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Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA2, NSC-624244) in Patients with Advanced Cancer

Jorge E. Cura, Daniel P. Blanzaco, Cecilia Brisson, Marco A. Cura, Rosa Cabrol, Luis Larrateguy, Carlos Mendez, Jose Carlos Sechi, Jorge Solana Silveira, Elvira Theiller, Adolfo R. de Roodt and Juan Carlos Vidal
Jorge E. Cura
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Daniel P. Blanzaco
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Cecilia Brisson
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Marco A. Cura
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Rosa Cabrol
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Luis Larrateguy
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Carlos Mendez
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Jose Carlos Sechi
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Jorge Solana Silveira
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Elvira Theiller
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Adolfo R. de Roodt
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Juan Carlos Vidal
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DOI:  Published April 2002
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    Fig. 1.

    Plasma concentration versus time curves of crotoxin after the i.m. administration to patients at the dose level of 0.21 mg/m2. Curve A, the points represent means obtained from five patients on study day 1; bars, ± SD. The points were fitted to the pharmacokinetic equation: Ct = 1.11 × exp (− 0.0315 × t) + 0.38 × exp (− 0.002 × t) − 1.53 × exp (− 0.112 × t) where Ct is the crotoxin concentration in ng/ml at time t; the constants are expressed in ng/ml, and the exponential coefficients represent the rate constants for the distribution, elimination, and absorption phases, in that order, expressed in min−1. Curve B, data obtained for a patient after the i.m. injection of crotoxin at the dose level of 0.21 mg/m2 on study day 30. Inset, calibration curve for determination of crotoxin. The change in absorbance (ΔA450/min/ml × total volume of the eluate) was plotted as a function of the amount of crotoxin added to the sample. The results are presented as mean ± SD obtained from three different immunoaffinity columns. Linear regression analysis indicates: slope = ± 0.013; intercept = 0.0318 ± 0.0153; and r2 = 0.998. Dotted lines, the limits of 95% CI.

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  • Table 1

    Patients characteristicsa

    A. Enrollment data
    Entered (total)26
    Entered and evaluated23
    Median age (range) (yr)52 (25–76)
    Sex (M/F)12/11
    ECOG Performance Status
    03
     114
     26
    B. Tumor description and metastasis
    Tumor typeNo. of patientsNo. of metastasisNo. of patients
    Bladder1
    Breast400
    Cervix215
    Gastrointestinal726
    Larynx1≥315
    Lung (non-small cell lung cancer)3
    Prostate2
    Head and neck1
    Fallopian adenocarcinoma1
    Fibrosarcoma1
    Ewing’s sarcoma1
    Thyroid carcinoma1
    Liposarcoma1
    C. Prior treatment
    Chemotherapy25
    (1 cycle 5 pts, 2 cycles 12 pts, 3 cycles 8 pts)
    Mytomycin C/nitrosurea2
    Immunotherapy5
    Other (antihormone therapy)4
    Radiation therapy20
    D. Responding patients prior treatment
    Principal diagnosisPrior study treatment
    Gastroduodenal + hepatomegaliaSurgery and chemotherapy (2 cycles)
    Thyroid carcinomaSurgery, chemotherapy (2 cycles), radiation
    FibrosarcomaChemotherapy (1 cycle), immunotherapy
    Larynx carcinomaSurgery, chemotherapy (1 cycle), radiation
    Rectal carcinomaChemotherapy (3 cycles)
    BreastSurgery, chemotherapy (2 cycles), radiation, and hormone therapy
    • a One patient with fibrosarcoma died on study day 3 for reasons unrelated to drug treatment. Another patient with gastrointestinal cancer presented a biliary obstruction and was removed from protocol on study day 6 for treatment. A patient with prostate cancer abandoned the protocol on study day 8, unable to adapt to the obligatory in-patient protocol conditions.

  • Table 2

    Neurotoxicity in patients treated with crotoxin

    Dose (mg/m2)Days of treatmentNeurotoxicitya grade (study days)
    DiplopiabPalpebral ptosisNystagmusAnxiety
    0.18302 (9–19)———
    0.18302 (6–14)
    0.18302 (2–10)
    0.21302 (2–20)
    0.21302 (1–14)
    0.21902 (11–21)
    0.22302 (2–4)(19–22)2 (15–16)2 (15), 3 (16)
    0.22902 (6–14)—2 (16–17)3 (17)
    0.22302 (8)———
    0.22302 (4, 5)
    0.22302 (2–21)(18–20)2 (15)3 (15)
    0.22302 (8–21)(12–18)2 (19–20)2 (19); 3 (20)
    0.212Died on study day 3c
    0.21902 (2–21)
    0.21602 (2–11)
    0.21902 (1–5)
    0.21302 (10–21)Discharged on study day 31d
    0.2182 (4–5)Abandoned protocol on day 8e
    • a No neural toxicity was observed at doses up to 0.18 mg/m2.

    • b Diplopia appeared intermittently within the study days indicated in parenthesis.

    • c This patient died on study day 3 of pulmonary edema.

    • d Patient had a mild allergic reaction on study day 3 and a grade 3 anaphylactic reaction on day 31.

    • e Patient abandoned the protocol on study day 8, unable to adapt to the obligatory in-patient condition required by this study.

  • Table 3

    Non-neurological toxicity

    Dose (mg/m2)Clinical signsLaboratoryRemarks
    FVCOtherEosinophiliaALTaASTaCKa
    Grade
    0.06−—−−−−Dischargedb
    0.06−—+−−−DPc
    0.12−—−121DP
    0.12−Sialorrhea, IBPd−121DP
    0.18↓—−221DP
    0.18−Diarrhea, IBP−221SDe A.T.f
    0.21 Embedded Image —−221CRg
    0.22−−+221SD A.T.f
    0.22−—+221PRh
    0.22↓Sialorrhea+221DP
    0.21−−221PR
    0.21↓—+221DP
    0.21−−+121PR
    0.21−Diarrhea, IBP, Anaphylaxis−221Dischargedb
    0.21−IBP−121A.T.h
    • a The increases in ALT, AST, and CK listed are observed during the first 2 weeks of treatment. They decrease during the third week and return to normal during the fourth week of treatment.

    • b Patient was removed from protocol on study day 6 because of biliary obstruction and required surgery. Another patient presented grade 3 anaphilaxis on study day 31.

    • c DP, disease progression.

    • d Grade 1 increase in blood pressure.

    • e SD, stable disease. Three patients abandoned the treatment after the first 30-day cycle, unable to continue with the obligatory in-patient condition required for this study.

    • f A.T., abandoned treatment.

    • g CR, complete response.

    • h PR, measurable partial response.

  • Table 4

    Pharmacokinetic parameters of crotoxin administered i.m. to patients at the dose of 0.21 mg/m2 on study days 1 and 15

    Parameter (units)Day 1 × (± SD)Day 15 × (± SD)
    aC (ng/ml−1)1.53 (±0.14)1.63 (±0.12)
    aKA (min−1)0.121 (±0.003)0.173 (±0.002)
    at1/2A (min)5.2 (±0.6)4.8 (±0.3)
    bA (ng/ml−1)1.11 (±0.16)1.2 (±0.2)
    bα (min−1)0.032 (±0.01)0.038 (±0.02)
    bt1/2α (min)22 (±3)18.2 (±4.2)
    cB (ng/ml−1)0.38 (±0.12)0.38 (±0.10)
    cβ (h−1)0.136 (±0.03)0.163 (±0.03)
    ct1/2 β (h)5.2 (±0.6)4.3 (±0.6)
    dCl (ml/min−1)26.0 (±8)25.5 (±5)
    AUC (μg/min/ml−1)0.190 (±0.05)0.196 (±0.03)
    eVd (liter/kg−1)12 (±3)9.1 (±4)
    • a C, KA, and t1/2A are the coefficient, rate constant, and half-life for the absorption phase, respectively.

    • b A, α, and t1/2α are the coefficient, rate constant, and half-life for the distribution phase, respectively.

    • c B, β, and t1/2β are the coefficient, rate constant, and half-life for the elimination phase, respectively.

    • d Cl = Clearance.

    • e Vd, apparent volume of distribution.

  • Table 5

    Urine data following the i.m. injection of crotoxin (0.21 mg/m2)

    Time of collection (h)Volume of urine (ml)Crotoxin in urine (ng/ml)Amount excreted in time interval (μg)Excretion rate (μg/h)AUC within interval (ng/min/ml)
    0–2100 ± 2068.5 ± 7.57 ± 23.5 ± 161 ± 10
    2–4160 ± 3221.2 ± 5.03.5 ± 1.41.75 ± 1.935 ± 7
    4–690 ± 2225.1 ± 5.22.8 ± 1.31.4 ± 0.628 ± 9
    6–8340 ± 465.9 ± 1.92.1 ± 0.91.05 ± 0.416 ± 4
     8–12192 ± 1818.3 ± 3.13.5 ± 1.00.88 ± 0.523 ± 6
    12–24910 ± 433.1 ± 2.02.8 ± 2.40.23 ± 0.220 ± 3
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April 2002
Volume 8, Issue 4
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Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA2, NSC-624244) in Patients with Advanced Cancer
Jorge E. Cura, Daniel P. Blanzaco, Cecilia Brisson, Marco A. Cura, Rosa Cabrol, Luis Larrateguy, Carlos Mendez, Jose Carlos Sechi, Jorge Solana Silveira, Elvira Theiller, Adolfo R. de Roodt and Juan Carlos Vidal
Clin Cancer Res April 1 2002 (8) (4) 1033-1041;

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Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA2, NSC-624244) in Patients with Advanced Cancer
Jorge E. Cura, Daniel P. Blanzaco, Cecilia Brisson, Marco A. Cura, Rosa Cabrol, Luis Larrateguy, Carlos Mendez, Jose Carlos Sechi, Jorge Solana Silveira, Elvira Theiller, Adolfo R. de Roodt and Juan Carlos Vidal
Clin Cancer Res April 1 2002 (8) (4) 1033-1041;
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