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

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: C_t = 1.11 × exp (− 0.0315 × t) + 0.38 × exp (− 0.002 × t) − 1.53 × exp (− 0.112 × t) where C_t 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.

Table 1

Patients characteristics^a

B. Tumor description and metastasis
Tumor type	No. of patients	No. of metastasis	No. of patients
Bladder	1
Breast	4	0	0
Cervix	2	1	5
Gastrointestinal	7	2	6
Larynx	1	≥3	15
Lung (non-small cell lung cancer)	3
Prostate	2
Head and neck	1
Fallopian adenocarcinoma	1
Fibrosarcoma	1
Ewing’s sarcoma	1
Thyroid carcinoma	1
Liposarcoma	1

C. Prior treatment
Chemotherapy	25
	(1 cycle 5 pts, 2 cycles 12 pts, 3 cycles 8 pts)
Mytomycin C/nitrosurea	2
Immunotherapy	5
Other (antihormone therapy)	4
Radiation therapy	20

D. Responding patients prior treatment
Principal diagnosis	Prior study treatment
Gastroduodenal + hepatomegalia	Surgery and chemotherapy (2 cycles)
Thyroid carcinoma	Surgery, chemotherapy (2 cycles), radiation
Fibrosarcoma	Chemotherapy (1 cycle), immunotherapy
Larynx carcinoma	Surgery, chemotherapy (1 cycle), radiation
Rectal carcinoma	Chemotherapy (3 cycles)
Breast	Surgery, 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 treatment	Neurotoxicity^a grade (study days)
Dose (mg/m²)	Days of treatment			Diplopia^b	Palpebral ptosis	Nystagmus	Anxiety
0.18	30	2 (9–19)	—	—	—
0.18	30	2 (6–14)
0.18	30	2 (2–10)
0.21	30	2 (2–20)
0.21	30	2 (1–14)
0.21	90	2 (11–21)
0.22	30	2 (2–4)	(19–22)	2 (15–16)	2 (15), 3 (16)
0.22	90	2 (6–14)	—	2 (16–17)	3 (17)
0.22	30	2 (8)	—	—	—
0.22	30	2 (4, 5)
0.22	30	2 (2–21)	(18–20)	2 (15)	3 (15)
0.22	30	2 (8–21)	(12–18)	2 (19–20)	2 (19); 3 (20)
0.21	2		Died on study day 3^c
0.21	90	2 (2–21)
0.21	60	2 (2–11)
0.21	90	2 (1–5)
0.21	30	2 (10–21)	Discharged on study day 31^d
0.21	8	2 (4–5)	Abandoned protocol on day 8^e

^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 signs			Laboratory
		FVC	Other	Eosinophilia	ALT^a	AST^a	CK^a
		FVC	Other	Eosinophilia				Grade
0.06	−	—	−	−	−	−	Discharged^b
0.06	−	—	+	−	−	−	DP^c
0.12	−	—	−	1	2	1	DP
0.12	−	Sialorrhea, IBP^d	−	1	2	1	DP
0.18	↓	—	−	2	2	1	DP
0.18	−	Diarrhea, IBP	−	2	2	1	SD^e A.T.^f
0.21		—	−	2	2	1	CR^g
0.22	−	−	+	2	2	1	SD A.T.^f
0.22	−	—	+	2	2	1	PR^h
0.22	↓	Sialorrhea	+	2	2	1	DP
0.21	−		−	2	2	1	PR
0.21	↓	—	+	2	2	1	DP
0.21	−	−	+	1	2	1	PR
0.21	−	Diarrhea, IBP, Anaphylaxis	−	2	2	1	Discharged^b
0.21	−	IBP	−	1	2	1	A.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

^a C, K_A, and t_{1/2_A} are the coefficient, rate constant, and half-life for the absorption phase, respectively.
^b A, α, and t_1/2α are the coefficient, rate constant, and half-life for the distribution phase, respectively.
^c B, β, and t_1/2β are the coefficient, rate constant, and half-life for the elimination phase, respectively.
^d C_l = Clearance.
^e V_d, 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)
0–2	100 ± 20	68.5 ± 7.5	7 ± 2	3.5 ± 1	61 ± 10
2–4	160 ± 32	21.2 ± 5.0	3.5 ± 1.4	1.75 ± 1.9	35 ± 7
4–6	90 ± 22	25.1 ± 5.2	2.8 ± 1.3	1.4 ± 0.6	28 ± 9
6–8	340 ± 46	5.9 ± 1.9	2.1 ± 0.9	1.05 ± 0.4	16 ± 4
8–12	192 ± 18	18.3 ± 3.1	3.5 ± 1.0	0.88 ± 0.5	23 ± 6
12–24	910 ± 43	3.1 ± 2.0	2.8 ± 2.4	0.23 ± 0.2	20 ± 3