A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

Figures & data

Table 1. Demographics

Characteristic	RT + TMZ + HCQ phase I	RT + TMZ + HCQ phase II	NABTT phase II historical RT + Chemo	EORTC phase III RT + TMZ
	n = 16	n = 76	n = 235	n = 287
Age, y
Median	55	59	55	55
Rage	24–69	20–83	21–82	23–70
Sex, no. (%)
Male	12 (75)	46 (61)	151 (64)	151 (64)
Female	4 (25)	30 (39)	84 (36)	84 (36)
Karnofsky Performance Status, no. (%)
100	5 (31)	15 (20)	33 (18)	113 (39)
90	7 (44)	31 (41)	93 (50)	136 (47)
80	3 (19)	18 (24)	31 (17)
70	1 (6)	10 (13)	21 (11)	38 (13)
60		1 (1.3)	7 (4)
Surgical procedure no. (%)
Biopsy	6 (37)	18 (24)	29 (16)	48 (17)
Craniotomy	10 (63)	58 (76)	156 (84)	239 (83)
Histological diagnosis no. (%)
Glioblastoma	16 (100)	73 (96)	181 (98)	221 (92)
Other		3 (4)	3 (2)	18 (8)

Table 2. Phase II adverse events related to study drug

Toxicity, number of patients (%)	Grade 3	Grade 4	Total
Abdominal pain	1 (1)		1 (1)
Alanine aminotransferase increased	2 (3)		2 (3)
Anemia	6 (8)		6 (8)
Blood bilirubin increased		1 (1)	1 (1)
Constipation		1 (1)	1 (1)
Eye disorders	1 (1)		1 (1)
Fatigue	1 (1)		1 (1)
Hemolysis	1 (1)		1 (1)
Lymphocyte count decreased	6 (8)		6 (8)
Muscle weakness upper limb	1 (1)		1 (1)
Neutrophil count decreased	3 (4)	8 (10)	11 (15)
Platelet count decreased	4 (5)	7 (9)	11 (15)
Pruritus	1 (1)		1 (1)
Rash maculo-papular	9 (12)		9 (12)
White blood cell decreased	7 (9)	4 (5)	11 (15)

Table 3. Overall survival

Age group	Median overall survival, mo (95% CI)	12-mo survival % (95% CI)	18-mo survival % (95% CI)	24-mo survival % (95% CI)
ABTC 0603 radiation + temozolomide + hydroxychloroquine
≥ 18 (n = 76)	15.6 (13–17)	69.7 (58–80)	35.5 (25–47)	25.0 (16–36)
18–70 (n = 63)	16.5 (13–18)	74.6 (62–85)	41.3 (29–54)	30.2 (19–43)
EORTC phase III radiation + temozolomide vs. radiation alone
18–70 (n = 287)	14.6 (13–17)	61.1 (55–67)	39.4 (34–45)	26.5 (21–32)

Figure 1. Pharmacodynamic evidence of autophagy inhibition in patients treated with temozolomide (TMZ), radiation (RT), and hydroxychloroquine (HCQ). (A) Mixed-effects model of mean ± SD autophagic vacuoles (AVs)/cell. Dotted line: regression line. (B) Representative electron micrographs from a patient treated with chemoradiation and HCQ 800 mg/d for 3 wk. Arrows, AV; scale bar: 2 µm. (C) Immunoblotting against LC3 in the lysates of PBMC obtained from the same patient in (B). P, pretreatment; W3, 3 wk of treatment.

Figure 2. Population pharmacokinetic-pharmacodynamic analysis. (A) Individual predicted HCQ whole blood concentrations vs. observed concentrations using a 2-compartment population pharmacokinetic model. (B) Observed HCQ concentrations in whole blood by dose cohort. (C) CART analysis. (D) Median AV change in patients with estimated HCQ C_max above or below 1785 ng/mL.

Table 4. Hydroxychloroquine population pharmacokinetic parameter estimates

Parameter	Model estimate	Bootstrap estimate	CV%	2.5% CI	97.5% CI
tlag (h)	1.06	0.95	38.7	0.04	1.34
Ka (h^−1)	0.49	0.05	54.5	0.43	1.06
V/F (L)	361.28	256.27	60.7	20.34	590.48
V2/F (L)	947.26	1078.94	22.0	640.30	1563.76
CL/F (L/h)	11.44	11.39	3.9	10.54	12.31
Q (L/h)	103.9	192.65	180.5	59.86	802.21
Stdev0	0.205	0.203	8.0	0.171	0.236

t_lag, lag time; Ka, first-order absorption rate constant; V/F, apparent volume of distribution of central compartment; V2/F, apparent volume of distribution of peripheral compartment; Cl/F, apparent oral clearance; Q, intercompartmental clearance; Stdev0, standard deviation; CI, confidence interval; L, liters; h, hours.