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Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia

Alan S. Wayne, Nirali N. Shah, Deepa Bhojwani, Lewis B. Silverman, James A. Whitlock, Maryalice Stetler-Stevenson, Weili Sun, Meina Liang, Jie Yang, Robert J. Kreitman, Mark C. Lanasa and Ira Pastan

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Treatment-emergent AEs (by preferred term) reported in ≥15% of patients in the DLT-evaluable population, regardless of attribution. Each AE was counted only once per patient, regardless of the number of events observed in an individual patient. Events are rank ordered by overall frequency, and maximum event grade is displayed. *AEs were coded by preferred term by the reporting investigator according to MedDRA, which includes edema and peripheral edema.

  • Figure 2.

    Mean concentration-time profiles for cycle 1 (dose 1). Error bars represent standard error of the mean. LLOQ, lower limit of quantification. *Manufacturing process change: 32 µg/kg bioactively equivalent to 40 µg/kg of prior product.

  • Figure 3.

    Responses: patient examples. (A) Flow cytometric CRc in patients #14 and #37. Pretreatment (left panels) bone marrow aspirates demonstrated ALL blasts expressing abnormally bright CD20 and CD10. Posttreatment (right panels) bone marrow aspirates demonstrated only pre–B cells with a normal maturation profile based on CD20 and CD10 expression. Both patients achieved CRc (#14, CR; #37, CR incomplete blood count recovery [CRi]) after cycle 1 and were MRD negative after cycle 2. The limit of detection for this assay was 0.004%. (B) Patient #2: pretreatment (left panel) and posttreatment (right panel) bone marrow biopsies revealed decreased blast infiltration with 1 cycle of therapy (original magnification ×100; hematoxylin and eosin stain). Patient achieved PR after cycle 1 and CRi after cycle 2. (C) Patient #22: pretreatment (left panel) and posttreatment (right panel) fluorodeoxyglucose positron emission tomography scans show marked reduction in areas of uptake after 2 cycles of therapy.

Tables

  • Table 1.

    Response criteria

    ResponseCriteria
    cCRPatients achieving criteria for either CR or CRi:
    CR: M1 marrow,* absence of peripheral blasts (morphologic), absence of extramedullary sites of disease, peripheral blood neutrophil count ≥1000/μL, and platelet count ≥100 000/μL
    CRi: above CR criteria without specified blood counts
    PRM2 marrow* and decrease in percentage of marrow blasts by ≥50%, absence of peripheral blasts (morphologic), absence of extramedullary sites of disease
    Hematologic activityDoes not meet criteria for CR or PR, with any of the following:
    ≥50% decrease in percentage of marrow blasts
    ≥50% decrease in absolute peripheral blast count
    Improvement of peripheral blood neutrophil count to ≥1000/μL or platelet count to ≥100 000/μL
    Stable diseaseDoes not meet criteria for CR, PR, HA, or PD
    Progressive disease or relapseDeterioration in marrow classification (ie, M status*) with ≥50% increase in percentage of marrow blasts compared with best response OR
    No change in marrow classification (ie, M status*) but ≥50% increase in absolute peripheral blast count or extent of extramedullary disease compared with best response
    • cCR, composite CR; CRi, CR with incomplete blood count recovery; HA, hematologic activity; PD, progressive disease; PR, partial response.

    • * Bone marrow classification (blast percentage, ≥200 cells counted): M1, <5%; M2, 5% to 25%; M3, >25%.

    • Central nervous system classification (cerebrospinal fluid cell count and cytology): CNS1, 0 blasts on cytospin; CNS2, white cell count <5/µL and blasts on cytospin; CNS3, white cell count ≥5/µL and blasts on cytospin.

  • Table 2.

    Patient demographics and baseline characteristics

    ParameterMoxetumomab pasudotox (n = 55)
    No.%
    Age, y
     Median13
     Range1-25
    Age category, y
     ≤347
     >3 to ≤122138
     >12 to ≤192138
     >19916
    Male sex3156
    Race
     White4582
     Black713
     Asian12
     Other24
    Ethnicity
     Hispanic1324
     Non-Hispanic4276
    Time from diagnosis to study entry, months
     Median29
     Range7-145
    ECOG performance status (≥12 y)n = 32
     059
     11527
     2 or 3815
    Lansky scale score (<12 y)n = 20
     Normal range1833
     Mild to moderate restriction224
    Prior treatment
     Chemotherapy55100
     Transplantation2647
     Radiation therapy1018
     Biologic36
     Other815
    • ECOG, Eastern Cooperative Oncology Group.

  • Table 3.

    DLT

    Dose levelDose and scheduleNumber treatedDLT
    1A5 µg/kg × 61None
    2A10 µg/kg × 61None
    3A20 µg/kg × 61None
    3B20 µg/kg × 64None
    4A30 µg/kg × 64Grade 3 and 4 CLS (1 case each*)
    4B30 µg/kg × 65None
    5B40 µg/kg × 68Grade 5 hypercalcemia (1 case)
    5C32 [40] µg/kg × 1011Grade 4 hepatobiliary disorder (1 case)
    6B50 µg/kg × 66None
    6C50 µg/kg × 1014Grade 4 HUS (2 cases)
    • Cohorts: A: every other day × 6, no steroids; B: every other day × 6, dexamethasone prophylaxis cycle 1; C: every other day × 10, dexamethasone prophylaxis in cycle 1, doses 1 to 6.

    • * DLT preferred terms: vascular leak syndrome in 1 patient and bilateral pleural effusions, hypoxia, and hypertension in the other patient.

    • Manufacturing process change: 32 µg/kg equivalent to 40 µg/kg of prior product.

  • Table 4.

    Best protocol response

    Dose levelDose, µg/kgNumber treatedNumber evaluablecCRPRHematologic activityStable diseaseProgressive diseaseNot evaluable
    1A5111
    2A10111 (CRi)
    3A20111
    3B2044121
    4A304431
    4B30541 (MRD negative)1111
    5B40871 (MRD negative)3211
    5C32* (40)117211124
    6B50662 (1 MRD negative)13
    6C5014122 CR (1 MRD negative), 1 CRi (MRD negative)21512
    554711 (23%)4 (9%)11 (23%)12 (26%)9 (19%)8
    • Response rates based on evaluable population (response criteria listed in Table 1). Cohorts: A: every other day × 6 doses, no steroids; B: every other day × 6 doses, dexamethasone prophylaxis cycle 1; C: every other day × 10 doses, dexamethasone prophylaxis cycle 1, doses 1 to 6.

    • CRi, CR with incomplete blood count recovery.

    • * 32 µg/kg process 3 equivalent bioactivity to 40 µg/kg of prior product.