Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine – a Phase I trial

Figures & data

Figure 1 Consort diagram.

Abbreviations: DLT, dose-limiting toxicity; ITT, intention-to-treat population; MTD, maximum tolerated dose population; RD, recommended dose population; RESP, response population; SAF, safety population.

Table 1 Demographic data and disease characteristics

Characteristics	ITT/SAF (n=27)	RESP (n=21)	MTD (n=17)	RD (n=7)
Gender
Male	15 (55.6%)	11 (52.4%)	10 (58.8%)	2 (28.6%)
Female	12 (44.4%)	10 (47.6%)	7 (41.2%)	5 (71.4%)
Age (years)
Mean ± StD (median)	65±8 (65)	63±8 (64)	64±8 (64)	68±8 (69)
Body surface area (m^2)
Mean ± StD (median)	1.9±0.3 (1.9)	1.9±0.3 (1.9)	1.8±0.2 (1.9)	1.8±0.2 (1.7)
Karnofsky index
70%	6 (22.2%)	3 (14.3%)	2 (11.8%)	3 (42.9%)
80%	11 (40.7%)	9 (42.9%)	8 (47.1%)	2 (28.6%)
90%	7 (25.9%)	6 (28.6%)	5 (29.4%)	1 (14.3%)
100%	3 (11.1%)	3 (14.3%)	2 (11.8%)	1 (14.3%)
Smoking status
Never	6 (22.2%)	5 (23.8%)	5 (29.4%)	1 (14.3%)
Former	8 (29.6%)	6 (28.6%)	4 (23.5%)	2 (28.6%)
Current	7 (25.9%)	7 (33.3%)	5 (29.4%)	2 (28.6%)
Missing information	6 (22.2%)	3 (14.3%)	3 (17.6%)	2 (28.6%)
Histology
Squamous cell carcinoma	12 (44.4%)	11 (52.4%)	10 (58.8%)	1 (14.3%)
Adeno carcinoma	13 (48.1%)	9 (42.9%)	6 (35.3%)	6 (85.7%)
Adeno (bronchoalveolar)	2 (7.4%)	1 (4.8%)	1 (5.9%)	0
Tumor stage at study entry
IIIBa	6 (22.2%)	6 (28.6%)	6 (35.3%)	0
IV	21 (77.8%)	15 (71.4%)	11 (64.7%)	7 (100%)
Previous surgery for primary tumor	3 (11.1%)	2 (9.5%)	2 (11.8%)	1 (14.3%)
Prior chemotherapy	25 (92.6%)	20 (95.2%)	16 (94.1%)	7 (100%)
Neoadjuvant	1 (3.7%)	1 (4.8%)	1 (5.9%)	0
Adjuvant	3 (11.1%)	2 (9.5%)	1 (5.9%)	2 (28.6%)
Curative	4 (14.8%)	4 (19.0%)	3 (17.6%)	0
Palliative	21 (77.8%)	17 (81.0%)	15 (88.2%)	5 (71.4%)
Prior palliative lines, median (range)	3 (0–5)	3 (0–5)	3 (0–5)	2 (1–3)
Prior radiation	14 (51.9%)	11 (52.4%)	9 (52.9%)	4 (57.1%)

Notes: Data were represented as n (% of patients).

a One of the patients had recurrence after local therapy.

Abbreviations: ITT, intention-to-treat population; MTD, maximum tolerated dose population; RD, recommended dose population; RESP, response population; SAF, safety population; StD, standard deviation.

Table 2 Dose escalation – DLTs observed during the dose escalation phase of the trial including toxicities observed at the MTD

Dose level	Number of patients enrolled	Number of patients with DLT	Cycle with DLT	DLT fever	DLT neutropenia	DLT thrombocytopenia	DLT non-hematological
Level I (20 mg/d)	3	0	–	–	–	–	–
Level II (30 mg/d)	3	0		–	–	–	–
Level III (40 mg/d)	3	1	2 (n=1)a	–	1	–	–
Level IV (50 mg/d) = MTD	6	3	1 (n=2), 2 (n=1)	3	1	–	1
Draft RD (40 mg/d)b	2	1	1 (n=1)	1	–	–	–

Notes: Based on these results, the extension phase was initiated with a recommended dose of 30 mg vinorelbine/d and the option to increase to 40 mg/d in individual patients.

a At that time, only cycle 1 was taken into account for DLT assessment; the study design was amended from level IV taking now into account cycles 1 and 2.

b After recruitment of two further patients at this draft RD level, one patient experienced a DLT during cycle 1. Earlier, on the same dose (see level III) another patient had experienced a DLT during cycle 2. As a total of two of five patients had experienced DLTs at 40 mg/d, it was concluded that the final recommended dose level should range between 30 and 40 mg, rather than to follow a strict 40 mg dose.

Abbreviations: d, days; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RD, recommended dose.

Figure 2 Vinorelbine blood concentrations on day 1 and day 21 (cycle 1) after daily dosing of oral vinorelbine.

Abbreviations: d, day; h, hours.

Table 3 AEs potentially related to vinorelbine occurring in at least 10% of the SAF and/or RD population

AE, n (% patients)	SAF (n=27)		RD (n=7)
	Any grade	≥Grade 3	Any grade	≥Grade 3
Any event	20 (74.1%)	11 (40.7%)	3 (42.9%)	2 (28.6%)
Hematological events
Leukopenia	9 (33.3%)	8 (29.6%)	1 (14.3%)	1 (14.3%)
Lymphopenia	6 (22.2%)	5 (18.5%)	1 (14.3%)	1 (14.3%)
Neutropenia	5 (18.5%)	5 (18.5%)	1 (14.3%)	1 (14.3%)
Febrile neutropenia	4 (14.8%)	4 (14.8%)	1 (14.3%)	1 (14.3%)
Non-hematological events
Decreased appetite	9 (33.3%)	0	3 (42.9%)	0
Diarrhea	9 (33.3%)	0	1 (14.3%)	0
Nausea	8 (29.6%)	1 (3.7%)	1 (14.3%)	0
Vomiting	7 (25.9%)	0	2 (28.6%)	0
Fatigue	5 (18.5%)	1 (3.7%)	1 (14.3%)	0
Dizziness	4 (14.8%)	0	0	0
Asthenia	3 (11.1%)	0	1 (14.3%)	0
Constipation	3 (11.1%)	0	0	0
Weight decreased	3 (11.1%)	0	0	0
Colitis	1 (3.7%)	1 (3.7%)	1 (14.3%)	1 (14.3%)
Pneumonia	1 (3.7%)	1 (3.7%)	1 (14.3%)	1 (14.3%)
Sepsis	1 (3.7%)	1 (3.7%)	1 (14.3%)	1 (14.3%)

Abbreviations: AE, adverse event; RD, recommended dose population; SAF, safety population.

Table 4 Efficacy parameters

n (% patients)	ITT/SAF (n=27)	RESP (n=21)	RD (n=7)
Tumor response (RECIST)
CR	0	0	0
PR	0	0	0
SD	4 (14.8%)	4 (19.0%)	1 (14.3%)
PD	17 (63.0%)	17 (81.0%)	3 (42.9%)
Not evaluable	6 (22.2%)	0	3 (42.9%)
ORR (CR + PR)	0	0	0
DCR (CR + PR + SD)	4 (14.8%)	4 (19.0%)	1 (14.3%)
TTP
Patients with events	20 (74.1%)	20 (95.2%)	3 (42.9%)
TTP (median months)a (95% CI)a	1.7 (1.4–2.1)	1.7 (1.4–2.1)	1.3 (0.7–NR)
OS
Patients with events	26 (96.3%)		7 (100%)
OS (median months)a (95% CI)a	5.7 (3.5–9.6)	NA	3.9 (1.8–9.6)

Note:

a Kaplan–Meier analysis.

Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; ITT, intention-to-treat population; NA, not analyzed; NR, not reached; ORR, overall response rate; OS, overall survival; PD, progressive disease; PR, partial response; RD, recommended dose population; RECIST, Response Evaluation Criteria in Solid Tumors; RESP, response population; SAF, safety population; SD, stable disease; TTP, time to progression.