A comprehensive analysis of liver safety across zibotentan oncology trials: knowledge of the past offers new perspectives on the present

Figures & data

Table 1. Study design, demographics, baseline characteristics, and exposure for the six oncology clinical trials included in the analysis.

Study ID	Study description	Total patients treated in clinical trial	Total patients in this analysis	Mean age, years/sex split	Age group, two most frequently occurring (%)	Race, two most frequently occurring (%)	Liver-related eligibility criteria
Castration-resistant prostate cancer
D4320C00006	A phase 2, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to assess the efficacy and safety of once-daily orally administered ZD4054 15 mg and 10 mg doses in pain-free or mildly symptomatic patients with prostate cancer and bone metastases who have rising serum prostate-specific antigen levels, despite medical or surgical castration	Zibo 10 mg: 107 Zibo 15 mg: 98 Placebo: 107	Zibo 10 mg: 99 Zibo 15 mg: 88 Placebo: 101	70/100% male	Zibo: ≥65 – ≤80: 60·4% ≥50 – <65: 31·0% Placebo: ≥65 – ≤80: 56·4% ≥50 – <65: 25·7%	Zibo: White: 98·4% Black or African American: 0·5% Asian: 0·5% Placebo: White: 99·0% Asian: 1·0%	Liver metastases were not excluded. Exclusions were: TBILI > 1·5× ULN; ALT or AST > 1·5× ULN
D4320C00014	A phase 3, randomized, double-blind study to assess the efficacy and safety of 10 mg ZD4054 versus placebo in patients with hormone-resistant prostate cancer and bone metastasis who are pain-free or mildly symptomatic	Zibo 10 mg: 298 placebo: 295	Zibo: 256 placebo: 261	71/100% male	Zibo: ≥65 – ≤80: 68·8% ≥50 – <65: 19·9% Placebo: ≥65 – ≤80: 64·4% ≥50 – <65: 21·5%	Zibo: White: 71·1% Asian: 26·2% Placebo: White: 71·3% Asian: 26·1%	Liver metastases were not excluded. Excluded: serum bilirubin TBILI > 1·5× ULN (except for patients with Gilbert’s syndrome); ALT or AST > 2·5× ULN, or > 5× ULN in the presence of liver metastasis
D4320C00015	A phase 3, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of once-daily orally administered ZD4054 10 mg in non-metastatic hormone-resistant prostate cancer patients	Zibo 10 mg: 703 placebo: 712	Zibo: 503 placebo: 519	73/100% male	Zibo: ≥65 – ≤80: 69·6% ≥50 – <65: 15·3% Placebo: ≥65 – ≤80: 70·1% >80: 16·0%	Zibo: White: 80·5% Asian: 14·5% Placebo: White: 78·4% Asian: 15·0%	No liver or other metastatic disease permitted. Excluded: TBILI > 1·5× ULN (except for Gilbert’s syndrome); ALT or AST > 2·5× ULN
D4320C00033	A phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 10 mg ZD4054 in combination with docetaxel in comparison with docetaxel in patients with metastatic hormone-resistant prostate cancer	Zibo 10 mg + Docetaxel: 523 placebo + Docetaxel: 525	Zibo: 502 placebo: 511	68/100% male	Zibo: ≥65 – ≤80: 62·7% ≥50 – <65: 30·5% Placebo: ≥65 – ≤80: 63·2% ≥50 – <65: 30·7	Zibo: White: 75·5% Asian: 13·9% Placebo: White: 73·8% Asian: 14·1%	Liver metastases were not excluded. Excluded: TBILI > 1·5× ULN (except for patients with Gilbert’s syndrome); ALT or AST > 2·5× ULN, or > 5× ULN in the presence of liver metastasis
Non-small cell lung cancer
D4320C00035	A phase 2, double-blind, placebo-controlled, randomized study to assess the efficacy and safety of ZD4054 in combination with pemetrexed (Alimta®) versus pemetrexed alone in patients with non-small cell lung cancer who have failed one prior platinum-based chemotherapy regimen	Zibo 10 mg + pemetrexed: 30 pemetrexed: 36	Zibo: 29 placebo: 36	57/71% male, 29% female	Zibo: ≥50 – <65: 55·2% ≥65 – ≤80: 27·6% Placebo: ≥50 – <65: 50·0% ≥65 – ≤80: 27·8%	Zibo: White: 100·0% Placebo: White: 100·0%	Excluded: TBILI > 1·5× ULN (except for patients with Gilbert’s syndrome); ALT or AST > 2·5× ULN, or > 5× ULN in the presence of liver metastasis; ALP > 3× ULN, or > 5× ULN in the presence of liver metastases
Ovarian cancer
D4320C00036	A phase 2, double-blind, placebo-controlled, multicenter, randomized study of ZD4054 plus carboplatin and paclitaxel or placebo plus carboplatin and paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy	Zibo 10 mg + C/P: 58 placebo + C/P: 58	Zibo: 55 placebo: 58	57/100% female	Zibo: ≥50 – <65: 40·0% ≥65 – ≤80: 30·9% Placebo: ≥50 – <65: 50·0% ≥30 – <50: 25·9%	Zibo: White: 98·2% Black or African American: 1·8% Placebo: White: 100·0%	Excluded: TBILI ≥ 2× ULN; ALT, AST, or ALP ≥ 2·5× ULN, or ≥ 5× ULN if considered related to liver metastases

Studies were grouped for pooled analysis according to the following.

Zibotentan monotherapy (data from studies D4320C00006, D4320C00014, and D4320C00015): Patients with agreement for data reuse treated with zibotentan ≥10 mg monotherapy (includes patients treated with either 10 mg or 15 mg monotherapy). Comparator group was patients with agreement for data reuse receiving placebo monotherapy from the same trials.

Zibotentan with chemotherapy (data from studies D4320C00033, D4320C00035, and D4320C00036): Patients with agreement for data reuse treated with zibotentan 10 mg with chemotherapy (either docetaxel alone, pemetrexed alone, or carboplatin plus paclitaxel combination). Comparator group was patients with agreement for data reuse treated with placebo plus chemotherapy (either docetaxel alone, pemetrexed alone, or carboplatin plus paclitaxel combination) from the same trials.

All zibotentan-treated patients (data from studies D4320C00006, D4320C00014, D4320C00015, D4320C00033, D4320C00035, and D4320C00036): Patients with agreement for data reuse treated with zibotentan across any of the 6 trials (either with or without chemotherapy). Comparator group was patients with agreement for data reuse receiving placebo across any of the 6 trials (either with or without chemotherapy).

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C/P, carboplatin and paclitaxel; Doce, docetaxel; SD, standard deviation; TBILI, total bilirubin; ULN, upper limit of normal; Zibo, zibotentan; ZD4054, zibotentan.

Table 2. Number of patients with any liver-related adverse event by preferred term, occurring in more than one patient per pooled treatment group.

Preferred term	Zibo 10 mg +15 mg (N = 947)	Placebo (N = 881)	Zibo 10 mg + Chemo^a (N = 585)	Placebo + Chemo^a (N = 605)
Patients with any drug-related hepatic disorders	22 (2·3)	30 (3·4)	32 (5·5)	53 (8·8)
Ascites	4 (0·4)	0	2 (0·3)	9 (1·5)
Hepatic cirrhosis	0	1 (0.1)	0	2 (0·3)
Hepatic function abnormal	8 (0·8)	7 (0·8)	0	1 (0·2)
Hepatomegaly	1 (0·1)	0	1 (0·2)	3 (0·5)
Hepatic steatosis	1 (0·1)	2 (0·2)	0	2 (0·3)
Hypertransaminasemia	0	1 (0·1)	2 (0·3)	5 (0·8)
Jaundice	2 (0·2)	0	1 (0·2)	0
Alanine aminotransferase increased	2 (0·2)	1 (0·1)	9 (1·5)	13 (2·1)
Aspartate aminotransferase increased	3 (0·3)	2 (0·2)	10 (1·7)	9 (1·5)
Blood alkaline phosphatase increased	2 (0·2)	5 (0·6)	7 (1·2)	7 (1·2)
Hepatic enzyme increased	0	1 (0·1)	1 (0·2)	2 (0·3)
Gamma-glutamyl transferase increased	0	3 (0·3)	2 (0·3)	2 (0·3)
Transaminases increased	0	4 (0·5)	2 (0·3)	1 (0·2)
Hypoalbuminemia	2 (0·2)	1 (0·1)	6 (1·0)	3 (0·5)
Any ‘drug-related hepatic disorders’ PT leading to treatment interruption or discontinuation	2 (0·2)	3 (0·3)	4 (0·7)	5 (0·8)

Data are presented as n (%).

^aChemotherapy includes docetaxel, pemetrexed, or carboplatin plus paclitaxel.

AE, adverse event; Chemo, chemotherapy; Zibo, zibotentan.

Table 3. Liver biochemistry parameters and risk difference on treatment.

Parameter	Zibo ≥10 mg (N = 947)^,a n (%)	Placebo (N = 881), n (%)	Risk difference, % (95% CI)	Zibo 10 mg + Chemo (N = 585)^,b n (%)	Placebo + Chemo (N = 605)^,b n (%)	Risk difference, % (95% CI)
ALT, high (U/L)
>3·0× ULN	13 (1·4)	15 (1·7)	−0·33 (−1·46 to 0·80)	30 (5·1)	42 (6·9)	−1·81 (−4·52 to 0·89)
>5·0× ULN	4 (0·4)	8 (0·9)	−0·49 (−1·24 to 0·26)	15 (2·6)	15 (2·5)	0·08 (−1·70 to 1·87)
>10·0× ULN	0	4 (0·5)	−0·45 (−0·90 to −0·01)	3 (0·5)	4 (0·7)	−0·15 (−1·02 to 0·72)
>20·0× ULN	0	1 (0·1)	−0·11 (−0·34 to 0·11)	0	1 (0·2)	−0·17 (−0·49 to 0·16)
AST, high (U/L)
>3·0× ULN	21 (2·2)	17 (1·9)	0·29 (−1·02 to 1·59)	32 (5·5)	45 (7·4)	−1·97 (−4·75 to 0·82)
>5·0× ULN	6 (0·6)	4 (0·5)	0·18 (−0·49 to 0·85)	10 (1·7)	14 (2·3)	−0·60 (−2·20 to 0·99)
>10·0× ULN	2 (0·2)	1 (0·1)	0·10 (−0·27 to 0·47)	5 (0·9)	3 (0·5)	0·36 (−0·57 to 1·29)
>20·0× ULN	0	0		0	2 (0·3)	−0·33 (−0·79 to 0·13)
ALP, high (U/L)
>1·5× ULN	265 (28·0)	286 (32·5)	−4·48 (−8·69 to −0·27)	262 (44·8)	313 (51·7)	−6·95 (−12·61 to −1·28)
>2·0× ULN	209 (22·1)	225 (25·5)	−3·47 (−7·38 to 0·44)	201 (34·4)	251 (41·5)	−7·13 (−12·63 to −1·63)
>3·0× ULN	128 (13·5)	147 (16·7)	−3·17 (−6·46 to 0·12)	130 (22·2)	177 (29·3)	−7·03 (−11·98 to −2·09)
>5·0× ULN	68 (7·2)	82 (9·3)	−2·13 (−4·65 to 0·40)	71 (12·1)	91 (15·0)	−2·90 (−6·79 to 0·98)
Bilirubin (total), high (mg/dL)
>1·5× ULN	9 (1·0)	4 (0·5)	0·50 (−0·26 to 1·26)	6 (1·0)	9 (1·5)	−0·46 (−1·73 to 0·80)
>2·0× ULN	5 (0·5)	1 (0·1)	0·41 (−0·10 to 0·93)	3 (0·5)	5 (0·8)	−0·31 (−1·24 to 0·61)
>3·0× ULN	4 (0·4)	1 (0·1)	0·31 (−0·16 to 0·78)	2 (0·3)	1 (0·2)	0·18 (−0·40 to 0·75)
>5·0× ULN	3 (0·3)	1 (0·1)	0·20 (−0·22 to 0·62)	1 (0·2)	0	0·17 (−0·16 to 0·51)

^aThis group included all patients who received Zibo 10 mg or Zibo 15 mg per day. ^bChemotherapy included docetaxel, pemetrexed, or carboplatin plus paclitaxel. Patients with one or more liver biochemistry analyte value exceeding specified levels in the same category are counted only once in that category. Patients who fall into more than one category are counted once in each of those categories.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chemo, chemotherapy; CI, confidence interval; ULN, upper limit of normal; Zibo, zibotentan.

Figure 1. Mean liver biochemistry data change from baseline in (a) Alanine aminotransferase, (b) Aspartate aminotransferase, (c) Alkaline phosphatase, and (d) total bilirubin over time.

Figure shows mean change from baseline in absolute units (units per liter for alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; µmol/L for bilirubin). The error bars show the 95% confidence intervals. Zibotentan-treated group includes all patients treated with zibotentan 10 mg monotherapy or 15 mg monotherapy per day, or zibotentan 10 mg per day plus chemotherapy. Placebo-treated group includes all patients who received placebo or placebo plus chemotherapy. Chemotherapy includes docetaxel, pemetrexed, or carboplatin plus paclitaxel. Results are provided from baseline until <5% of the pooled population remains in study to avoid presentation of noise in data due to a very small number of patients remaining in the trial.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; PBO, placebo; TBILI, total bilirubin; U/L, units per liter; Zibo, zibotentan.

Table 4. Narratives of the seven zibotentan cases with alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal and total bilirubin ≥2× upper limit of normal.

Patient number	Treatment group	Sex/Age^a	Case assessment narrative
1	Zibo 10 mg	M/61	This 61-year-old male patient with CRPC and metastatic disease, with normal baseline ALT and ALP, experienced a cholestatic pattern of liver injury (R = 0·45), with a 12-fold increase in ALP from baseline, at day 273 of study. A non-serious AE of jaundice unrelated to study drug was reported at day 266, and study drug was continued. Treatment was discontinued on day 294 due to death. The cholestatic nature of the liver injury in the period shortly before death suggests disease progression.
2	Zibo 10 mg	M/68	This 68-year-old male patient with CRPC and metastatic disease, with normal baseline ALT, and ALP 5× ULN at baseline, experienced a cholestatic pattern of liver injury on day 27 (R = 0·23, with a > 2-fold increase in ALP from baseline), with nonspecific symptoms (vomiting, hyporexia and peripheral edema) considered unrelated to study drug. Peak ALT was 3× ULN. The patient was lost to follow up. However, the rapid increase in ALP from baseline, the nonspecific symptoms considered unrelated to study drug and the modest increase in ALT suggest a cause of bilirubin elevation other than from hepatocellular injury. However, given the lack of information due to the patient being lost to follow-up, there are insufficient data to assess the possibility of DILI.
3	Zibo 10 mg	M/77	This 77-year-old male patient with CRPC and metastatic disease, with normal baseline ALT and ALP at 1× ULN, experienced a cholestatic pattern of liver injury at day 59 (R = 0·43, with a 9-fold increase in ALP from baseline), with a modest peak ALT of 4× ULN. No AEs were reported and study treatment was discontinued due to disease progression. This history, and the cholestatic pattern of injury, suggest liver test abnormalities relating to disease progression.
4	Zibo 10 mg	M/80	This 80-year-old male patient without metastatic disease experienced raised ALT and bilirubin on day 332, where a concurrent serious AE of bile duct stone was reported. Liver test abnormalities resolved within 30 days on continued study drug. The liver test abnormality is most likely explained by the bile duct stone.
5	Zibo 10 mg + Chemo	M/65	This 65-year-old male patient with CRPC and metastatic disease had a baseline ALT of 2·7× ULN, with no liver-related medical history reported. Peak ALT was reported as 14× ULN on study day 29 (a 5-fold change from baseline), with ALT increased and AST increased reported as non-serious adverse events and unrelated to study drug, with study drug continued, and continued ALT fluctuation on study. Bilirubin elevation first occurred at day 148 and peaked at day 169 at 3× ULN, at which point the ALT was 4·4× ULN and the ALP was 1·9× ULN (R = 2·3); no AEs were reported at this time. Study treatment was discontinued at day 195 due to death. Although the underlying hepatic diagnosis is not clear, it appears there is a preexisting liver pathology leading to elevated baseline liver tests and fluctuating ALT and AST values on study, with bilirubin and ALP elevation occurring within a month of death, suggesting cholestatic injury associated with disease progression.
6	Zibo 10 mg + Chemo	M/61	This 61-year-old male patient with CRPC and metastatic disease experienced a cholestatic pattern of liver injury (R = 0·94) and a 2·3-fold change in ALP from baseline at day 83, with no AEs reported at the time, with study drug discontinued at day 86 due to death. The cholestatic nature of the liver injury shortly before death would be consistent with disease progression.
7	Zibo 10 mg + Chemo	M/50	This 50-year-old male patient with CRPC and metastatic disease experienced a cholestatic pattern of liver injury (R = 0·75, with a 2·5-fold change from baseline in ALP, on day 244, with no liver-related AEs reported at the time of the event. Study treatment had already been discontinued due to disease progression reported at day 234. Review of concomitant medications shows a single dose of cefotaxime given for an ERCP (endoscopic retrograde cholangial pancreatography) procedure on study day 230, suggesting extrahepatic biliary obstruction, though no further information is reported. This suggests that the cholestatic liver injury likely related to extrahepatic obstruction and disease progression.

^aAge at study entry.

AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chemo, chemotherapy; CRPC, castration-resistant prostate cancer; DILI, drug-induced liver injury; ERCP, endoscopic retrograde cholangiopancreatography; ULN, upper limit of normal; Zibo, zibotentan.