Study No: Title : Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Statistical Methods:

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1 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: VEG10003 Title : A Phase I, Open-Label, Multiple, Escalation Study of GW in Patients with Solid Tumors Rationale: Neoplastic growth and metastases depend upon tumor angiogenesis and lymphangiogenesis. Vascular endothelial growth factor (VEGF) is one of several proangiogenic molecules that play a pivotal role in both processes. Signalling via the VEGF receptor (VEGFR) and platelet-derived growth factor (PDGF) receptor (PDGFR) is involved in tumor angiogenesis. Preclinical data suggest that simultaneous targeting of VEGF and PDGF pathways may be more effective than targeting either one alone because of the potentially distinct and possibly interrelated mechanisms by which VEGFR and PDGFR signaling mediate tumor angiogenesis. Thus, combined inhibition of multiple VEGFRs and PDGFRs could potentially inhibit both angiogenesis and lymphangiogenesis, thereby inhibiting tumor growth and metastases. Pazopanib (GW786034) is an orally active, potent, small molecule tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, and c-kit. Pazopanib had demonstrated inhibition of VEGF mediated endothelial cell proliferation, and anti-tumor activity in human tumor xenograft models. This study was the first doseescalation Phase I study of pazopanib in subjects with solid tumors. Phase: I Study Period: 16 Dec Sep 2006 Study Design: Multicenter, Phase I, open-label, non-randomized, multiple dose-finding study. Subjects received a single dose of pazopanib on Day 1 followed by approximately 96 hours of pharmacokinetic (PK) sampling. Multiple dosing began after PK analyses of plasma pazopanib cntration-time data from Day 1 were available (approximately 1 week after drug administration) in the first cohort, and after PK sampling was completed following the Day 1 dose in subsequent cohorts. Pharmacokinetic samples were obtained up to 96 hours. Daily dosing with 800 mg commenced after the 96 hour PK sample was collected. Pharmacokinetic samples were obtained after 21 consecutive days of dosing. Maximum tolerated dose (MTD) was defined as the highest dose of pazopanib administered at which no more than one of six subjects experienced a dose-limiting toxicity (DLT). DLTs were defined as follows: Grade 3 or 4 clinically significant non-hematological toxicity. Grade 3 hypertension was evaluated and managed as outlined in the protocol and did not necessarily represent a DLT Hematological toxicity, including Grade 4 granulocytopenia lasting at least days, febrile neutropenia, or thrombocytopenia Grade 3 or 4. Treatment delay of 14 days or greater due to unresolved toxicity Greater than or equal to Grade 2 non-hematological toxicity that persisted beyond the first 22 days of dosing that in the judgement of the investigator and GlaxoSmithKline (GSK) medical monitor was dose-limiting Certain Grade 2 toxicity (e.g. renal, neurological, cardiovascular, gastro-intestinal) which in the judgement of the investigator and GSK medical monitor was dose-limiting. Centres: Two centers in the United States Indication: Adult subjects with solid tumors Treatment: Sixty- subjects received oral doses of pazopanib ranging from (TIW) to 2000 mg. Objectives: The primary objectives were (1) to assess the safety and tolerability of oral pazopanib after multiple dosing in cancer subjects and (2) to characterize the PK of pazopanib after single dose and multiple dose administration. The secondary objectives were to evaluate the effect of pazopanib on biomarkers of angiogenesis activity in order to estimate biologic activity and to determine the minimum biologically active dose, to observe clinical response as described in the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Statistical Methods: Adverse events (AEs), vital signs data and laboratory data (chemistry, hematology, coagulation, and urinalysis) were summarized. Plasma cntration data were summarized. PK endpoints included area under the plasma drug cntration-time curve to the time of the last measurable cntration (AUClast), area under the plasma drug cntration-time curve to 24 hours post-dose (AUC(0-24)), maximum observed plasma cntration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2), if there were sufficient data. A descriptive summary was presented by dose cohort and study day. -proportionality of AUC and Cmax for pazopanib was assessed using a regression model and evaluated visually in graphical form. Overall tumor response was categorized into one of the following categories: progressive disease, stable disease (SD), 1

2 partial response (PR), and complete response. Data were listed and summarized by category and dose cohort. The safety population consisted of all subjects who received at least one dose of study drug. The PK population included all subjects for whom a PK sample was obtained and analyzed. All subjects who received an active dose of pazopanib, and had evaluable PK data were included in the formal statistical analysis of the PK data. PD analyses were exploratory in nature and a formal PD population was not defined. Study Population: Subjects were male or female, at least 21 years of age, with a Karnofsky performance status (KPS) greater than or equal to 70%, and with a histologically-confirmed diagnosis of advanced solid tumor refractory to standard therapy or for whom no standard therapy existed. Number of Subjects Levels 1 through 7): Level 1 Level 2 Level 3 Level 4 Level mg Level mg Level 7 Entered N d N Completed n 5 (71) 6 (67) 1 (50) 2 (67) 3 (100) 5 (83) 4 (100) Total Number Subjects Prematurely Withdrawn a N Reasons for Premature Withdrawal Withdrawn due to Adverse Events n Withdrawn due to Progressive Disease, n Withdrawn for Other Reasons, n Number of Subjects Levels 8 through 13): 2 (29) 3 (33) 1 (50) 1 (33) 0 1 (17) 0 1 (14) 3 (33) (17) (50) 1 (33) (14) Level 8 Level mg Level mg Level mg Level 12 1 Level mg Entered N d N Completed n 3 (100) 3 (100) 14 (100) 2 (67) 2 (67) 3 (100) 53 (84) Total Number Subjects Prematurely Withdrawn a N Reasons for Premature Withdrawal Withdrawn due to Adverse Events n Withdrawn due to Progressive Disease, n Total (33) 1 (33) 0 10 (16) (33) (10) (33) 0 3 (5) Withdrawn for Other Reasons, n (2) a. Premature withdrawal was defined as those subjects who stopped taking study drug within the first 22 days of the study (inclusive of Day 22) Demographics N 63 Females: Males 28:35 Mean Age in Years (sd) 56.5 (12.07) Mean Weight, kg (SD) (17.363) 2

3 White n 52 (83) 3

4 Pharmacokinetic (PK) Results: Study Day 1 Plasma pazopanib cntrations were measurable in all subjects. Overall, mean Cmax and AUC(0-24) on Day 1 increased as the pazopanib dose increased, with the highest mean values observed in the 2000 mg dose group. However, mean Cmax and AUC(0-24) on Day 1 increased in a less than proportional fashion with increasing dose over the entire range of doses examined. Pazopanib was eliminated slowly with mean t1/2 values ranging from 18.1 to 52.3 hours for the TIW to 2000 mg dose levels. The geometric mean t1/2 was 30.9 hours in the 800 mg dose group with 95% confidence interval (22.1, 43.2). Study Day 22 The Cmax and AUC values were greater following repeated administration compared with single dose administration at dose levels from TIW to 2000 mg, indicating accumulation following multiple dosing. Mean plasma AUC(0-24) values on Day 22 of pazopanib administration were approximately to 4.0-fold greater than mean values observed after single doses. There was no trend apparent in the accumulation ratio versus pazopanib dose at dose levels from to 800 mg. Mean accumulation ratios and the ratio of AUC(0-24) at steady state and AUC(0- ) calculated in dose cohorts of to 2000 mg suggest that there were no obvious time-dependent changes in the PK of pazopanib. Steady-state exposure to pazopanib appeared to plateau at the 800 mg dose. Mean AUC(0-24) and Cmax on Day 22 did not increase, or increased only modestly, when the dose increased to greater than 800 mg. The difference between mean Cmax values on Day 22 in the 300 mg BID and BID dose groups was less than 10% and both values were less than the mean Cmax values in the 800 mg and 1000 mg cohorts. However, mean C24 (trough cntration) values on Day 22 were similar in all four dosing regimens. There were no obvious time-dependent changes in pazopanib PK after 22 days of 300 mg BID or BID dosing. Median tmax values ranged from 2.0 to 4.0 hours and 2.0 to 8.0 hours following single and multiple dose administration, respectively. A MTD was not determined in this trial, in part because a plateau in exposure was encountered at doses of 800 mg. However, clinical and biological effects were observed more frequently in association with a Day 22 C24 of at least 15,000 ng/ml, which was achieved in 93% of subjects receiving doses of at least 800 mg. Parameter Day Level 1 AUC(0-24) (μg*h/ml) a (28.7) (CVb%) e (43.6) AUC(0-12) (μg*h/ml) (CVb%) Level 2 Level 3 Level 4 Level mg Level mg 51.8 b (24.0) 89.4 f (20.6) 96.9 (17.6) (54.6) e g f (54.2) (NC) (9.4) (29.3) 22 NR NR NR NR NR e (36.4) Level c (56.0) (89.2) NC (31.3) NR Cmax (μg/ml) (CVb%) a (28.8) 5.8 e (40.3) 3.3 h (22.6) 8.4 a (35.2) 6.3 f (33.5) 12.2 f (13.2) 6.5 (25.7) 11.0 f (4.6) 7.5 (54.5) 23.7 (8.7) 8.4 a (51.0) 36.7 e (36.1) 10.3 c (82.0) 21.8 c (56.3) t1/2 (h) NC g 39.3 c 33.9 c tmax (h) j a 3.0 h 3.0 f c e 3.0 a 8.0 f 8.0 f e 3.0 c C24 (μg/ml) i (41.7) (CVb%) a (44.8) Parameter Day Level h (45.5) 5.1 a (57.9) Level mg 3.0 f (16.0) 7.5 f (25.9) Level mg 2.8 (11.2) 4.9 f (71.1) Level mg 2.9 (53.6) 12.4 (35.9) Level a (68.2) 29.5 e (53.0) Level mg 3.9 c (86.2) 10.4 (86.6) 4

5 AUC(0-24) (μg*h/ml) (CVb%) (229.3) NC (44.8) (29.4) d (202.6) b (76.1) (55.8) g (NC) (71.3) (98.2) (46.4) (58.3) AUC(0-12) NR NR NR NR NR (μg*h/ml) (CVb%) (71.8) Cmax (μg/ml) (231.8) 11.2 (54.6) 19.4 d (176.0) 36.1 (70.9) 20.8 (70.2) 44.5 (44.7) (67.7) 18.2 (25.7) 45.1 d (68.8) 53.2 f (2.2) 32.7 (95.5) 52.7 (60.3) t1/2 (h) g f 20.3 f tmax (h) j d d 4.5 f d C24 (μg/ml) (264.1) (CVb%) (54.9) (38.2) (240.0) (63.6) (79.8) (54.8) d 28.8 f (23.5 (67.4) (37.8) (99.9) (53.5) NOTE: There were patients per cohort unless otherwise noted. Abbreviations: t1/2, elimination half-life; tmax, time to maximum observed plasma cntration; NC, not calculated; NR, not reported. a. n = 6 b. n = 8 c. n = 4 d. n = 10 e. n = 5 f. n = 2 g. n = 1 h. n = 9 i. N=7 j. Median tmax Biomarkers and Pharmacodynamic (PD) Marker Results: Transient increases in plasma VEGF levels were observed during treatment, but no consistent changes from baseline in VCAM-1, E-selectin, Factor VIII VWF, d-dimer, or thrombin cntrations were observed. Dynamic contrast magnetic resonance imaging data obtained in subjects from the dose-escalation cohorts could not be analyzed. Data from the expanded cohorts obtained following an amendment to the protocol were of good quality and were analyzed. Ten of 11 subjects in the 800 mg and 300- BID cohorts for whom data were available had at least 50% reduction in tumor blood flow after treatment with pazopanib as determined by the initial area under the gadolinium cntration versus time curve at 60 seconds (IAUGC60). No consistent treatment related changes in vascular scores or p-vegfr2 were seen in the wound angiogenesis model performed in this study. Hair depigmentation was a PD marker observed at total doses of 600 mg and above. PK/PD Relationships: A logistic regression model was fit to the steady-state trough plasma pazopanib cntrations versus the blood pressure data to determine the probability of developing a significant increase in blood pressure at a given trough pazopanib cntration. The steady-state trough plasma pazopanib cntration at which there was a 50% probability of a significant increase in blood pressure was approximately 15,000 ng/ml (34 μm). Safety Results: An on therapy AE was defined as an AE with onset on or after the start date of study medication but not later than one day after the last date of study medication. Adverse Events occurring in more than one subject in any treatment group, Number of Subjects with AEs, n ( Levels 1 through 7): Level 1 Level 2 Level 3 Level 4 Level mg Level mg N Level 7 5

6 No. subjects with any AEs n 6 (86) 9 (100) 2 (100) 3 (100) 3 (100) 6 (100) 4 (100) Nausea 2 (29) 5 (56) 0 1 (33) 2 (67) 2 (33) 1 (25) Diarrhea 2 (29) 4 (44) 1 (50) 1 (33) 1 (33) 3 (50) 3 (75) Anorexia 3 (43) 4 (44) 0 2 (67) 0 2 (33) 2 (50) Hypertension 1 (14) 0 1 (50) 0 2 (67) 0 2 (50) Fatigue 1 (14) 4 (44) 1 (50) (33) 1 (25) Hair depigmentation/hair color 0 1 (11) (33) 4 (67) 0 changes Vomiting 2 (29) 3 (33) (67) 2 (33) 1 (25) Constipation 2 (29) 1 (11) (33) 2 (33) 0 Abdominal pain 1 (14) (67) 0 2 (33) 0 Headache (33) 0 1 (25) Dizziness 2 (29) (17) 1 (25) Cough (17) 1 (25) Dysgeusia (17) 0 Peripheral oedema (50) (17) 0 Rash 0 1 (11) (33) 0 Dyspnea 0 3 (33) 0 1 (33) 0 1 (17) 1 (25) Muscle spasms 1 (14) (17) 0 Insomnia (50) Urinary tract infection 0 2 (22) Alopecia 0 1 (11) (33) 0 Musculoskeletal pain 0 2 (22) (33) 0 Pain in extremity (17) 0 Paresthesia 2 (29) Pyrexia 1 (14) 2 (22) (33) 0 0 Vision blurred (17) 0 Chills (33) 1 (17) 0 Depression (67) 0 1 (17) 0 Skin depigmentation 0 1 (11) Skin hypopigmentation (17) 0 Abdominal distension 1 (14) 0 1 (50) Flatulence 1 (14) (25) Proteinuria (25) Visual disturbance (25) Asthenia 0 1 (11) Postnasal drip 1 (14) 2 (22) Bone pain Neutropenia Adverse Events occurring in Total more than one subject in any treatment group, Number of Subjects with AEs, n ( Levels 8 through 13): Level 8 Level mg Level mg Level mg Level 12 1 Level mg N No. subjects with any AEs n 3 (100) 3 (100) 13 (93) 3 (100) 3 (100) 3 (100) 61 (97) 6

7 Nausea 2 (67) 2 (67) 7 (50) 2 (67) 2 (67) 2 (67) 30 (48) Diarrhea 1 (33) 2 (67) 6 (43) 2 (67) 1 (33) 1 (33) 28 (44) Anorexia 3 (100) 0 4 (29) 1 (33) 1 (33) 2 (67) 24 (38) Hypertension 2 (67) 1 (33) 6 (43) 3 (100) 2 (67) 2 (67) 22 (35) Fatigue 1 (33) 2 (67) 5 (36) 0 1 (33) 3 (100) 21 (33) Hair depigmentation/hair color 0 3 (100) 7 (50) 2 (67) 1 (33) 2 (67) 21 (33) changes Vomiting 1 (33) 0 4 (29) 1 (33) 1 (33) 1 (33) 19 (30) Constipation 0 1 (33) 4 (29) 1 (33) 0 1 (33) 13 (21) Abdominal pain 0 1 (33) 3 (21) 2 (67) 0 1 (33) 12 (19) Headache 1 (33) 2 (67) 5 (36) 1 (33) 1 (33) 12 (19) Dizziness 0 1 (33) 3 (21) 0 1 (33) 1 (33) 11 (17) Cough 0 1 (33) 2 (14) 2 (67) 1 (33) 0 9 (14) Dysgeusia (21) 1 (33) 1 (33) 2 (67) 9 (14) Peripheral oedema 1 (33) 1 (33) 3 (21) 0 1 (33) 1 (33) 9 (14) Rash 0 1 (33) 3 (21) 0 1 (33) 1 (33) 9 (14) Dyspnea 0 1 (33) 1 (7) (13) Muscle spasms 0 1 (33) 3 (21) 0 1 (33) 1 (33) 8 (13) Insomnia 0 1 (33) 3 (21) (11) Urinary tract infection (21) 1 (33) 0 1 (33) 7 (11) Alopecia 0 1 (33) 1 (7) 0 1 (33) 0 6 (10) Musculoskeletal pain (7) (33) 6 (10) Pain in extremity (21) 0 1 (33) 6 (10) Paresthesia (10) Pyrexia (14) (10) Vision blurred 2 (67) (33) 0 1 (33) 6 (10) Chills 0 1 (33) 2 (14) (8) Depression (7) (33) 5 (8) Skin depigmentation (21) (33) 5 (8) Skin hypopigmentation 1 (33) 0 1 (7) 1 (33) 0 1 (33) 5 (8) Abdominal distension (14) (6) Flatulence (14) (6) Proteinuria (14) 1 (33) 0 4 (6) Visual disturbance (14) 0 1 (33) 4 (6) Asthenia (14) (5) Postnasal drip (5) Bone pain (14) (3) Neutropenia (14) (3) Serious Adverse Events, n [n considered by the investigator to be related, possibly related, or probably related to study medication]: Level 1 Level 2 Level 3 Level 4 Level mg Level mg Level 7 N Subjects with any SAEs, n 2 (29) 3 (33) 0 1 (33) 2 (67) 1 (17) 1 (25) Subjects with any fatal SAEs, n Subjects with any non-fatal 2 (29) 3 (33) 0 1 (33) 2 (67) 1 (17) 1 (25) SAEs, n Cellulitis (33) 0 0 Pneumonia 0 1 (11) (33) 0 0 Bone pain

8 Bradycardia Deep vein thrombosis (17) [1] 0 Electrocardiogram change Extrapyramidal disorder 0 1 (11) [1] Hypertension Impaired gastric emptying 1 (14) Intestinal obstruction Nausea Pain 1 (14) Pelvic venous thrombosis (17) [1] 0 Pneumonia klebsiella (17) 0 Post-operative ileus 0 1 (11) Pulmonary embolism (33) [1] Pyrexia (33) 0 0 Spinal cord compression (25) Tumor hemorrhage 0 1 (11) [1] Level 8 Level mg Level mg Level mg Level 12 1 Level mg N Subjects with any SAEs, n (21) 1 (33) 1 (33) 0 15 (24) Subjects with any fatal SAEs, n Subjects with any non-fatal (21) 1 (33) 1 (33) 0 15 (24) SAEs, n Cellulitis (7) (3) Pneumonia (3) Bone pain (7) (2) Bradycardia (33) (2) [1] Deep vein thrombosis (2) [1] Electrocardiogram change (33) [1] (2) [1] Extrapyramidal disorder (2) [1] Hypertension (33) [1] (2) [1] Impaired gastric emptying (2) Intestinal obstruction (7) (2) Nausea (33) [1] 0 1 (2) [1] Pain (2) Pelvic venous thrombosis (2) [1] Pneumonia klebsiella (2) Post-operative ileus (2) Pulmonary embolism (2) [1] Pyrexia (2) Spinal cord compression (2) Tumor hemorrhage (2) [1] Number of Subjects with -Limiting Toxicities a n : Level 2 Level mg N No. subjects with DLTs n 2 (22) 1 (7) b 1 (33) Total Level mg 8

9 Extrapyramidal disorder Gastrointestinal bleed/ Tumor bleed Hypertension Proteinuria Fatigue a. All DLTs were Toxicity Grade 3. b. One subject experienced two DLTs. Maximum tolerated dose: An MTD was not determined in this study, although the final cohort was not fully evaluated because of the steady-state exposure to pazopanib appeared to plateau at doses of 800 mg to 2000 mg. A dose limiting toxicity of Grade 3 fatigue occurred in the first cycle in one of subjects receiving 2000 mg. A second subject in this dose cohort experienced grade 2 fatigue in cycle 5 and was dose reduced. The 800 mg dose was selected for evaluation in Phase II studies based on: (1) a manageable safety profile with median administration of 10 weeks (range weeks); (2) a plateau in exposure at doses 800 mg ; (3) attaining a target trough cntration of 15,000 ng/ml based on PD markers (hypertension and clinical activity) that was similar to trough cntrations from preclinical data ( 20,000 ng/ml); and (4) 93% of subjects receiving this dose achieved the target trough cntration. 9