Intravenous administration of CP-4055 (ELACYT™) in patients with solid tumours. A phase I study

Figures & data

Table I.  Patient characteristics.

			Dose of CP-4055 mg/m^2/day
		30	60	100	150	175	200	240
	Total		30 min infusion						2 hr
No of patients
Total enrolled	34	3	3	3	3	6	6	6	4
Evaluable	34	3	3	3	3	6	6	6	4
Sex
Female	19	2	2	1	2	4	4	2	2
Male	15	1	1	2	1	2	2	4	2
Age (years)
Mean	56	43.6	61.9	63.5	60.4	48.1	56.6	54.9	62.3
Range	27–76	33–54	57–69	43–76	50–69	27–75	32–71	47–64	57–69
Performance status (ECOG-WHO)
0	14	0	2	1	0	3	1	4	3
1	20	3	1	2	3	3	5	2	1
Tumour type
Malignant melanoma	19	3	1	2	2	2	3	4	2
Ovarian cancer	8	0	1	1	1	2	0	2	1
Non-small cell lung cancer	7	0	1	0	0	2	3	0	1

*Axillary block dissection–.

Table II.  Patient pre treatment prior to enter in the study.

Dose	Diagnosis	1	2	3	4	5	6	7
30 mg/m^2/day 30 min infusion	MM	surg	surg	Ch 1	imm
	MM	surg	surg	surg	radio	Ch 1
	MM	surg	imm	surg	Ch 2	radio	surg
60 mg/m^2/day 30 min infusion	MM	surg	Ch 1	Ch 1
	OVA	surg	Ch 3	anti
	NSCLC	Ch 4 + Ch 5	radio	Ch 6
100 mg/m^2/day 30 min infusion	MM	surg	imm	surg	Ch 1	surg
	OVA	surg	Ch 7	Ch 8	Ch 9
	MM	surg	Ch 10
150 mg/m^2/day 30 min infusion	MM	surg	surg	surg	imm	radio	Ch 1
	MM	surg	surg	imm	Ch 1	imm
	OVA	3 surg	Ch 4	Ch 9	Ch 11
175 mg/m^2/day 30 min infusion	MM	surg	surg	surg	surg	surg	imm	Ch 1
	MM	surg	Ch 1	imm
	NSCLC	Ch 12	Ch 13	Ch 6
	OVA	surg	Ch 4	Ch 11	Ch 4	Ch 14
	OVA	Ch 4	Ch 11
	NSCLC	Ch 12	radio	Ch 13	radio
200 mg/m^2/day 30 min infusion	NSCLC	Ch 15	Ch 13	Ch 16
	MM	Ch 1	Ch 17	Ch 18
	MM	surg	Ch 1	Ch 17	Ch 17	Ch 18
	MM	Ch 19	imm
	NSCLC	Ch 20 + Ch 21
	NSCLC	Ch 12	radio
240 mg/m^2/day 30 min infusion	MM	Ch 1
	MM	surg	surg	surg	Ch 19	imm	Ch 18
	MM	surg	surg	Ch 19	imm
	MM	imm
	OVA	Ch 4	Ch 11
	OVA	Ch 4	Ch 11
240 mg/m^2/day 2 hr infusion	MM	surg	Ch 1
	MM	surg	surg	surg	surg	surg	surg	rad.	surg	Ch 1	Ch 18
	NSCLC	surg	Ch 6	rad	rad	Ch 22
	OVA	surg	Ch 23	Ch 4	Ch 11	rad	Ch 14

surg = surgery; imm = immunotherapy; rad = radiotherapy, Ch = chemotherapy.

Ch 1, DTIC – Dacarbacin; Ch 2, Paclitaxel (Taxol) + Temozolomide (Temodal); Ch 3, Adriamycin (Docorubicin) + Cyclopgosphamide; Ch 4 Carboplatin + Paclitaxel (Taxol); Ch 5, ISIS 3521 (clinical study); Ch 6, Gemcitabine; Ch 7, PSC 833 (clinical study); Ch 8, BMS-18844 (clinical study); Ch 9, Carboplatin; Ch 10, Vindesine + Dacarbacin (DTIC); Ch 11, Caelyx (Doxorubicin); Ch 12, Cisplatin + Navelbine (vinorelbine); Ch 13, Docetaxel (Taxotere); Ch 14, Topotecan; Ch 15, PV-Cisplatin + Vepesid; Ch 16, MOC-31-PE (clinical study); Ch 17, Velbe (Vinblastine); Ch 18, Lomustine; Ch 19, Temozolomide (Temodal); Ch 20; Cisplatin + Gemcitabine; Ch 21, LY900003 (clinical study); Ch 22, Navelbine (vinorelbine); Ch 23, Treosulfan.

Table III.  Number of adverse events with > 10 occurrences and their CTC grade, whether the AEs were related to study treatment or not.

Event	CTC grade	Total number of events	Total of related events
Nausea	Grade 1–2	76	70
	Grade 3–4	2	2
Fatigue	Grade 1–2	36	32
	Grade 3–4	4	3
Vomiting	Grade 1–2	37	33
	Grade 3–4	1	1
Neutropenia	Grade 1–2	3	3
	Grade 3–4	24	24
Anorexia	Grade 1–2	26	22
	Grade 3–4	1	1
Pyrexia	Grade 1–2	26	22
	Grade 3–4	1	0
Anemia	Grade 1–2	7	6
	Grade 3–4	7	7
Headache	Grade 1–2	14	9
	Grade 3–4	0	0
Constipation	Grade 1–2	11	4
	Grade 3–4	1	0
Thrombocytopenia	Grade 1–2	12	0
	Grade 3–4	3	3
All Events	Grade 1–2	244	201
	Grade 3–4	44	42
Grand Total		288	243

Table IV.  Mean (SD) PK parameters for CP-4055, ara-C and ara-U for all dose levels on Day 1.

	CP-4055 infusion dose (mg/m^2) 30 min							2 hr
	30 (n = 3)	60 (n = 3)	100 (n = 3)	150 (n = 3)	175 (n = 6)	200 (n = 6)	240 (n = 3)	240 (n = 3)
CP-4055
Cmax (µM)	6.6±0.9	9.9±6.5	22.0±6.6	39.5±13.6	53.6±15.4	64.0±13.7	80.9±4.1	30.9±11.8
AUC0-∞ (hr*µM)	4.2±0.9	6.7±3.7	14.2±6.6	30.2±12.4	36.4±11.5	45.9±11.8	57.0±2.8	65.1±27.0
CL (L/hr/m2)	14.6±2.9	24.5±19.4	15.8±6.6	11.5±6.1	10.4±3.8	9.2±3.0	8.4±0.4	9.9±4.4
t1/2*(hr)	0.26±0.01	0.37±0.12	0.28±0.02	0.35±0.05	0.40±0.02	0.40±0.01	0.37±0.01	0.48±0.02
Vss (L/m^2)	6.6±0.9	24.4±24.0	6.3±2.7	10.6 ±11.2	4.7 ±1.2	4.4±0.9	3.9±0.2	7.1±1.75
ara-C
Cmax (µM)	0.18±0.02	0.67±0.41	3.12±1.97	1.85±0.73	2.06±1.21	2.61±0.65	1.99±0.14	1.79±0.85
AUC0-∞ (hr*µM)	0.22±0.01	0.80±0.23	1.78±0.57	2.57±0.71	2.05±0.62	3.03±0.89	3.01±0.55	3.72±1.71
t1/2*(hr)	0.53±0.05	0.63±0.43	0.38±0.08	0.53±0.10	0.60±0.18	0.62±0.07	0.64±0.02	0.74±0.24
ara-U
Cmax (µM)	1.7±0.2	3.9±0.7	6.6±1.0	13.8±4.7	11.2±2.8	12.8±2.0	13.0±0.9	14.7±1.7
AUC0–∞ (hr*µM)	15.5±3.0	41.1±1.3	7.0±19.4	145.4±64.4	107.5±24.0	122.9±49.4	136.8±13.5	184.3±10.2
t1/2*(hr)	5.79±1.08	6.79±1.46	6.85±1.01	8.38±3.85	6.89±1.72	5.69±1.40	6.19±0.4	7.75±1.44

*harmonic mean for t_1/2.

Figure 1.  Concentrations of CP-4055 (♦), ara-C (▪) and ara-U (•) after a 30 min (—) and 2 hr (---) infusion of CP-4055 at dose level 240 mg/m².

Table V.  Occurrence and duration of partial response and stable disease by tumour type and CP-4055 dose.

Dose mg/m^2	Number of cycles	Duration of Partial Response and Stable Disease	Time to progression
Malignant melanoma (8/19) 42%
240	2	17 months	22 months
240	4	8 weeks	16 weeks
240*	4	8 weeks	16 weeks
200	2	8 weeks	8 weeks
175	6	16 weeks	20 weeks
175	3	8 weeks	11 weeks
60	4	14 weeks	14 weeks
30	4	8 weeks	14 weeks
Non-small cell lung cancer (3/7) 43%
240	4	10 weeks	21 weeks
200	4	11 weeks	18 weeks
60	8	33 weeks	13 months
Ovarian cancer (2/8) 25%
240	2	9 weeks	19 weeks
60	3	11 weeks	17 weeks

*2 hr infusion.