and/or relapsed AML,DS or MPAL.
III. To define and describe the toxicities of uproleselan (GMI-1271) in combination withudarabine 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 blastsuproleselan (GMI-1271) in combination with fludarabine andytarabine 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 ofherapy) 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 andV 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 receiveytarabine 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) orV BID on days 1, 8, 15, 22, and 29.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    Down Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Mixed Phenotype Acute Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Mixed Phenotype Acute Leukemia, Refractory Myelodysplastic Syndrome, Therapy-Related Acute Myeloid Leukemia, Therapy-Related Myelodysplastic Syndrome
  • Age: - 17 Years
  • Gender: All

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,herapy-related acute myeloid leukemia, myelodysplastic syndrome or mixed phenotypeute leukemia that expresses E-selectin ligand on the cell membrane according toAPAL2020SC screening results and meet one of the following:
    • Second or greater relapse or refractory AML as defined below, including isolateddullary disease (EMD), but excluding isolated central nervous system (CNS)d 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 cytometryd at the central laboratory, fluorescence in situ hybridization (FISH)g or other molecular method
    • A single bone marrow with at least two tests showing >= 1% leukemic blasts;ude:
      • Flow cytometry showing leukemia >= 1% by multidimensional flow cytometry(MDF) performed at the central laboratory (performed at Hematologics Inc.hrough the screening study APAL2020SC)
      • Karyotypic abnormality with at least one metaphase similar or identical todiagnosis
      • FISH abnormality identical to one present at diagnosis
      • Polymerase chain reaction (PCR) or next generation sequencing (NGS)-baseddemonstration 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 andequate bone marrow core biopsy. A complete blood count documenting the presence1,000/ 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(blasts) can also be used if a bone marrow aspirate or biopsy cannot bed
  • 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 (performedy at Hematologics through the screening study APAL2020SC), OR there is persistentdullary disease
  • Patient's current disease state must be one for which there is no known curativeherapy 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 =< 16years of age. Patients must have a performance status corresponding to EasternCooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16years of age and Lansky for patients =< 16 years of age
  • Patients must have fully recovered from the acute toxic effects of all priorherapy and must meet the following minimum duration from priordirected therapy prior to enrollment. If after the required timeframe, theumerical eligibility criteria are met, e.g., blood count criteria, the patient isdered 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 cytotoxicherapy, with the exception of hydroxyurea
      • NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours priorhe 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 thedose of agent
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Corticosteroids: If used to modify immune adverse events related to priorherapy, >= 14 days must have elapsed since last dose of corticosteroid
    • Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (eg. pegfilgrastim) or 7 days for short acting growth factor. Forgents that have known adverse events occurring beyond 7 days afterdministration, this period must be extended beyond the time during which adversevents are known to occur
    • Interleukins, interferons and cytokines (other than hematopoietic growth): >= 21 days after the completion of interleukins, interferon orytokines (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 stemusion 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: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT ordiation 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/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% bygated radionuclide study
Exclusion Criteria:
  • Patients with any of the following diagnoses
    • Patients with isolated or refractory central nervous system (CNS) disease ord 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 thereyet no available information regarding human fetal or teratogenic toxicities.Pregnancy tests must be obtained in girls who are post-menarchal. Males or females ofductive potential may not participate unless they have agreed to use twove methods of birth control, including a medically accepted barrier orve method (e.g., male or female condom) for the duration of the study and3 months after the last dose of uproleselan (GMI-1271). Abstinence is anble method of birth control
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose ofd for at least 7 days prior to enrollment are not eligible. If used todify immune adverse events related to prior therapy, >= 14 days must have elapseddose 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 exceptving hydroxyurea, which may be continued until 24 hours prior to startherapy
  • Patients who are receiving cyclosporine, tacrolimus or other agents to preventgraft-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 they monitoring requirements of the study are not eligible

Updated on 27 Apr 2024. Study ID: NCI-2021-10020
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