Phase I Open-Label Study of Continuous Treatment with BIBF 1120, a Triple Angiokinase Inhibitor, and Pemetrexed in Pretreated Non–Small Cell Lung Cancer Patients

Peter M. Ellis; Rolf Kaiser; Yihua Zhao; Peter Stopfer; Steve Gyorffy; Nasser Hanna

doi:10.1158/1078-0432.CCR-09-2944

DOI: 10.1158/1078-0432.CCR-09-2944 Published May 2010

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Fig. 1.
gMean drug plasma concentration-time profiles of BIBF 1120 after multiple oral administrations of 100 mg, 150 mg, and 200 mg bid BIBF 1120 for TCs 1 to 3, with only a single dose of BIBF 1120 administered on day 2 of TC 2.
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Fig. 2.
Individual and gMean drug plasma concentration-time profiles of pemetrexed after a single dose of 500 mg/m² i.v. to MTD patients on day 1 of TC 2 (semi-log scale).

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Table 1.

Patient demographics and clinical characteristics

	100 mg bid BIBF 1120 plus 500 mg/m² pemetrexed	150 mg bid BIBF 1120 plus 500 mg/m² pemetrexed	200 mg bid BIBF 1120 plus 500 mg/m² pemetrexed	250 mg bid BIBF 1120 plus 500 mg/m² pemetrexed	Total
Patients treated	6 (100.0)	6 (100.0)	12 (100.0)	2 (100.0)	26 (100.0)
Gender
Male	2 (33.3)	4 (66.7)	7 (58.3)	0	13 (50.0)
Female	4 (66.7)	2 (33.3)	5 (41.7)	2 (100.0)	13 (50.0)
Race
White	6 (100.0)	6 (100.0)	12 (100.0)	2 (100.0)	26 (100.0)
Age (y)
Mean	60.5	65.0	60.1	75.0	62.5
Weight (kg)
Mean	69.7	81.8	81.0	72.4	77.9
Smoking history
Never smoker	3 (50.0)	0	0	1 (50.0)	4 (15.4)
Ex-smoker	2 (33.3)	4 (66.7)	6 (50.0)	1 (50.0)	13 (50.0)
Current smoker	1 (16.7)	2 (33.3)	6 (50.0)	0	9 (34.6)
Baseline ECOG
0	4 (66.7)	3 (50.0)	2 (16.7)	1 (50.0)	10 (38.5)
1	2 (33.3)	3 (50.0)	10 (83.3)	1 (50.0)	16 (61.5)
Tumor histology
Adenocarcinoma	3 (50.0)	1 (16.7)	2 (16.7)	1 (50.0)	7 (26.9)
Large cell	0	0	1 (8.3)	0	1 (3.8)
Squamous cell	0	1 (16.7)	2 (16.7)	0	3 (11.5)
Adenosquamous	0	0	0	1 (50.0)	1 (3.8)
NSCLC (not specified)	3 (50.0)	4 (66.7)	7 (58.3)	0	14 (53.8)
Clinical stage at screening
IIIB	1 (16.7)	2 (33.3)	1 (8.3)	1 (50.0)	5 (19.2)
IV	5 (83.3)	4 (66.7)	11 (91.7)	1 (50.0)	21 (80.8)
Prior chemotherapy regimens
1	4 (66.7)	5 (83.3)	11 (91.7)	2 (100.0)	22 (84.6)
2	1 (16.7)	1 (16.7)	1 (8.3)	0	3 (11.5)
≥3	1 (16.7)	0	0	0	1 (3.8)

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Table 2.

Frequency of patients with drug-related adverse events (≥10%) across all dose groups

	All CTCAE grades, n (%)	CTCAE grade 3,^*n (%)
Fatigue	17 (65.4)	6 (23.1)
Nausea	16 (61.5)	1 (3.8)
Anorexia	14 (53.8)	2 (7.7)
Rash	10 (38.5)	0
Diarrhea	9 (34.6)	1 (3.8)
Vomiting	9 (34.6)	1 (3.8)
ALT increases	7 (26.9)	3 (11.5)
Abdominal pain	6 (23.1)	2 (7.7)
Dysgeusia	6 (23.1)	0
Pruritus	6 (23.1)	0
Insomnia	5 (19.2)	1 (3.8)
AST increases	5 (19.2)	0
Dyspepsia	4 (15.4)	0
Headache	4 (15.4)	0
Constipation	3 (11.5)	0
Stomatitis	3 (11.5)	0
Chills	3 (11.5)	0
Dermatitis acneiform	3 (11.5)	0

NOTE: Data presented are the highest ever reached CTCAE grade. One patient may have experienced more than one event.

↵*No grade 4 adverse events were observed.

Table 3.

Frequency of patients with bleeding events

	Below MTD (n = 12)	At MTD (n = 12)	Above MTD (n = 2)	Total (n = 26)
Patients with any bleeding events^* [n (%)]	7 (58.3)	3 (25.0)	1 (50.0)	11 (42.3)
CTCAE grade of most intense bleeding event [n (%)]
CTCAE grade 1	6 (50.0)	2 (16.7)	1 (50.0)	9 (34.6)
CTCAE grade 2	1 (8.3)	1 (8.3)	0 (0.0)	2 (7.7)
Patients with drug-related bleeding event [n (%)]	4 (33.3)	0 (0.0)	0 (0.0)	4 (15.4)
Patients with any bleeding event determined to be DLT [n (%)]	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)

↵*Bleeding events include the MedDRA PT of “epistaxis,” “hematuria,” “hemoptysis,” and “rectal hemorrhage.”

Table 4.

BIBF 1120 and pemetrexed PK parameters

A
BIBF 1120 day 2, TC 2	200 mg bid (n = 8)
BIBF 1120 day 2, TC 2	gMean	gCV (%)
AUC_0-24 (ng h/mL)	308^*	43.9^*
C_max (ng/mL)	50.4	81.2
t_max^† (h)	2.00	1.00-23.8
t_1/2 (h)	12.1^*	43.4^*
CL/F (mL/min)	8,180^*	33.5^*
V_z/F (L)	8,580^*	56.0^*

B
Pemetrexed day 1, TC 2 (MTD)	TC 2 (n = 8)
Pemetrexed day 1, TC 2 (MTD)	gMean	gCV (%)
AUC_0-24 (μg h/mL)	200^‡	17.1^‡
C_max (μg/mL)	98.0	21.8
t_max^† (h)	0.275	0.0160-0.500
t_1/2 (h)	3.71^‡	31.6^‡
CL (L/h)	4.78^‡	24.2^‡
V_z (liter)	25.6^‡	31.1^‡
V_ss (liter)	15.4^‡	18.9^‡

NOTE: A, comparison of BIBF 1120 PK parameters for the 200 mg bid BIBF 1120 dose group (MTD). B, PK parameters (gMean and gCV%) of pemetrexed after administration of 500 mg/m² pemetrexed over 8 to 15 min on day 1 (TC 2) after continuous treatment of 200 mg bid BIBF 1120 (days 2-21 of TC 1).