The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: VEG109693 Title : A Phase I, Open-Label, Multiple Dose of Pazopanib Alone and in Combination with Lapatinib in Japanese Patients with Solid Tumors - An Interim Report Rationale: Neoplastic growth and metastases are dependent upon angiogenesis occurring in and around the malignant tumor. Vascular endothelial growth factor (VEGF) is one of several proangiogenic molecules believed to play a pivotal role in tumor angiogenesis. VEGF binds to three primary tyrosine kinase receptors on the endothelial cell surface, vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. VEGFR signalling as well as platelet-derived growth factor receptor (PDGFR) signalling is involved in tumor angiogenesis. Pazopanib is an orally active, potent, small molecule tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, and c-kit. Lapatinib is a small molecule inhibitor of ErbB-1 (epidermal growth factor receptor [EGFR]) and ErbB-2 receptor tyrosine kinases. Pre-clinical data support clinical evaluation of a VEGFR inhibitor in combination with an ErbB1/ErbB2 antagonist. This combination of pazopanib and lapatinib has been evaluated in overseas studies. This Phase I study was designed for Japanese subjects with solid tumors to determine if the overseas dose of pazopanib monotherapy was safe and tolerated and to determine the optimally tolerated regimen (OTR) of pazopanib in combination with lapatinib. Phase: I Study Period: 10 Sep. 2007-30 Aug. 2010* (data cut-off date) * This report includes the data on serious adverse events (SAEs) collected up to 29 Oct. 2010 (database freeze date). Study Design: An open-label, non-controlled, multicenter, multiple-dose study Centres: Two medical institutions in Japan Indication: Solid tumor Treatment: This study consisted of two parts: Part A of pazopanib monotherapy and Part B of combination therapy of pazopanib with lapatinib. Both parts were intended for the evaluation of safety, tolerability, and pharmacokinetics (PK). Part A comprised Original Cohort and Additional Cohort, while Part B comprised Dose Escalation Cohort and PK Cohort. Original Cohort of Part A Subjects in the dose group received a single dose of pazopanib (P) at 800 mg on Day 1. Multiple dosing of 800 mg once daily began after completion of PK blood sampling at pre-dose and up to 96 hours post-dose on Day 1; the first day of multiple dosing was defined as Day 2. PK blood samples were collected pre-dose on Day 8 and Day 15, followed by pre-dose and up to 24 hours post-dose on Day 22. A minimum of 6 subjects were enrolled and monitored for dose limiting toxicity (DLT). If no more than 1 of 6 subjects experienced a DLT, 800 mg was settled as the appropriate dose level in Part B. If 2 or more subjects experienced a DLT, a lower dose level of 600 mg was to be explored to define the OTR (the dose at which no more than 1 of 6 subjects experiences a DLT). If no more than 1 of 6 subjects experienced a DLT in the lower dose level, 600 mg was settled as the appropriate dose level in Part B. DLT was defined as follows (severity was evaluated according to Common terminology criteria for adverse events [CTCAE] Version 3.0): Grade 3 or 4 non-hematological toxicity Amylase or lipase without clinical correlates such as abdominal pain was not considered as a DLT. Grade 3 nausea, vomiting, or diarrhea for which adequate supportive therapy had not been instituted was not considered as a DLT. Grade 3 hypertension that was not adequately controlled with addition of up to 2 antihypertensive medications or Grade 4 hypertension was considered as a DLT. Grade 3 hypertension that was adequately controlled by medications may not necessarily represent a DLT. Grade 3 proteinuria in the setting of uncontrolled hypertension and/or renal impairment, Grade 3 proteinuria without improvement to Grade 2 upon interruption of pazopanib in an otherwise asymptomatic subject (without hypertension or renal impairment), or Grade 4 proteinuria (nephrotic syndrome) was considered as a DLT. Grade 3 neutropenia with duration greater than 5 days, Grade 4 neutropenia, or febrile neutropenia Grade 3 or 4 thrombocytopenia Inability to begin next treatment period within 14 days of scheduled dosing due to unresolved toxicity 1
Inability to receive 75% of scheduled doses in a treatment period due to toxicity Greater than or equal to Grade 2 toxicity that occurred beyond 21 days of pazopanib dosing in Part A or 21 days of pazopanib dosing in combination with lapatinib in Part B which, in the judgement of the investigator and medical expert, was considered as a DLT Grade 2 toxicity (e.g. renal, neurological, and cardiovascular) which, in the judgement of the investigator and medical expert, was considered as a DLT. If the investigator's opinion and medical expert's opinion was different, the safety review committee reviewed and determined it. Additional Cohort of Part A Subjects in the P400/800 mg dose group received a single dose of pazopanib at 400 mg on Day 1. Multiple dosing of 800 mg once daily began after completion of PK blood sampling at pre-dose and up to 96 hours post-dose on Day 1; the first day of multiple dosing was defined as Day 2. Subjects in the dose group received a single dose of pazopanib at 1000 mg on Day 1. Multiple dosing of 1000 mg once daily began after completion of PK blood sampling at pre-dose and up to 96 hours post-dose on Day 1; the first day of multiple dosing was defined as Day 2. PK blood samples were collected pre-dose on Day 8 and Day 15, followed by pre-dose and up to 24 hours post-dose on Day 22. A minimum of 3 subjects were enrolled in the P400/800 mg dose group and monitored for safety. On the other hand, a minimum of 3 subjects were enrolled in the dose group and monitored for DLT. If 1 of 3 subjects in the dose group experienced a DLT, an additional 3 subjects were to be enrolled and a total of 6 subjects were to be monitored. If 2 of 3 subjects or 2 or more of 6 subjects experienced a DLT, 1000 mg once daily was to be considered to exceed the maximum tolerated dose (MTD). Dose Escalation Cohort of Part B Following determination of a pazopanib monotherapy dose in Original Cohort of Part A, subjects started to receive lapatinib (L) and pazopanib (P) sequentially once daily on Day 1. PK blood sampling was performed pre-dose and up to 24 hours post-dose on Day 1 and Day 22. PK blood samples were also collected pre-dose on Day 8 and Day 15. A minimum of 3 subjects were enrolled at Dose Level 1 (P400 mg/day + /day) and monitored for DLT with the following definitions: If no DLT was observed, a minimum of 3 subjects were to be enrolled at Dose Level 2. If 1 of 3 subjects experienced a DLT, an additional 3 subjects were to be enrolled at Dose Level 1. If 1 of 6 subjects experienced a DLT, 3 subjects were to be enrolled at Dose Level 2. If 2 of 6 subjects experienced a DLT, 3 subjects were to be enrolled at Dose Level -1 (P400 mg/day + L750 mg/day). If 2 or more of 3 subjects experienced a DLT, 3 subjects were to be enrolled at Dose Level -1. A minimum of 3 subjects each were enrolled at Dose Level 2P (/day [or 600 mg/day if it was settled as an appropriate dose with the result of Original Cohort of Part A] + /day) and 2L (P400 mg/day + L1500 mg/day) and monitored concurrently for DLT. If no DLT was observed both at Dose Level 2P and 2L, 6 subjects were to be enrolled in PK Cohort at Dose Level 3 (P600 mg/day + L1250 mg/day). If 1 of 3 subjects experienced a DLT at either Dose Level 2P or 2L, an additional 3 subjects were to be enrolled at that Dose Level. If 1 of 6 subjects experienced a DLT, 6 subjects were to be enrolled in PK Cohort at Dose Level 3. If 2 or more of 6 subjects experienced a DLT, the MTD was judged to have been achieved and no subjects were to be enrolled in PK Cohort at Dose Level 3. If 2 or more of 3 subjects experienced a DLT at either Dose Level 2P or 2L, the MTD was judged to have been achieved and no subjects were to be enrolled in PK Cohort at Dose Level 3. PK Cohort of Part B If MTD was not achieved at Dose Escalation Cohort, a minimum of 6 subjects were to be enrolled in PK Cohort. Three subjects received 600 mg of pazopanib alone once daily from Day 1 through Day 15 and 3 subjects received 1250 mg of lapatinib alone once daily from Day 1 through Day 15. PK blood sampling was performed pre-dose and up to 24 hours post-dose on Day 15. Subjects received 600 mg of pazopanib in combination with 1250 mg of lapatinib once daily from Day 16. PK blood sampling was performed pre-dose on Day 22 and Day 29, followed by pre-dose and up to 24 hours post-dose on Day 37. A minimum of 3 subjects were enrolled in each of the two groups receiving pazopanib alone or lapatinib alone so that a total of at least 6 subjects (evaluable for DLT) were monitored for DLT. If 2 or more of 6 subjects experienced a DLT, the MTD was judged to have been achieved. 2
DLT observation period was defined as the first 21 days of pazopanib monotherapy for Original Cohort and Additional Cohort of Part A (Day 1 through Day 21) and the first 21 days of combination therapy of pazopanib with lapatinib for Part B (Day 1 through Day 21 in Dose Escalation Cohort, Day 16 through Day 36 in PK Cohort). A subject was considered evaluable if she/he had completed the DLT observation period. A subject was also considered evaluable for DLT if she/he had been withdrawn from study due to toxicity during the DLT observation period. After completion of the DLT observation period, subjects could remain in the study and they visited the medical institution every 3 weeks for the evaluation of safety and efficacy until they met any of the withdrawal criteria. Objectives: Part A (pazopanib monotherapy) To assess the safety and tolerability of oral pazopanib following multiple dosing in cancer subjects To determine if the overseas monotherapy dose of pazopanib (800 mg once daily) is safe in Japanese subjects The tolerability of multiple dosing of pazopanib 800 mg was to be confirmed in Original Cohort. Part B (combination therapy of pazopanib with lapatinib) To assess the safety and tolerability of oral pazopanib when administered in combination with lapatinib following multiple dosing in cancer subjects Statistical Methods: In this study, the summary was made for each treatment groups, but it was not intended for comparison between treatment groups. In Part A, P400/800 mg dose group and dose group were pooled as multiple dose groups (pooled dose group). In Part B at PK Cohort, the effect on PK parameters, area under the plasma drug concentration-time curve from time of dose to 24 hours (AUC [0-24]) and the maximum concentration (Cmax), were compared between combination therapy of pazopanib and lapatinib and either pazopanib monotherapy or lapatinib monotherapy. Safety All subjects (excluding subjects in the P400/800 mg dose group) who completed the DLT observation period or were withdrawn from study due to toxicity during the DLT observation period were included in the DLT Population, which was used for DLT analyses. All subjects who received at least one dose of pazopanib or lapatinib were included in the Safety Population, which was used for analyses of safety. Subjects experiencing a DLT were summarized. All adverse events (AEs) and treatment-related AEs were summarized to show the number and proportion of subjects reporting AEs in each treatment group. Deaths and other SAEs were summarized. Efficacy All subjects for whom valid efficacy parameter could be estimated were included in the Efficacy Population. Also subjects who had no changes of measurable disease or those who had only non-measurable diseases were included in the Efficacy Population and in the denominator for the calculation of response rate. Clinical activity and disease status were assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines. The number and proportion of subjects with each of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were summarized by treatment group. Pharmacokinetics All subjects for whom a PK sample was obtained and analyzed were included in the PK Concentration Population. All subjects for whom sufficient data were available to calculate the derived valid PK parameters were included in the PK Parameter Population. In addition to these populations, PK Concentration Population 2 and PK Parameter Population 2 were defined. These populations excluded a subject from original PK populations respectively, because the subject experienced a dose interruption due to an AE, and then received a reduced dose at PK sampling. These populations were used for PK analyses. Plasma concentration data were analyzed using a conventional non-compartment model to calculate PK parameter values for individual subjects. These PK parameter values were summarized by treatment group. Study Population: Male or female subjects aged 20 years with histologically or cytologically confirmed diagnosis of advanced solid tumor who had failed therapy or for whom there was no standard therapy (Note: those with uterocervical cancer were excluded from Part B), Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow reserve and hepato-renal function were enrolled in this study. Subjects with any of central nervous system metastases or leptomeningeal carcinomatosis, clinically significant gastrointestinal abnormalities, uncontrolled infection, prolongation of corrected QT interval (QTc) >480 msec, history of cardiovascular conditions including cardiac angioplasty or stenting, or poorly controlled hypertension were excluded from this study. 3
Number of Subjects: Part A Pooled P400/800 mg Planned, N 3 6-12 9-15 3-6 Dosed, N 3 7 10 3 Total Number Subjects Who 2 (67) 7 (100) 9 (90) 3 (100) Discontinued the Investigational Products, n (%) Discontinued due to AEs, n (%) 1 (33) 2 (29) 3 (30) 0 Discontinued due to Disease 1 (33) 5 (71) 6 (60) 3 (100) Progression, n (%) Discontinued for Other 0 0 0 0 Reasons, n (%) Continuing treatment at data 1 (33) 0 1 (10) 0 cut-off, n (%) Part B + L1500 mg P600 mg + L1250 mg Planned, N 3-6 3-6 3-6 6 Dosed, N 4 3 3 7 Total Number Subjects Who 3 (75) 3 (100) 3 (100) 5 (71) Discontinued the Investigational Products, n (%) Discontinued due to AEs, n (%) 0 1 (33) 0 1 (14) Discontinued due to Disease 3 (75) 2 (67) 3 (100) 3 (43) Progression, n (%) Discontinued for Other 0 0 0 1 (14) Reasons, n (%) Continuing treatment at data 1 (25) 0 0 2 (29) cut-off, n (%) Demographics Part A Pooled P400/800 mg N (Safety Population) 3 7 10 3 Females: Males 1:2 3:4 4:6 0:3 Age in Years (SD*) 56.0 (10.82) 59.4 (11.46) 58.4 (10.78) 44.3 (4.73) Weight in Kg (SD*) 59.10 (8.202) 56.53 (8.301) 57.30 (7.901) 57.77 (2.268) Asian - Japanese Heritage, n (%) 3 (100) 7 (100) 10 (100) 3 (100) Part B + L1500 mg P600 mg + L1250 mg N (Safety Population) 4 3 3 7 Females: Males 2:2 2:1 2:1 6:1 Age in Years (SD*) 49.8 (11.84) 44.7 (17.04) 53.0 (13.00) 56.3 (11.31) Weight in Kg (SD*) 54.83 (7.588) 45.33 (4.028) 47.40 (6.791) 50.93 (9.292) Asian - Japanese Heritage, n (%) 4 (100) 3 (100) 3 (100) 7 (100) * SD: standard deviation Pharmacokinetics (PK) Results: In Part A, the PK of pazopanib and its 4 metabolites (GSK1071306, GSK1268992, GSK1268997, and GW700201) were assessed. In Part B, the PK of pazopanib and its 3 metabolites (GSK1071306, GSK1268992, and GSK1268997), as well as the PK of lapatinib, were assessed. Part A Concentrations of pazopanib and its 4 metabolites varied widely among individuals. PK parameter values of pazopanib also showed a wide inter-individual variability: the median of tmax ranged from approximately 2.5 to 4 hours and the geometric mean of t1/2 ranged from approximately 28 to 42 hours. Every metabolite accounted for less than 5% of AUC (0-24) of pazopanib. Analyses using power model and analysis of variance revealed no correlation between the doses of pazopanib and either AUC (0-24) or Cmax on Day 1. The ratio of AUC (0-24) on Day 22 to 4
AUC (0-inf) on Day 1 varied widely among individuals in the range of 0.54 to 1.52; this result suggested no obvious change was observed in PK with multiple doses of pazopanib. The geometric mean of C24 after multiple doses of pazopanib was higher than the target trough plasma concentration for inhibition of VEGFR-2 activity (20 μg/ml) in all dose groups. Part B (Dose Escalation Cohort) Concentrations of pazopanib and its 3 metabolites varied widely among individuals. PK parameter values of pazopanib also showed a wide inter-individual variability. No dose correlation was observed between pazopanib or lapatinib and either AUC (0-24) or Cmax, and no effect of the concomitant drug was observed. The geometric mean of C24 in plasma concentration of pazopanib after multiple doses of a combination of pazopanib and lapatinib was higher than the target trough plasma concentration for inhibition of VEGFR-2 activity (20 μg/ml) in all dose groups. Part B (PK Cohort) Concentrations of pazopanib and its 3 metabolites varied widely among individuals. All of the point estimates of the ratio of combination therapy to monotherapy for Cmax and AUC (0-24) of pazopanib and lapatinib were less than 1 with these 90% confidence intervals including 1; however, no inference could be made with this small number of subjects. The geometric mean of C24 of pazopanib after multiple doses was higher than the target trough plasma concentration for inhibition of VEGFR-2 activity (20 μg/ml) both after monotherapy of pazopanib and after combination therapy with lapatinib. Plasma PK Parameters of Pazopanib, Part A (PK Parameter Population) P400/800 mg Parameter (N=7) Cmax tmax AUC (0-24) (hr*μg/ml) AUC (0-inf) (hr*μg/ml) t1/2 C24 Median (Min-Max) Day 1 Day 22 Day 1 Day 22 Day 1 Day 22 25.0620 55.7836 22.8746 40.5563 21.2590 53.8773 (33.9806) (35.2274) (69.5202) (47.6780) (118.1477) (55.3685) 4.000 (3.00-23.72) 402.273 (17.669) 1223.799 (10.822) 28.420 (35.869) 14.7920 (12.6782) 2.500 (2.00-3.00) 962.394 (46.277) 2.983 (1.97-5.95) 324.596 (76.714) - 863.971 (95.220) - 42.452 (31.620) 34.5532 (47.1789) 9.0711 (90.1403) 2.517 (1.92-3.97) 677.287 (45.454) 3.000 (2.97-3.00) 304.965 (128.594) - 714.494 (147.573) - 33.028 (23.754) 22.0015 (48.3833) 8.5234 (139.5893) 4.000 (3.00-4.05) 759.454 (63.848) - - 21.0562 (80.5234) Note 1: Results of t1/2 and AUC (0-inf) are not reported for Day 22 because blood samples were collected up to 24 hours after multiple dosing. Note 2: The number of subjects analyzed was N-1 in each of P400/800 mg and dose groups for Day 22 (excluding the number of subjects analyzed for C24 in P400/800 mg dose group [3 subjects]). Plasma PK Parameters of Pazopanib in Dose Escalation Cohort, Part B (PK Parameter Population) Parameter Cmax tmax AUC (0-24) (hr*μg/ml) Median (Min-Max) (N=4) + L1500 mg Day 1 Day 22 Day 1 Day 22 Day 1 Day 22 46.4085 57.8856 48.9024 55.6024 31.7287 51.6543 (10.0529) (18.6173) (51.0734) (7.3316) (68.6364) (69.7934) 5.025 (3.03-8.00) 754.994 (15.008) 4.050 (3.98-8.00) 988.144 (33.209) 6.000 (3.98-7.98) 853.393 (53.791) 3.000 (0.48-6.15) 1140.596 (18.397) 4.000 (2.95-4.03) 523.700 (66.594) 3.950 (3.00-7.98) 1003.848 (65.556) 5
t1/2 C24 30.133 (21.545) 26.7847 (17.9341) - 33.718 (48.275) 34.7888 (27.6355) 31.0160 (37.5413) - 29.295 (24.803) 41.9049 (28.5226) 17.6129 (61.1735) - 35.2389 (65.1923) Note 1: Results of t1/2 are not reported for Day 22 because blood samples were collected up to 24 hours after multiple dosing. Note 2: The number of subjects analyzed was 3 in P400 + dose group for Day 22. Plasma PK Parameters of Lapatinib in Dose Escalation Cohort, Part B (PK Parameter Population) Parameter Cmax tmax AUC (0-24) (hr* μg/ml) t1/2 Median (Min - Max) (N=4) + L1500 mg Day 1 Day 22 Day 1 Day 22 Day 1 Day 22 2.3676 1.5977 1.5486 1.6347 2.7597 1.9729 (21.4306) (39.1091) (50.5210) (77.3264) (36.9383) (107.1239) 6.033 (3.03-8.00) 33.769 (25.947) 11.576 (30.798) 4.050 (2.98-6.00) 22.806 (44.219) 6.000 (6.00-8.00) 18.038 (61.518) - 7.792 (21.543) 4.000 (3.98-6.00) 23.573 (36.092) 6.000 (4.05-6.08) 32.620 (52.272) - 9.845 (19.046) 6.000 (4.00-7.97) 31.999 (92.064) Note 1: Results of t1/2 are not reported for Day 22 because blood samples were collected up to 24 hours after multiple dosing. Note 2: The number of subjects analyzed was 3 in P400 + dose group for Day 22. Plasma PK Parameters of Pazopanib in PK Cohort, Part B (PK Parameter Population 2) P600 mg + L1250 mg (N=6) Day 15 Day 37 Ratio of 90% Parameter (Pazopanib (Combination Combination Confidence Monotherapy) with Lapatinib) Therapy/ Interval (n=6) Monotherapy Cmax 79.6321 63.5309 0.684 (0.270, 1.732) (10.2812) (40.6121) tmax Median 3.000 3.000 - - (Min-Max) (3.00-3.98) (2.95-5.93) AUC (0-24) 1331.444 1188.806 0.766 (0.327, 1.793) (hr*μg/ml) (13.825) (37.125) C24 45.0658 (4.1660) 43.0003 (38.4397) - - Plasma PK Parameters of Lapatinib in PK Cohort, Part B (PK Parameter Population 2) P600 mg + L1250 mg (N=6) Parameter Cmax tmax AUC (0-24) (hr*μg/ml) Median (Min-Max) Day 15 (Lapatinib Monotherapy) 2.0894 (49.1872) 3.950 (3.00-3.97) 28.391 (45.350) Day 37 (Combination with Pazopanib) (n=6) 2.0658 (36.9560) 4.000 (3.00-6.00) 29.547 (41.616) Ratio of Combination Therapy/ Monotherapy - 90% Confidence Interval 0.891 (0.489, 1.624) - - 0.973 (0.453, 2.088) 6
Safety Results: No DLT was observed in both Part A and Part B. MTD was not achieved in this study. An on-therapy AE was defined as an AE that occurred after a subject consented to participate in this study up to follow-up visit. An on-therapy SAE was defined same as an on-therapy AE. Adverse Events: Adverse Events Occurring in More Than One Subject in Any Treatment Group, Part A (Safety Population) Preferred Term n (%) P400/800 mg Pooled Total N (Safety Population) 3 7 10 3 13 No. of Subjects with Any AE 3 (100) 7(100) 10 (100) 3 (100) 13 (100) Diarrhoea 1 (33) 4 (57) 5 (50) 2 (67) 7 (54) Aspartate aminotransferase 2 (67) 3 (43) 5 (50) 0 5 (38) Hypertension 3 (100) 1 (14) 4 (40) 1 (33) 5 (38) Leukopenia 3 (100) 1 (14) 4 (40) 1 (33) 5 (38) Lipase 2 (67) 2 (29) 4 (40) 1 (33) 5 (38) Nausea 1 (33) 1 (14) 2 (20) 3 (100) 5 (38) Neutropenia 3 (100) 1 (14) 4 (40) 1 (33) 5 (38) Rash 1 (33) 3 (43) 4 (40) 1 (33) 5 (38) Alanine aminotransferase 2 (67) 2 (29) 4 (40) 0 4 (31) Lymphopenia 2 (67) 1 (14) 3 (30) 1 (33) 4 (31) Platelet count decreased 0 4 (57) 4 (40) 0 4 (31) Thrombocytopenia 3 (100) 0 3 (30) 1 (33) 4 (31) Vomiting 1 (33) 1 (14) 2 (20) 2 (67) 4 (31) Blood alkaline phosphatase 1 (33) 0 1 (10) 2 (67) 3 (23) Blood thyroid stimulating hormone 2 (67) 1 (14) 3 (30) 0 3 (23) Fatigue 0 1 (14) 1 (10) 2 (67) 3 (23) Headache 1 (33) 1 (14) 2 (20) 1 (33) 3 (23) Hepatic function abnormal 1 (33) 1 (14) 2 (20) 1 (33) 3 (23) Neutrophil count decreased 0 3 (43) 3 (30) 0 3 (23) Proteinuria 1 (33) 2 (29) 3 (30) 0 3 (23) Skin hypopigmentation 2 (67) 0 2 (20) 1 (33) 3 (23) White blood cell count decreased 0 3 (43) 3 (30) 0 3 (23) Blood lactate dehydrogenase 1 (33) 1 (14) 2 (20) 0 2 (15) Blood thyroid stimulating hormone 0 2 (29) 2 (20) 0 2 (15) decreased Decreased appetite 1 (33) 1 (14) 2 (20) 0 2 (15) Dizziness 1 (33) 1 (14) 2 (20) 0 2 (15) Hair colour changes 0 2 (29) 2 (20) 0 2 (15) Pyrexia 1 (33) 1 (14) 2 (20) 0 2 (15) Adverse Events Occurring in More Than One Subject in Any Treatment Group, Part B (Safety Population) Preferred Term n (%) + L1500 mg P600 mg + L1250 mg N (Safety Population) 4 3 3 7 17 No. of Subjects with Any AE 4 (100) 3 (100) 3 (100) 7 (100) 17 (100) Diarrhoea 4 (100) 3 (100) 3 (100) 7 (100) 17 (100) Decreased appetite 3 (75) 1 (33) 3 (100) 5 (71) 12 (71) Fatigue 3 (75) 2 (67) 2 (67) 4 (57) 11 (65) Neutropenia 2 (50) 3 (100) 2 (67) 4 (57) 11 (65) Total 7
Rash 3 (75) 1 (33) 2 (67) 5 (71) 11 (65) Blood thyroid stimulating hormone 1 (25) 3 (100) 1 (33) 5 (71) 10 (59) Dysgeusia 1 (25) 1 (33) 3 (100) 4 (57) 9 (53) Hypertension 2 (50) 1 (33) 2 (67) 4 (57) 9 (53) Leukopenia 2 (50) 3 (100) 0 4 (57) 9 (53) Nausea 3 (75) 1 (33) 2 (67) 3 (43) 9 (53) Weight decreased 3 (75) 2 (67) 1 (33) 2 (29) 8 (47) Alanine aminotransferase 1 (25) 1 (33) 3 (100) 2 (29) 7 (41) Lymphopenia 2 (50) 1 (33) 1 (33) 3 (43) 7 (41) Skin hypopigmentation 2 (50) 2 (67) 1 (33) 2 (29) 7 (41) Stomatitis 0 1 (33) 2 (67) 4 (57) 7 (41) Thrombocytopenia 0 2 (67) 0 5 (71) 7 (41) Vomiting 3 (75) 1 (33) 1 (33) 2 (29) 7 (41) Blood amylase 2 (50) 2 (67) 0 2 (29) 6 (35) Hair colour changes 1 (25) 1 (33) 0 4 (57) 6 (35) Proteinuria 1 (25) 2 (67) 1 (33) 2 (29) 6 (35) Alopecia 1 (25) 1 (33) 1 (33) 2 (29) 5 (29) Arthralgia 1 (25) 0 1 (33) 3 (43) 5 (29) Aspartate aminotransferase 1 (25) 1 (33) 3 (100) 0 5 (29) Blood alkaline phosphatase 1 (25) 2 (67) 1 (33) 1 (14) 5 (29) Blood lactate dehydrogenase 0 2 (67) 3 (100) 0 5 (29) Dry skin 0 0 2 (67) 3 (43) 5 (29) Hypoalbuminaemia 1 (25) 1 (33) 0 3 (43) 5 (29) Palmar-plantar erythrodysaesthesia 0 1 (33) 1 (33) 3 (43) 5 (29) syndrome Platelet count decreased 3 (75) 0 1 (33) 1 (14) 5 (29) Epistaxis 1 (25) 1 (33) 0 2 (29) 4 (24) Hyperbilirubinaemia 0 1 (33) 0 3 (43) 4 (24) Lipase 2 (50) 0 1 (33) 1 (14) 4 (24) Nail disorder 2 (50) 0 1 (33) 1 (14) 4 (24) Nasopharyngitis 2 (50) 0 2 (67) 0 4 (24) C-reactive protein 2 (50) 0 1 (33) 0 3 (18) Haemoglobin decreased 1 (25) 0 0 2 (29) 3 (18) Headache 2 (50) 0 1 (33) 0 3 (18) Insomnia 0 0 1 (33) 2 (29) 3 (18) Menstruation irregular 1 (25) 0 0 2 (29) 3 (18) Muscle spasms 0 0 1 (33) 2 (29) 3 (18) Eczema 0 0 0 2 (29) 2 (12) Gamma-glutamyltransferase 0 0 2 (67) 0 2 (12) Hyperkalaemia 0 0 2 (67) 0 2 (12) Ileus 2 (50) 0 0 0 2 (12) Serious Adverse Events, n (%) [n considered by the investigator to be related to study medication], Part A (Safety Population): Preferred Term n (%) [related] P400/800 mg Pooled N (Safety Population) 3 7 10 3 Subjects with Any Non-Fatal SAE 1 (33) [1] 4 (57) [1] 5 (50) [2] 1 (33) [1] Enterocolitis infectious 0 1 (14) [0] 1 (10) [0] 0 8
Hepatic function abnormal 1 (33) [1] 0 1 (10) [1] 1 (33) [1] Ileus 0 1 (14) [0] 1 (10) [0] 0 Lower respiratory tract infection 0 1 (14) [0] 1 (10) [0] 0 Pneumonitis 0 1 (14) [1] 1 (10) [1] 0 Subjects with Any Fatal SAE 0 0 0 0 Serious Adverse Events, n (%) [n considered by the investigator to be related to study medication], Part B (Safety Population): Preferred Term n (%) [related] + L1500 mg P600 mg + L1250 mg N (Safety Population) 4 3 3 7 Subjects with Any Non-Fatal SAE 4 (100) [0] 1 (33) [0] 0 2 (29) [2] Dysuria 0 1 (33) [0] 0 0 Headache 1 (25) [0] 0 0 0 Hepatic function abnormal 0 0 0 1 (14) [1] Ileus 2 (50) [0] 0 0 0 Liver function test abnormal 0 0 0 1 (14) [1] Pericoronitis 1 (25) [0] 0 0 0 Pneumonia 0 0 0 1 (14) [1] Pyrexia 0 1 (33) [0] 0 0 Syncope 1 (25) [0] 0 0 0 Urinary tract infection 1 (25) [0] 0 0 0 Subjects with Any Fatal SAE 0 1 (33) [0] 0 0 Disease progression 0 1 (33) [0] 0 0 Efficacy Results: Best Overall Response (Efficacy Population) Part A Best Overall Response, n (%) Pooled (N=10) P400/800 mg (N=7) CR 0 0 0 0 PR 0 0 0 0 SD 1 (33) 2 (29) 3 (30) 0 PD 2 (67) 4 (57) 6 (60) 3 (100) Not Evaluable 0 0 0 0 Unknown 0 1 (14) 1 (10) 0 Part B Best Overall Response, n (%) (N=4) + L1500 mg P600 mg + L1250 mg (N=7) CR 0 0 0 0 PR 2 (50) 0 1 (33) 0 SD 1 (25) 2 (67) 1 (33) 5 (71) PD 1 (25) 1 (33) 1 (33) 2 (29) Not Evaluable 0 0 0 0 Unknown 0 0 0 0 9
Conclusion: Part A The most common AE associated with pazopanib monotherapy was diarrhoea, followed by aspartate aminotransferase, hypertension, leukopenia, lipase, nausea, neutropenia, and rash. Most AEs were Grade 2 and could be managed by dose reduction or dose interruption. There was no distinct difference in types of AEs between pooled dose group and dose group. The results of safety, tolerability, PK, and efficacy suggested that 800 mg once daily of pazopanib, the overseas monotherapy dose, would be appropriate for Japanese subjects. Part B The most common AE associated with combination therapy of pazopanib with lapatinib was diarrhoea, followed by decreased appetite, fatigue, neutropenia, and rash. Most AEs were Grade 2 and could be managed by dose reduction or dose interruption. There was no distinct difference in types of AEs among the 4 dose groups. The results of safety, tolerability, PK, and efficacy suggested that all of these dose regimens of pazopanib in combination with lapatinib would be able to be used in Japanese subjects. 10