In February 2013, GlaxoSmithKline (GSK) announced …...In February 2013, GlaxoSmithKline (GSK)...

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all namedpersons associated with the study

Patient data listings will be completely removed* to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved research

proposal. For further information please see the Patient Level Data section of the GSK

Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded

*Complete removal of patient data listings may mean that page numbers are no longer consecutively

numbered

CONFIDENTIAL 2011N114107_00 The GlaxoSmithKline group of companies ILI108621

- 1 -

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Study Report

Title: A Phase 1, Dose Escalation Study to Assess the Safety and Biological Activity of Recombinant Human Interleukin-18 (SB-485232) Administered by Intravenous Infusion in Combination with Pegylated Liposomal Doxorubicin (Doxil) in Adult Patients with Advanced Stage Epithelial Ovarian Cancer

Phase: I

Compound Number: SB-485232

Effective Date: 13-FEB-2012

Description: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. The current study was a Phase I protocol evaluating the safety and biological activity of IL-18 in combination with pegylated liposomal doxorubicin (Doxil) in subjects with advanced stage epithelial ovarian cancer. This study used a standard treatment regimen of Doxil (40 mg/m2) in combination with rising doses of IL-18 (1, 3, 10, 30, and 100 µg/kg) to identify a dose which is safe, tolerable, and gives a maximum biological effect. SB-485232 at doses up to 100 µg/kg administered in 28-day cycles consisting of one dose of Doxil (40 mg/m2 intravenous) on Day 1 plus two doses of SB-485232 (on Days 2 and 9) had an acceptable safety profile in this population of subjects with advanced stage epithelial ovarian cancer. The safety and tolerability profile of SB-485232/Doxil was similar to SB-485232 as monotherapy with the exception that higher rates of anemia and neutropenia were observed, as expected with Doxil monotherapy. Maximal biological activity was generally observed at 10 µg/kg to 100 µg/kg for the measured soluble mediators; absolute cell number and cell activation responses that were near maximal biological activity were observed at 3 µg/kg SB-485232. Mean maximum concentration and area under the concentration-time curve values were generally similar in Cycles 1 and 4, indicating no accumulation after multiple dosing of SB-485232 in combination with 40 mg/m2 Doxil. SB-485232 was slowly eliminated (mean t1/2 values ranged from 44 to 80 hours) following intravenous infusion administration in combination with 40 mg/m2 Doxil and mean clearance and volume of distribution at steady state values appeared to increase with dose. The investigator-assessed best responses based on RECIST criteria provided a partial response rate of 6% and a stable disease rate of 38%. The median progression-free survival (PFS) time was 4.5 months. These data were similar to the historical objective response rate and PFS rate observed when Doxil is used as monotherapy in ovarian cancer patients with platinum-resistant disease.

Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited

CONFIDENTIAL 2011N114107_00 The GlaxoSmithKline group of companies ILI108621

- 2 -

Subject: IL-18, cytokine, combination study, pegylated liposomal doxorubicin, Doxil, oncology

Author(s):

Indication Studied: Advanced Stage Epithelial Ovarian Cancer

Initiation Date: 18 June 2008

Completion Date: 14 March 2011

Date of Report: [FEB 2012]

Sponsor Signatory: (and Medical Officer)

MD Director, Discovery Medicine, Biopharmaceuticals Clinical Development, R&D, GSK

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents.

Table of Contents Page TITLE ...................................................................................................................... List of Abbreviations ...............................................................................................

1. INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION ................. 2. LIST OF INVESTIGATORS ............................................................................... 3. ETHICAL CONDUCT OF THE STUDY ............................................................. 4. OBJECTIVES & ENDPOINTS ...........................................................................

4.1. Objectives ...................................................................................................... 4.2. Endpoints ......................................................................................................

4.2.1. Primary ............................................................................................... 4.2.2. Secondary ........................................................................................... 4.2.3. Exploratory Endpoint (Tumor Biomarkers) ..........................................

5. STUDY RATIONALE AND DESIGN .................................................................. 5.1. Study Rationale ............................................................................................. 5.2. Study Design .................................................................................................

6. DIAGNOSIS AND CRITERIA FOR INCLUSION................................................ 6.1. Inclusion Criteria ............................................................................................ 6.2. Exclusion Criteria ..........................................................................................

6.2.1. Other Eligibility Considerations ........................................................... 6.3. Subject Withdrawal ........................................................................................

6.3.1. Discontinuation of SB-485232 Due to Toxicity .................................... 6.3.2. Discontinuation of Doxil Due to Toxicity ..............................................

6.4. Subject Withdrawal from Study ..................................................................... 6.5. Permitted Medications ................................................................................... 6.6. Prohibited Medications ..................................................................................

7. TREATMENT ADMINISTRATION ..................................................................... 7.1. Treatments Administered ..............................................................................

7.1.1. Dose-Limiting Toxicity ......................................................................... 7.1.2. Criteria for Continuing Experimental Treatment ..................................

7.2. Identity of Investigational Products ................................................................ 7.3. Dose Rationale ..............................................................................................

8. STUDY ASSESSMENTS AND PROCEDURES ................................................ 8.1. Safety Assessments ......................................................................................

8.1.1. Adverse Events and Serious Adverse Events ..................................... 8.1.2. Clinical Laboratory Evaluations ........................................................... 8.1.3. Other Safety Assessments .................................................................

8.2. Pharmacokinetic Assessments ...................................................................... 8.3. Pharmacodynamic Assessments .................................................................. 8.4. Pharmacogenetic Assessments .................................................................... 8.5. Evaluation of Efficacy ....................................................................................

8.5.1. Definition of Measurable and Non-Measurable Disease ..................... 8.5.2. Baseline Documentation of Target and Nontarget Lesions ................. 8.5.3. Response Criteria ............................................................................... 8.5.4. Evaluation of Target Lesions ..............................................................

1151819192020202021222222242525272829293031313132323232333334343436374041424343444444

3

CONFIDENTIAL 2011N114107_00ILI108621

9. METHODS ......................................................................................................... 9.1. Data Quality Assurance ................................................................................. 9.2. Data Analysis Methods ..................................................................................

9.2.1. Sample Size Considerations ............................................................... 9.2.2. Interim Analyses ................................................................................. 9.2.3. Final Analyses .................................................................................... 9.2.4. Changes in Conduct of the Study or Planned Analyses .....................

10. STUDY POPULATION RESULTS ................................................................... 10.1. Subject Disposition and Demographics ....................................................... 10.2. Baseline Characteristics ..............................................................................

10.2.1. Previous Cancer Therapy ................................................................. 10.3. Protocol Deviations...................................................................................... 10.4. Populations of Interest ................................................................................. 10.5. Concomitant Medications ............................................................................ 10.6. Treatment Compliance ................................................................................

11. SAFETY RESULTS ......................................................................................... 11.1. Extent of Exposure ...................................................................................... 11.2. Adverse Events ...........................................................................................

11.2.1. Adverse Events by Intensity .............................................................. 11.3. Drug-Related Adverse Events ..................................................................... 11.4. Serious Adverse Events ..............................................................................

11.4.1. Fatal Events ...................................................................................... 11.4.2. Non-Fatal Serious Adverse Events ...................................................

11.5. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study ..............................................................................

11.6. Other Relevant Adverse Events .................................................................. 11.6.1. Infusion-related Reactions ................................................................ 11.6.2. Anemia.............................................................................................. 11.6.3. Dose-Limiting Toxicities ....................................................................

11.7. Pregnancies ................................................................................................ 11.8. Clinical Laboratory Evaluations ...................................................................

11.8.1. Change in Laboratory Values Over Time .......................................... 11.8.2. Individual Subject Changes .............................................................. 11.8.3. Abnormalities of Potential Clinical Importance ..................................

11.9. Vital Signs ................................................................................................... 11.10. ECGs ......................................................................................................... 11.11. Other Safety Evaluations ...........................................................................

11.11.1. ECOG Performance Status ............................................................. 11.11.2. Immunogenicity ............................................................................... 11.11.3. MUGA .............................................................................................

12. PHARMACOKINETIC RESULTS .................................................................... 12.1. Drug Concentration Data .............................................................................

13. PHARMACODYNAMIC AND BIOMARKER RESULTS ................................... 13.1. Biomarker Results ....................................................................................... 13.2. Novel Biomarker Results .............................................................................

13.2.1. Cytokines and Chemokines ..............................................................

4545464646475052525557585858585959596161626263

64646464656565656668727273737373747476767676

4


13.2.2. IL-18BP ............................................................................................. 13.2.3. Flow Cytometry Biomarkers ..............................................................

14. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS .....................................................

14.1. Cytokines and Chemokines ........................................................................ 14.2. IL-18 Binding Protein ................................................................................... 14.3. Flow Cytometry ...........................................................................................

15. EFFICACY RESULTS ..................................................................................... 16. DISCUSSION AND CONCLUSIONS ...............................................................

16.1. Discussion ................................................................................................... 16.2. Conclusions .................................................................................................

17. REFERENCES ................................................................................................ 18. CASE NARRATIVES .......................................................................................

STUDY POPULATION DATA SOURCE TABLES

Table 10.1 Summary of Subject Disposition (All Treated Subjects Population) ...... Table 10.2 Listing of Reasons for Withdrawal (All Treated Subjects Population) ... Table 10.3 Listing of Subjects with Inclusion/Exclusion Criteria Deviations SB-

485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ........ Table 10.4 Summary of Analysis Populations (All Treated Subjects Population) ... Table 10.5 Summary of Demographic Characteristics SB-485232 Doses + Doxil

40 mg/m2 (All Treated Subjects Population) ............................................ Table 10.6 Summary of Race and Racial Combination Details SB-485232 Doses

+ Doxil 40 mg/m2 (All Treated Subjects Population) ................................ Table 10.7 Summary of Disease Characteristics at Initial Diagnosis SB-485232

Doses + Doxil 40 mg/m2 (All Treated Subjects Population) .................... Table 10.8 Summary of Disease Characteristics at Screening SB-485232 Doses

+ Doxil 40 mg/m2 (All Treated Subjects Population) ................................ Table 10.9 Summary of Prior Anti-Cancer Therapy SB-485232 Doses + Doxil 40

mg/m2 (All Treated Subjects Population) ................................................. Table 10.10 Summary of Number of Prior Anti-Cancer Therapy Regimens SB-

485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ........ Table 10.11 Summary of Best Response and Duration of Response to Most

Recent Prior Chemotherapy SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ...................................................................

Table 10.12 Summary of Concomitant Medications SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) .................................................

Table 10.13 Listing of Tumour Tissue Biopsy Sample Accountability (All Treated Subjects Population) ................................................................................

Table 10.14 Listing of Disease Characteristics at Screening (All Treated Subjects Population) ...............................................................................................

Table 10.15 Listing of Prior Anti-Cancer Chemotherapy, Hormonal, Immunotherapy, and Biologic Therapy (All Treated Subjects Population)

7777

78788080859090939598

107108

110111

112

114

115

117

120

121

123

124

132

134

139

5


SAFETY DATA SOURCE FIGURES

Figure 11.1 Individual Patient Profiles of Glucose (mg/dL) (Safety Population) ...... Figure 11.2 Individual Patient Profiles of Hematology Counts Over Time:

Lymphocytes (GI/L) (Safety Population) .................................................. Figure 11.3 Individual Patient Profiles of Hematology Counts Over Time: WBC

(GI/L) (Safety Population) ........................................................................ Figure 11.4 Individual Patient Profiles of QTcB (msec) Over Time (Safety

Population) ............................................................................................... Figure 11.5 Individual Patient Profiles of QTcF (msec) Over Time (Safety

Population) ............................................................................................... SAFETY DATA SOURCE TABLES

Table 11.1 Listing of Exposure to Investigational Product (All Treated Subjects Population) ...............................................................................................

Table 11.2 Summary of Exposure to Investigational Product SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ...................................

Table 11.3 Summary of All Adverse Events SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ............................................................

Table 11.4 Summary of Drug-Related Adverse Events SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ............................................

Table 11.5 Summary of All Adverse Events by Maximum Grade (All Treated Subjects Population) ................................................................................

Table 11.6 Summary of Drug-Related Adverse Events by Maximum Grade (All Treated Subjects Population) ...................................................................

Table 11.7 Listing of All Serious Adverse Events (All Treated Subjects Population) ...............................................................................................

Table 11.8 Listing of Drug-Related Serious Adverse Events (All Treated Subjects Population) ...............................................................................................

Table 11.9 Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug (All Treated Subjects Population) ..........................................

Table 11.10 Listing of Fatal Adverse Events (All Treated Subjects Population) ..... Table 11.11 Listing of Deaths (All Treated Subjects Population) ............................ Table 11.12 Listing of Adverse Events with Toxicity Grade >=2 in Cycle 1 (All

Treated Subjects Population) ................................................................... Table 11.13 Listing of Pregnancy Status (All Treated Subjects Population) ........... Table 11.14 Listing of Urinalysis Data with Positive Dipstick Results (All Treated

Subjects Population) ................................................................................ Table 11.15 Listing of Clinical Chemistry Data with Toxicity Grade >=2 (All

Treated Subjects Population) ................................................................... Table 11.16 Listing of Hematology Data with Toxicity Grade >=2 (All Treated

Subjects Population) ................................................................................ Table 11.17 Summary of Chemistry Toxicities by Post-Baseline Maximum

Toxicity Grade (All Treated Subjects Population) ....................................

163

168

173

178

183

188

212

213

220

225

246

260

265

267269270

274288

289

290

321

372

6


Table 11.18 Summary of Hematology Toxicities by Post-Baseline Maximum Toxicity Grade (All Treated Subjects Population) ....................................

Table 11.19 Summary of Toxicities by Post-Baseline Maximum Toxicity Grade and Direction of Toxicity - Calcium, Glucose, Potassium, Magnesium, and Sodium (All Treated Subjects Population) ........................................

Table 11.20 Summary of Chemistry Toxicity Grade Shifts from Baseline Toxicity Grade (All Treated Subjects Population) ..................................................

Table 11.21 Summary of Hematology Toxicity Grade Shifts from Baseline Toxicity Grade (All Treated Subjects Population) ..................................................

Table 11.22 Summary of Toxicity Grade Treatment-Emergent Shifts from Baseline Toxicity Grade - Calcium, Glucose, Potassium, Magnesium, and Sodium (All Treated Subjects Population) ........................................

Table 11.23 Summary of Vital Signs SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ...................................................................

Table 11.24 Summary of Change from Baseline for Vital Signs SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ................................

Table 11.25 Listing of Vital Signs of Potential Clinical Importance (All Treated Subjects Population) ................................................................................

Table 11.26 Summary of ECG Findings SB-485232 Doses + Rituximab 375 mg/m2 (All Treated Subjects Population) .................................................

Table 11.27 Summary of ECG Values SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ...................................................................

Table 11.28 Summary of Change from Baseline ECG Values SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ...................................

Table 11.29 Listing of ECG Values of Potential Clinical Interest (All Treated Subjects Population) ................................................................................

Table 11.30 Listing of ECOG Performance Status (All Treated Subjects Population) ...............................................................................................

Table 11.31 Summary of ECOG Performance Status SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ............................................

Table 11.32 Summary of Incidence of Immunogenicity SB-485232 Doses + Doxil 40 mg/m2 (All Treated Subjects Population) ............................................

Table 11.33 Listing of Immunogenicity Results for Anti-SB-485232 Positive Subjects (All Treated Subjects Population) ..............................................

Table 11.34 Listing of Multigated acquistion (MUGA) scans (All Treated Subjects Population) ...............................................................................................

Table 11.35 Listing of Adverse Events of Special Interest (All Treated Subjects Population) ...............................................................................................

Table 11.36 Listing of All Adverse Events (All Treated Subjects Population) ......... Table 11.37 Listing of Clinical Chemistry Data (All Treated Subjects Population) .. Table 11.38 Listing of Hematology Data (All Treated Subjects Population) ............ Table 11.39 Listing of Vital Signs (All Treated Subjects Population) ......................

PHARMACOKINETIC DATA SOURCE FIGURES

377

382

387

402

412

417

501

586

597

603

612

619

620

625

626

627

628

633641792

18252618

7


Figure 12.1 Individual Plasma SB-485232 Concentration-Time Plot (Linear and Semi-log) (PK Population) .......................................................................

Figure 12.2 Mean Plasma SB-485232 Concentration-Time Plot (Linear and Semi-Log) (PK Population) ................................................................................

Figure 12.3 Median Plasma SB-485232 Concentration-Time Plot (Linear and Semi-Log) (PK Population) ......................................................................

Figure 12.4 Plot of Doxorubicin Concentration (ng/mL) vs. SB-485232 Dose (ug/kg) by Week (PK Population) .............................................................

PHARMACOKINETIC DATA SOURCE TABLES

Table 12.1 Summary of SB-485232 Concentration Data (ng/mL) SB-485232 Doses + Doxil 40 mg/m2 (PK Population) ................................................

Table 12.2 Summary of Pegylated Liposomal Doxorubicin Concentration Data (ng/mL) SB-485232 Doses + Doxil 40 mg/m2 (PK Population)................

Table 12.3 Summary of Derived Plasma SB-485232 Pharmacokinetic Parameters SB-485232 Doses + Doxil 40 mg/m2 (PK Population) .............................

Table 12.4 Listing of Plasma SB-485232 Concentration-Time Data (PK Population) ...............................................................................................

BIOMARKER DATA SOURCE FIGURES

Figure 13.1 Plot of Interferon-gamma (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.2 Plot of Interleukin 1 Beta (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.3 Plot of Interleukin 2 (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .........................................................





Figure 13.8 Plot of TNFa (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.9 Plot of GMCSF (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.10 Plot of IP-10 (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.11 Plot of MIG (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.12 Plot of MCP-1 (pg/mL) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .........................................................

2827

2842

2847

2852

2856

2861

2864

2888

2904

2909

2914

2919

2924

2929

2934

2939

2944

2949

2954

2959

8


Figure 13.13 Plot of CD3+ (%) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.14 Plot of CD3+ (cells/cumm) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.15 Plot of CD3+ CD8+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.16 Plot of CD3+ CD8+ (cells/cumm) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................






Figure 13.22 Plot of CD14+ CD45+ CD64+ CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.23 Plot of CD14+ CD45+ CD69+ CD64+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.24 Plot of CD14+ CD45+ CD64- CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.25 Plot of CD14+ CD45+ CD64- CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.26 Plot of CD45+ CD16+ CD11b+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.27 Plot of CD45+ CD16+ CD11b+ CD64+ CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.28 Plot of CD45+ CD16+ CD11b+ CD64+ CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.29 Plot of CD45+ CD16+ CD11b+ CD64- CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.30 Plot of CD45+ CD16+ CD11b+ CD64- CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.31 Plot of CD4+ CD25+ CD127- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.32 Plot of CD3+ CD8+ CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.33 Plot of CD3+ CD8+ CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.34 Plot of CD3+ CD8+ CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.35 Plot of CD3+ CD8+ CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

2964

2967

2970

2973

2976

2979

2982

2985

2988

2991

2994

2997

3000

3003

3006

3009

3012

3015

3018

3021

3024

3027

3030

9



Figure 13.37 Plot of CD3+ CD4+ CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.38 Plot of CD3+ CD4+ CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.39 Plot of CD3+ CD4+ CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................


Figure 13.41 Plot of CD3+ CD8+ CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.42 Plot of CD3+ CD8+ CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.43 Plot of CD3+ CD8+ CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................


Figure 13.45 Plot of CD3+ CD4+ CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.46 Plot of CD3+ CD4+ CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.47 Plot of CD3+ CD4+ CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ............................

Figure 13.48 Plot of CD3- CD56+ DIM CD16+ CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.49 Plot of CD3- CD56+ DIM CD16+ CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .......

Figure 13.50 Plot of CD3- CD56+ DIM CD16+ CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .......

Figure 13.51 Plot of CD3- CD56+ DIM CD16+ CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.52 Plot of CD3- CD56+ DIM CD16+ CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.53 Plot of CD3- CD56+ DIM CD16+ CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.54 Plot of CD3- CD56+ DIM CD16+ CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.55 Plot of CD3- CD56+ DIM CD16+ CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.56 Plot of CD3- CD56+ DIM CD16- CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.57 Plot of CD3- CD56+ DIM CD16- CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.58 Plot of CD3- CD56+ DIM CD16- CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

3033

3036

3039

3042

3045

3048

3051

3054

3057

3060

3063

3066

3069

3072

3075

3078

3081

3084

3087

3090

3093

3096

3099

10


Figure 13.59 Plot of CD3- CD56+ DIM CD16- CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.60 Plot of CD3- CD56+ DIM CD16- CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.61 Plot of CD3- CD56+ DIM CD16- CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.62 Plot of CD3- CD56+ DIM CD16- CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.63 Plot of CD3- CD56+ DIM CD16- CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.64 Plot of CD3- CD56+ b CD16+ CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.65 Plot of CD3- CD56+ b CD16+ CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......

Figure 13.66 Plot of CD3- CD56+ b CD16+ CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.67 Plot of CD3- CD56+ b CD16+ CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.68 Plot of CD3- CD56+ b CD16+ CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.69 Plot of CD3- CD56+ b CD16+ CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.70 Plot of CD3- CD56+ b CD16+ CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.71 Plot of CD3- CD56+ b CD16+ CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.72 Plot of CD3- CD56+ b CD16- CD69+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.73 Plot of CD3- CD56+ b CD16- CD69+ CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.74 Plot of CD3- CD56+ b CD16- CD69+ CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.75 Plot of CD3- CD56+ b CD16- CD69+ CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.76 Plot of CD3- CD56+ b CD16- CD69- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.77 Plot of CD3- CD56+ b CD16- CD69- CD95L+ IL18R Alpha- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.78 Plot of CD3- CD56+ b CD16- CD69- CD95L+ IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.79 Plot of CD3- CD56+ b CD16- CD69- CD95L- IL18R Alpha+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ........

Figure 13.80 Plot of CD56+b CD16+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.81 Plot of CD56+b CD16- (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

3102

3105

3108

3111

3114

3117

3120

3123

3126

3129

3132

3135

3138

3141

3144

3147

3150

3153

3156

3159

3162

3165

3168

11


Figure 13.82 Plot of CD56+ DIM CD16+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.83 Plot of CD56+ DIM CD16- (%) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.84 Plot of CD56- CD16+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.85 Plot of CD19+ (%) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.86 Plot of CD19+ (cells/cumm) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................


Figure 13.88 Plot of Activated Natural Killer Panel (hrs) versus Time by Treatment and Subject (PD/Biomarker Population) ..................................................

Figure 13.89 Plot of T Cell panel (hrs) versus Time by Treatment and Subject (PD/Biomarker Population) ......................................................................

Figure 13.90 Plot of T cell B cell natural killer Lymphocytes (cells/cumm) versus Time by Treatment and Subject (PD/Biomarker Population) ...................

Figure 13.91 Plot of MON/B/TREG Panel (hrs) versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.92 Plot of Helper/Suppressor ratio versus Time by Treatment and Subject (PD/Biomarker Population) .........................................................

Figure 13.93 Plot of Median Interferon-gamma (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) .....................................................

Figure 13.94 Plot of Median Interleukin 1 Beta (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) .....................................................

Figure 13.95 Plot of Median Interleukin 2 (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) .....................................................





Figure 13.100 Plot of Median TNFa (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.101 Plot of Median GMCSF (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.102 Plot of Median IP-10 (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.103 Plot of Median MIG (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.104 Plot of Median MCP-1 (pg/mL) versus Time (weeks) by Treatment (PD/Biomarker Population) ......................................................................

3171

3174

3177

3180

3183

3186

3189

3192

3195

3198

3201

3204

3205

3206

3207

3208

3209

3210

3211

3212

3213

3214

3215

12


Figure 13.105 Plot of Individual IL-18BP (ng/mL) vs. Time (PD/Biomarker Population) ...............................................................................................

Figure 13.106 Plot of Individual IL-18BP:IL-18 Complex (ng/mL) vs. Time (PD/Biomarker Population) ......................................................................

Figure 13.107 Plot of Mean IL-18BP (ng/mL) vs. Time by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.108 Plot of Mean IL-18BP:IL-18 Complex (ng/mL) vs. Time by Treatment (PD/Biomarker Population) .....................................................

Figure 13.109 Plot of Median IL-18BP (ng/mL) vs. Time by Treatment (PD/Biomarker Population) ......................................................................

Figure 13.110 Plot of Median IL-18BP:IL-18 Complex (ng/mL) vs. Time by Treatment (PD/Biomarker Population) .....................................................

Figure 13.111 Plot of CD3- CD19+ CD69+ (%) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) .................................

Figure 13.112 Plot of CD3- CD19+ CD69- (%) versus Time (weeks) by Treatment and Subject (PD/Biomarker Population) ..................................................

BIOMARKER DATA SOURCE TABLES

Table 13.1 Listing of Cytokine and Chemokine Data (PD/Biomarker Population) .. EFFICACY DATA SOURCE FIGURES

Figure 15.1 Plot of Individual CA-125 Levels by Treatment versus Time (All Treated Subjects Population) ...................................................................

Figure 15.2 Plot of Mean CA-125 Levels by Treatment versus Time (All Treated Subjects Population) ................................................................................

Figure 15.3 Plot of Maximum Percent Decrease from Baseline in CA-125 Level by Subject (All Treated Subjects Population) ................................................

Figure 15.4 Plot of Maximum Percent Reduction from Baseline in Tumour Size by Subject (All Treated Subjects Population) ................................................

Figure 15.5 Plot of Kaplan-Meier Estimates of Progression-Free Survival for All Subjects (All Treated Subjects Population) ..............................................

EFFICACY DATA SOURCE TABLES

Table 15.1 Listing of Investigator-Assessed Tumour Responses (RECIST Criteria) (All Treated Subjects Population) ...............................................

Table 15.2 Summary of Investigator-Assessed Best Response (RECIST Criteria) (All Treated Subjects Population) ............................................................

Table 15.3 Listing of Investigator-Assessed Target Lesions Assessments (RECIST Criteria) (All Treated Subjects Population) ...............................

Table 15.4 Listing of Investigator-Assessed Non-Target Lesions Assessments (RECIST Criteria) (All Treated Subjects Population) ...............................

Table 15.5 Listing of Investigator-Assessed New Lesions Assessment (RECIST Criteria) (All Treated Subjects Population) ...............................................

3216

3221

3226

3227

3228

3229

3230

3233

3236

3655

3660

3661

3662

3663

3664

3669

3670

3687

3695

13


Table 15.6 Listing of Investigator-Assessed Lesion Assessments (All Treated Subjects Population) ................................................................................

Table 15.7 Listing of Progression Free Survival (PFS) (All Treated Subjects Population) ...............................................................................................

Table 15.8 Summary of Progression Free Survival (PFS) (All Treated Subjects Population) ...............................................................................................

Attachment 1 - Times and Events Table .................................................................

3700

3731

3736

3737

14


CONFIDENTIAL 2011N114107_00 ILI108621

- 7 -

LIST OF ABBREVIATIONS

AE Adverse event ALT Alanine aminotransferase AST Aspartate aminotransferase AUC Area under the plasma drug concentration-time curve AUC(0-τ) Area under the plasma drug concentration-time curve over the treatment

period Bpm Beats per minute CL Systemic clearance Cmax Maximum observed plasma concentration Cmin Minimum observed plasma concentration oC Degrees Celsius Cm Centimeter CPSR Clinical pharmacology study report CR Complete response CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CTL Cytotoxic T lymphocytes CVb% Coefficient of variation (as a percentage) dL Deciliter DLT Dose-limiting toxicity DNA Deoxyribonucleic acid eCRF Electronic Case Report Form ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group Emax Maximal effect oF Degrees Fahrenheit FasL Fas ligand FDA Food and Drug Administration λz Terminal plasma-elimination rate constant G Gram(s) GCP Good Clinical Practice GM-CSF Granulocyte-macrophage colony-stimulating factor GSK GlaxoSmithKline HbA1c Hemoglobin A1c HCl hydrochloride Hr Hour(s) IEC Independent Ethics Committee IFN-γ Interferon gamma IL Interleukin IL-18BP Interleukin 18 binding protein IL-18R Interleukin 18 receptor INR International normalized ratio IP-10 Interferon gamma inducible protein-10 kilodaltons IRB Institutional Review Board

15


- 8 -

IV Intravenous Kg Kilogram L Liter(s) LVEF Left ventricular ejection fraction M Meter MABEL Minimally active biologically effective level MCP-1 Monocyte chemoattractant protein-1 MedDRA Medical Dictionary for Regulatory Activities Mg Milligram MHC-I Major histocompatibility complex I MIG Monokine induced by interferon gamma mL Milliliter(s) mM Millimolar mmHg Millimeters of mercury Msec Millisecond MRI Magnetic resonance imaging MTD Maximum tolerated dose MUGA Multigated acquisition N, n Number NA Not applicable Ng Nanogram(s) NK Natural killer NR Normal range PD Pharmacodynamics or progressive disease PEG Polyethylene glycol PFS Progression-free survival PGx Pharmacogenetic pH Potential of hydrogen PK Pharmacokinetic PK/PD Pharmacokinetic/pharmacodynamic PO By mouth PR Partial response; heart rate PR interval PT Prothrombin time PTT Partial thromboplastin time QC Quality control QRS Heart rate QRS interval QT QT interval QTc Heart rate-corrected QT interval QTcB Heart rate-corrected QT interval (Bazzett) QTcF Heart rate-corrected QT interval (Fridericia) RAP Reporting and Analysis Plan RECIST Response Evaluation Criteria in Solid Tumors RNA Ribonucleic acid RR Heart rate R-R interval SAE Serious adverse event SB SmithKline Beecham

16


- 9 -

SD Standard deviation or stable disease SLD Sum of longest diameter t1/2 Apparent terminal elimination half-life T-cell Thymus-derived immune system cell Th1 Helper T lymphocyte type 1 TNF-α Tumor necrosis factor alpha TRAILR-2 Tumor necrosis factor-related apoptosis-inducing ligand receptor-2 Tregs Regulatory T-cells µg Microgram ULN Upper limit of normal USA United States of America USP United States Pharmacopoeia Vss Volume of distribution at steady state

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NONE Aranesp Doxil Inform Procrit SAS/STAT SAS

17


- 10 -

1. INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION

Ethics Committee

(USA)

USA

USA

Role: Ethics Committee for



Central Laboratories

Aushon Biosystems, Inc. 43 Manning Road Billerica, Massachusetts 01821 USA

Role: Laboratory for Cytokine and Chemokine Analysis

Activities Outsourced to Other Companies

TRIO Clinical Research Durham, North Carolina 27713 USA

TRIO Clinical Research Durham, North Carolina 27713 USA

ClinForce LLC 4815 Emperor Blvd Durham, North Carolina USA

Pharmtrials Consultants, Inc. 7474 Creedmoor Rd, PMB 131 Raleigh, North Carolina 27613 USA

VinZ Inc. 1408 Hemby Ridge Lane Morrisville, North Carolina 27560 USA

Responsibilities: Study monitoring of USA sites Responsibilities: Study monitoring of USA sites Responsibilities: Statistical work for clinical pharmacology study report (CPSR) Responsibilities: Statistical programming for CPSR Responsibilities: Statistical programming for CPSR

18


- 11 -

SFP Consulting, LLC Chapel Hill, North Carolina 27516 USA

Covance Laboratories Inc Madison, Wisconsin 53704 USA Quest Diagnostic Clinical Trials 7600 Tyrone Avenue Van Nuys, California 91405 USA

Responsibilities: Medical writing of CPSR Responsibilities: Pharmacokinetic (PK) analysis and report Responsibilities: Laboratory for flow cytometry analysis

Central Laboratories

Quest Diagnostic Clinical Trials 7600 Tyrone Avenue Van Nuys, California 91405 USA

Responsibilities: Pharmacogenetics (PGx) sample storage

2. LIST OF INVESTIGATORS

Investigator Site/Center Number Hospital/ Institution and Address MD*

USA

MD

USA MD

USA

All centers participated in the study under the United States Investigational New Drug Application. *No subjects randomized

3. ETHICAL CONDUCT OF THE STUDY

The study protocol, any amendments, the informed consent form, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board.

This study was conducted in accordance with “good clinical practice” (GCP), all applicable regulatory requirements, and the guiding principles of the Declaration of Helsinki.

19


- 12 -

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. Case report forms (electronic; eCRF) were provided for each subject’s data to be recorded.

4. OBJECTIVES & ENDPOINTS

4.1. Objectives

Primary

• To assess the safety and tolerability of a range of SB-485232 doses administered as bimonthly intravenous (IV) infusions (on Days 2 and 9 of a 28-day cycle) in combination with a standard regimen of pegylated liposomal doxorubicin (40 mg/m2 administered intravenously on Day 1 of a 28-day cycle; Doxil) in subjects with advanced stage epithelial ovarian cancer.

Secondary

• To assess the pharmacokinetics (PK) of SB-485232 administered in combination with Doxil as a bimonthly IV infusion in subjects with advanced stage epithelial ovarian cancer.

• To assess the pharmacodynamic (PD) effects of SB-485232 administered in combination with Doxil to subjects with advanced stage epithelial ovarian cancer using cytokine and immune cell phenotypic markers of biological activity.

• To assess the PK/PD relationship of SB-485232 administered in combination with Doxil as a bimonthly IV infusion in subjects with advanced stage epithelial ovarian cancer.

• To assess the PK of Doxil treatment in combination with SB-485232 administered as monthly IV infusions in subjects with advanced stage epithelial ovarian cancer. (The PK parameters for Doxil were not analyzed, see Section 9.2.4 for details.)

• To assess the immunogenicity of SB-485232 and polyethylene glycol (PEG) associated with Doxil when SB-485232 was administered as a bimonthly IV infusion in combination with Doxil in subjects with advanced stage epithelial ovarian cancer. (Anti-PEG antibodies were not analyzed, see Section 9.2.4 for details.)

• To assess the anti-tumor activity of SB-485232 administered in combination with Doxil as a bimonthly IV infusion in subjects with advanced stage epithelial ovarian cancer.

4.2. Endpoints

4.2.1. Primary

The safety endpoints consisted of the evaluation of adverse events (AEs) and changes in laboratory values from baseline.

20


- 13 -

Safety and Tolerability Assessments

• Adverse events

• Changes in safety parameters, for example:

• Clinical laboratory tests (clinical chemistry, hematology, urinalysis)

• 12-Lead electrocardiogram (ECG) data including ventricular rate as well as QT, heart rate-corrected QT interval (QTc), PR, RR and QRS intervals

• Multigated acquisition (MUGA) scans

• Vital signs: systolic and diastolic blood pressure, heart rate

• Plasma cytokines: interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-2, IL-6, IL-10, IL-12, IL-8

4.2.2. Secondary

• Pharmacokinetic parameters for SB-485232 and Doxil: area under the plasma drug concentration-time curve over the treatment period (AUC[0-τ]), maximum observed plasma concentration (Cmax), and minimum observed plasma concentration (Cmin) (The PK parameters for Doxil were not analyzed, see Section 9.2.4 for details.)

• Pharmacodynamic biomarker responses:

• Plasma IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ–inducible protein-10 kilodaltons (IP-10), monokine induced by IFN-γ (MIG), and monocyte chemoattractant protein-1 (MCP-1) changes from baseline and pre-dose

• Plasma IL-18 binding protein (IL-18BP) change from baseline

• Whole blood phenotype changes from baseline and pre-dose

• Absolute numbers thymus-derived immune system cells (T) and natural killer (NK) cells (CD45+/CD56+/CD16+/CD3+/CD4+/CD8+)

• % Activated CD16+ NK cells (CD16+/CD56+/CD3-/CD69+/ Fas ligand [FasL]+ and IL-18 receptor [IL-18R]+)

• % Activated CD16- NK cells (CD16-/CD56+/CD3-/CD69+/FasL+ and IL-18R+)

• % Activated cytolytic T-cells (CD8+/CD4-/CD3+/CD69+ FasL+ and IL-18R+)

• % Activated neutrophils (CD45+/CD16+/CD11b+/CD69+/CD64+)

• % Activated monocytes (CD45+/CD14+/CD69+/CD64+)

• % Regulatory T-cells (Tregs; CD25+/CD4+/CD127-)

• Immunogenicity (anti–SB-485232 and anti-PEG antibodies) (Anti-PEG antibodies were not analyzed - see Section 9.2.4 for details.)

• Anti-tumor activity (radiographic tumor assessments and serum CA-125 levels)

21


- 14 -

4.2.3. Exploratory Endpoint (Tumor Biomarkers)

Tumor biopsy material was obtained and additional PD biomarkers were analyzed to determine the effect of Doxil and SB-485232 co-administration on tumor tissue and to indicate the presence of cellular infiltration into the tumor. Archival tumor samples were also analyzed for these same biomarkers. Tumor biopsy was obtained by fine needle aspiration or core needle biopsy. Ascites fluid was considered an additional source for tumor cells. For those subjects with ascites, cellular material was collected by paracentesis.

• Cellular phenotypic markers included but were not limited to:

• T-cells (CD8+, CD4+)

• NK cells (CD56+)

• Tregs (FoxP3+)

• Dendritic cells (CD86+, CD11c+)

• Tumor cells (e.g., MHC-I, Fas, TRAILR-2)

• Ribonucleic acid (RNA) microarray analysis could also be performed on tumor tissue samples.

5. STUDY RATIONALE AND DESIGN

5.1. Study Rationale

Interleukin-18 is an immunostimulatory cytokine that regulates both innate and adaptive immune responses [Logan, 2006]. In pre-clinical studies, IL-18 induces synthesis of IFN-γ by T-cells and NK cells, augments the cytolytic activity of NK cells and cytotoxic T lymphocytes (CTL), and promotes differentiation of activated CD4+ T-cells into helper effector cells [Nakanishi, 2001; Gracie, 2003]. IL-18 has anti-tumor activity in animal models [Micallef, 1997; Osaki, 1998; Hashimoto, 1999; Wigginton, 2002; Coughlin, 1998]. Regression of tumors in IL-18–treated animals is not dependent upon the presence of IFN-γ or IL-12, but does appear to require an intact Fas/FasL pathway [Osaki, 1998; Hashimoto, 1999].

When IL-18 was given as monotherapy in Phase I clinical studies, a range of biologically active doses was identified. IL-18 induced a number of dose-dependent biological markers such as cytokines (e.g., IFN-γ, GM-CSF, TNF-α, IP-10, MIG, and MCP-1), cellular activation markers on circulating NK, CD8+ and CD4+ cells (e.g., FasL and CD69) and IL-18BP. However, IL-18 failed to demonstrate sufficient evidence of clinical efficacy, measured by tumor response, in a Phase II study in subjects with metastatic melanoma. These clinical studies, however, did demonstrate that IL-18 was safe and well tolerated, induced a potent biological response and affirmed the endogenous role of IL-18 as a co-stimulatory cytokine, suggesting that optimal use would be in combination with other cancer therapies.

To this effect, IL-18 enhanced the anti-tumor activity of the cytotoxic chemotherapeutic agent doxorubicin and significantly increased overall survival in a mouse T-cell

22


- 15 -

lymphoma xenograft model. Analysis of isolated murine lymphocytes revealed that the combination of IL-18 and doxorubicin increased the number of activated CD8+ CTLs, NK cells, and activated NK cells to the same extent as treatment with doxorubicin alone. However, the increase in activated CD8+ CTLs and NK cells in response to combination therapy was more enhanced in circulating peripheral blood lymphocytes when compared to splenocytes. Moreover, while treatment with doxorubicin alone attenuated NK cell cytotoxicity, a common side effect of this single-agent chemotherapy, co-treatment with IL-18 reversed doxorubicin-induced NK cell inhibition and stimulated robust NK cell cytotoxicity. These data suggest that combination therapy with IL-18 and doxorubicin exert immunostimulatory, anti-tumor effects in vivo that are not observed following exposure to either agent alone.

In other experiments, the combination of IL-18 with Doxil substantially restricted tumor growth in murine ovarian cancer cells compared to either agent alone. To characterize the mechanism for this synergistic anti-tumor effect, in vitro studies showed that treatment with Doxil up-regulated the surface expression of Fas, tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAILR0-2, and major histocompatibility complex (MHC)-I on ovarian cancer cells. These data suggest that pegylated doxorubicin increases the immunogenicity of ovarian tumor cells by enhancing susceptibility to Fas- and TRAIL-mediated apoptosis. Interestingly, IL-18-dependent tumor regression is thought to involve the Fas/FasL signaling pathway [Hashimoto, 1999]. Moreover, IL-18 exerts immunostimulatory effects by strongly increasing IFN-γ, activating both NK cells and circulating T lymphocytes, and enhancing T infiltrating lymphocytes [Lebel-Binay , 2000] . Similar results were observed in biopsies obtained from established severe combined immunodeficiency mice grafted with human peripheral blood leukocytes and then treated with human IL-18. Tissue analysis revealed IL-18-dependent infiltration of NK, CTLs, and dendritic cells as well as depletion of Tregs in the tumor microenvironment.

It was hypothesized that the anti-tumor activity of Doxil may be enhanced by IL-18. Specifically, it was suggested that the chemotherapeutic agent provides the direct cytotoxicity, fragmentation, and modulation of tumor antigens, while IL-18 augments and activates effector cells, resulting in superior antigen presentation and synergistic anti-tumor activity. Moreover, combination therapy may not only exert anti-tumor effects but may also be capable of inducing immunological memory as data from pre-clinical studies have shown that mice who responded to treatment with Doxil and IL-18 were protected from subsequent tumor challenge.

Study ILI108621 was a Phase I protocol evaluating the safety and biological activity of IL-18 in combination with Doxil in subjects with advanced stage epithelial ovarian cancer. This study used a standard treatment regimen of Doxil in combination with rising doses of IL-18 to identify a dose which is safe and tolerable and gives a maximum biological effect as demonstrated by selected biomarkers (e.g., activated T and NK cells). The dose selected from this study may be used in a future Phase II study evaluating the efficacy of the IL-18/Doxil combination in subjects with advanced ovarian cancer. Given the good safety and tolerability profile of IL-18 when administered as monotherapy to subjects with metastatic melanoma, it was not anticipated that the maximum tolerated dose (MTD) of the combination would be reached in the current study; however, this

23


- 16 -

study was designed to define the MTD if dose-limiting toxicities (DLT) were identified in subjects with epithelial ovarian carcinoma.

5.2. Study Design

This was a Phase I, open-label, dose-escalation, safety and tolerability study of SB-485232 in combination with a standard regimen of Doxil in subjects with advanced epithelial ovarian cancer. Subjects received up to four cycles of combination therapy. One cycle of experimental treatment lasted 28 days, consisting of one dose of Doxil (40 mg/m2 IV) on Day 1 plus two doses of SB-485232 (on Days 2 and 9). The starting dose of SB-485232 was 1 µg/kg. The dose of SB-485232 was escalated in subsequent cohorts. Planned doses of SB-485232 above 1 µg/kg were escalated as follows: 3, 10, 30, and 100 µg/kg.

Each cohort consisted of three subjects but a cohort could be expanded up to six subjects if toxicity was observed (Section 7.1). Five cohorts were recruited (approximately 15 subjects were planned). If DLTs were observed, additional subjects could be enrolled to expand the size of a cohort in an effort to determine the MTD. Extra cohorts could also be opened based on this same rationale for defining the MTD.

On the first week of each cycle, dosing was staggered and Doxil was administered by IV infusion on Day 1 and SB-485232 was administered by IV infusion on Day 2. During Week 2, SB-485232 was administered on Day 9 (±1 day).

The first subject dosed within each cohort was considered a sentinel subject and dosing of subsequent subjects within the same cohort did not occur until the sentinel subject had completed at least two weeks of Cycle 1 without any safety or tolerability concerns.

For all infusions of Doxil, the complete delivery of the dose, from the initiation of infusion to the end of infusion, took place over a one-hour period. SB-485232 infusion took place over a two-hour period.

Subjects were screened up to a maximum of 28 days prior to dosing. On Day 1 of all four cycles, dosing took place by slow IV infusion of Doxil. Subjects remained in the unit for two hours after the end of the infusion and, in the absence of any safety concerns, were discharged from the unit. On Day 2, dosing took place by slow IV infusion of SB-485232. Subjects remained in the unit for at least six hours after the end of their first SB-485232 infusion on Cycle 1 Day 2 and then for at least two hours after the end of all subsequent doses of SB-485232. Upon completion of the minimum post-dose observation period, subjects were discharged as deemed clinically appropriate by the investigator. On Day 4 of Cycles 1 and 4, subjects returned to the clinic for PK/PD sampling and safety evaluations.

Subjects who completed all four cycles of experimental treatment were enrolled in the study for approximately 20 weeks (up to four weeks screening plus 16 weeks [i.e. four cycles] of dosing that included a follow-up visit [i.e., Follow-up Visit 1] at least two weeks after the final dose of SB-485232). Subjects were followed for progression or survival for one year after the initial follow-up period (Follow-up Visit 2). Subjects who

24


- 17 -

showed no evidence of clinical disease progression at the conclusion of this roughly 20-week period continued to be followed at three month intervals or more frequently as clinically indicated until the subject experienced disease progression and/or death, withdrew consent, or was lost to follow up, whichever came first. All subjects who experienced clinical benefit, as determined by the principal investigator, from Doxil after completing four cycles of experimental treatment were allowed to continue Doxil monotherapy during any follow-up period as per standard of care. However, additional doses of SB-485232 were not administered in conjunction with Doxil beyond the initial four cycles of experimental treatment. Continued dosing with SB-485232 in the compassionate setting was not recommended as the effect of long-term IL-18 treatment on the proven anti-tumor efficacy of Doxil remain unknown.

Dose-escalation conference calls were held with the investigative sites prior to dosing the next cohort. For all cohorts, a dose-escalation meeting occurred after three subjects within a cohort had completed Cycle 1 and at least one subject had completed Cycle 1 plus two weeks of Cycle 2. Safety and tolerability data from all preceding cohorts and the latest cohort were reviewed as part of each dose-escalation decision (Appendix 16.1, Protocol Section 8.4). If there was no evidence of toxicity greater than Grade 2 (using the Common Terminology Criteria for Adverse Events, Version 3.0 [CTCAE, v3.0]) with “suspected” or “probable” relationship to study drug, three subjects were treated in each subsequent cohort.

This study was designed to identify the MTD if DLTs were identified; therefore, the dose level could have been modified and the cohort expanded based on the frequency of these toxicities (Section 7.1.1).

6. DIAGNOSIS AND CRITERIA FOR INCLUSION

Approximately 15 subjects were planned for enrollment in this study (5 cohorts, 3 subjects each).

6.1. Inclusion Criteria

A subject was eligible for inclusion in this study only if all of the following criteria applied:

1. Female, age ≥18 years of age. 2. Histologically confirmed diagnosis of epithelial ovarian, fallopian tube, or primary

peritoneal carcinoma.

3. Candidate was to receive Doxil for treatment of advanced stage ovarian cancer as per standard of care and in the opinion of the treating principal investigator.

4. Measurable lesion(s) according to Response Evaluation Criteria in Solid Tumors (RECIST).

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

6. Predicted life expectancy of ≥4 months.

25


- 18 -

7. No chemotherapy, immunotherapy, hormonal therapy, or biological therapy for cancer, radiotherapy, or surgical procedures (except for minor surgical procedures) within four weeks before beginning treatment with SB-485232 (six weeks for nitrosoureas and mitomycin C). Subjects were required to have recovered from toxicities (incurred as a result of previous therapy) sufficiently to be entered into a Phase I study.

8. Disease-free period of at least five years from prior malignancies (except for curatively treated basal and squamous cell carcinomas of the skin and/or carcinoma of the cervix in situ).

9. Left ventricular ejection fraction (LVEF) ≥50 % as determined by MUGA scan. 10. A signed and dated written informed consent form was obtained from the subject. 11. The subject was able to understand and comply with protocol requirements,

timetables, instructions, and protocol-stated restrictions.

12. The subject was likely to maintain good venous blood access for PK and PD sampling throughout the study.

13. A female was eligible to enter and participate in the study if she was of: a. Non-childbearing potential (i.e., physiologically incapable of becoming

pregnant) including any female who:

• Has had a hysterectomy,

• Has had a bilateral oophorectomy (ovariectomy),

• Has had a bilateral tubal ligation, or

• Was post-menopausal (demonstrate total cessation of menses for greater than one year). If amenorrheic for less than one year, post-menopausal status was confirmed by serum follicle stimulating hormone and estradiol concentrations at screening.

or,

b. Childbearing potential, had a negative serum pregnancy test at the screening visit, and agreed to one of the following GSK acceptable contraceptive methods:

• Any intrauterine device with a documented failure rate of less than 1% per year.

• Vasectomized partner who was sterile prior to the female subject’s entry and was the sole sexual partner for that female.

• Oral contraceptive (either combined or progesterone only).

• Because of unacceptable failure rate of barrier (chemical and/or physical) methods, the barrier method of contraception were only to be used in combination with other acceptable methods described above.

14. Adequate organ function, as described in Table 1.

26


- 19 -

Table 1 Reference Table for Organ Functions

SYSTEM LABORATORY VALUES Hematologic Absolute neutrophil count ≥1.5 × 109/L Hemoglobin ≥9 g/dL (after transfusion if needed) Platelets ≥75 × 109/L Renal Serum creatinine ≤1.5 mg/dL OR

Calculated creatinine clearance* ≥50 mL/min within 14 days prior to treatment Hepatic Serum bilirubin ≤1.5 mg/dL AST and ALT ≤3 × ULN without liver metastases or

≤5 × ULN with documented liver metastases * Cockcroft and Gault method Calculated creatinine clearance (mL/min)

(140 − age [years] ) × weight (kilograms) 72 × serum creatinine (mg/dL)

Female subjects: multiply by 0.85 ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal

6.2. Exclusion Criteria

A subject was not eligible for enrollment in this study if any of the following criteria applied:

1. Significant cardiac, pulmonary, metabolic, renal, hepatic, gastrointestinal, or autoimmune conditions that, in the opinion of the investigator and/or GSK medical monitor, placed the subject at an unacceptable risk as participant in this study.

2. Any severe concurrent disease or condition, including significant active autoimmune diseases such as rheumatoid arthritis, which in the judgment of the principal investigator made the subject inappropriate for study participation.

3. History of myocardial infarction, unstable angina, or acute coronary syndrome within the past six months.

4. History of hypersensitivity reactions to a conventional formulation of doxorubicin hydrochloride (HCl) or the components of Doxil.

5. History of receiving a total cumulative dosage of doxorubicin HCl exceeding the currently recommended limit of 550 mg/m2 or would exceed the 550 mg/m2 dosage limit during the course of the current study. A subject was also excluded if she received a lower cumulative dosage of doxorubicin HCl (i.e., 400 mg/m2) and also had prior radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones was included in calculations of total cumulative doxorubicin HCl dosage.

6. Women who were pregnant or were breastfeeding.

27


- 20 -

7. Corrected QT interval ≥480 msec (average of three measurements were made at screening).

8. Diabetes mellitus with poor glycemic control. 9. History of human immunodeficiency virus or other immunodeficiency disease. 10. Positive Hepatitis B surface antigen. 11. History of a severe infusion-related reaction following treatment with Doxil (Section

6.3.2).

12. Had acute infection or severe or uncontrolled infections requiring systemic antibiotic therapy.

13. Any serious medical or psychiatric disorder that would have interfered with subject safety or informed consent.

14. Psychological, familial, sociological, or geographical conditions that did not permit compliance with the protocol.

15. Known leptomeningeal disease or evidence of prior or current metastatic brain disease. Routine screening with central nervous system imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) was required only if clinically indicated.

16. Receiving concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy.

17. Oral corticosteroids within 14 days of study entry. 18. History of ventricular arrhythmias requiring drug or device therapy. 19. Any investigational drug within 30 days or five half-lives (whichever was longer)

preceding the first dose of SB-485232.

20. Active signs of a bowel obstruction. 6.2.1. Other Eligibility Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator referred to the following documents for detailed information regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to the investigational products used in this study:

• SB-485232 Investigator’s Brochure

• Full prescribing information (i.e., package insert) [DOXIL Package Insert, 2008] for Doxil

28


- 21 -

6.3. Subject Withdrawal

6.3.1. Discontinuation of SB-485232 Due to Toxicity

Given concerns regarding cytokine interactions and possible immunogenicity, close monitoring of hemodynamics after SB-485232 infusion was essential. In accordance with the preparedness for treatment of anaphylaxis, emergency resuscitation equipment, advanced cardiac life support equipment, and medications were readily available at the bedside during SB-485232 administration.

Infusion of SB-485232 was required to be stopped if the following were observed at any time during the infusion:

• If the subject developed symptoms suggestive of hypersensitivity reactions (e.g., fever, flushing, urticaria, hypotension, chest tightness, wheezing), the infusion was to be stopped immediately and the management steps outlined in Recommendations for Management of Toxicity were considered (Appendix 16.1, Protocol Section 10.2.3).

• If a subject developed Grade 2 hypotension or a drop in blood pressure >20 mmHg compared to pre-dose measurements, the infusion was stopped and measures for hypotension management considered (Appendix 16.1, Protocol Section 10.2.3). For recurrent Grade 2 hypotension, despite pre-hydration or Grade 3 or 4 hypotension, the subject was removed from the protocol.

• If a subject developed a fever of ≥104°F (40°C) during the infusion, the infusion was stopped and measures for fever management were considered (Appendix 16.1, Protocol Section 10.2.3). If the temperature dropped to


- 22 -

• If indicated in the judgment of the principal investigator or GSK medical monitor.

• If any subject exhibited signs or symptoms of a severe infusion-related reaction, severe cytokine-release syndrome, or severe allergic reaction after receiving SB-485232, the infusion was stopped immediately and withdrawn from the study (i.e., subject did not receive Doxil).

• Disease progression (isolated elevation in CA-125 was not indicative of disease progression).

• The subject withdrew their consent for study participation. 6.3.2. Discontinuation of Doxil Due to Toxicity

The following rules were used to prevent administration of additional doses of Doxil to an individual subject experiencing drug-related toxicity. Infusion of Doxil was stopped and the symptom management guidelines considered (as described in Section 6.3.1) if hypersensitivity reaction, Grade 2 or drop in blood pressure >20 mmHg, fever of ≥104°F (40°C) during the infusion, or bradycardia or tachycardia occurred.

Treatment with Doxil could be discontinued and the subject withdrawn from the study for the following reasons:

• If any subject exhibited signs or symptoms of a severe infusion related reaction, severe cytokine release syndrome, or a severe allergic reaction after receiving Doxil (see paragraph below), the infusion was stopped immediately and withdrawn from the study (i.e., subject did not receive SB-485232).

• Left ventricular ejection fraction ≤45% or a 20% relative decrease from baseline.

• The next experimental treatment cycle was not started due to unresolved toxicity (as detailed in Appendix 16.1, Protocol).

• If indicated in the judgment of the principal investigator or GSK medical monitor.

• Disease progression (isolated elevation in CA-125 was not indicative of disease progression).

• The subject withdrew their consent for study participation. Signs and symptoms of a severe infusion-related reaction, severe cytokine release syndrome, and a severe allergic reaction:

• Grade 3 to 4 (using CTCAE, v3.0) urticaria, hypotension, laryngeal edema, and/or bronchospasm and/or any Grade 3 hypoxia that persisted for more than 24 hours or any Grade 4 hypoxia.

• Grade 3 or higher cytokine-release syndrome (using CTCAE, v3.0).

• Grade 3 or higher allergic reaction/hypersensitivity (using CTCAE, v3.0).

30


- 23 -

6.4. Subject Withdrawal from Study

A subject could voluntarily discontinue participation at any time. In addition, the investigator could, at his/her discretion, withdraw the subject from participating in this study at any time. If a subject was prematurely withdrawn from the study for any reason, the investigator was encouraged to make every effort to perform Follow-up Visit 1.

For any given cohort, at least one subject was required to complete Cycle 1 plus the first two weeks of Cycle 2 corresponding to at least four infusions of SB-485232. The remaining subjects in that cohort were required to complete Cycle 1 corresponding to at least two infusions of SB-485232. This ensured that the minimum amount of required safety and tolerability data was collected in order to make a dose-escalation decision for the subsequent cohort. Subjects were replaced within a cohort as necessary such that this collective cycle minimum was achieved. Data from subjects who received more frequent doses of SB-485232 (i.e., weekly IL-18 infusions) as required under previous versions of the protocol could be used to satisfy this cohort enrollment requirement provided that the subject received the minimum number of SB-485232 infusions as specified above.

6.5. Permitted Medications

Subjects were asked to provide a complete list of prescription, alternative, and over-the-counter medications they had taken within six weeks prior to the screening visit. All concomitant medications, along with complete list of all prior cancer therapies were recorded in the eCRF.

Subjects received appropriate supportive care during the study including but not limited to: transfusion of blood and blood products, erythropoietic agents (e.g., Aranesp, Procrit), treatment with antibiotics, antiemetics, antidiarrheals, or analgesics. For subjects who develop drug-related fever, symptomatic treatment with acetaminophen (paracetamol) was permitted. Other appropriate supportive medications, including pre-medications given for subsequent treatment, could be administered and recorded in the eCRF.

6.6. Prohibited Medications

Subjects were not allowed to receive other concurrent anticancer therapy (e.g., cytotoxic, biologic, radiation, steroid, or hormone therapy [other than for replacement purposes]) while on this study. Other anticancer therapy was not given unless one of the following occurred: an unacceptable toxicity developed; OR the subject was withdrawn from the study at the investigator’s discretion or consent was withdrawn. Subjects were not permitted to receive any other anticancer therapy within four weeks prior to the first dose of SB-485232 (Section 6.1 for complete details) continuing until completion of the final follow-up visit.

Within 14 days prior to study entry, the subject was not permitted to receive oral corticosteroids.

31


- 24 -

7. TREATMENT ADMINISTRATION

7.1. Treatments Administered

Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 was administered by IV infusion once a month for four consecutive months according to standard practice on Day 1 of Cycle 1 to 4. Specifically, 40 mg/m2 was administered at an initial rate of 1 mg/minute to minimize the risk of infusion reactions. The infusion rate could be slowed if acute infusion-related reactions were observed. If no infusion reactions occurred, the infusion rate was increased to achieve complete delivery of the dose, from the initiation of infusion to the end of infusion, over a minimum period of at least one hour.

Date post:	03-Jul-2020
Category:	Documents
Upload:	others
View:	3 times
Download:	0 times

In February 2013, GlaxoSmithKline (GSK) announced …...In February 2013, GlaxoSmithKline (GSK)...

Documents