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New directions in advanced kidney cancer: the ARISER and VEG102616 studies

New directions in advanced kidney cancer: the ARISER and VEG102616 studies. Jonathan Rosenberg, MD UCSF Cancer Center Survivor’s Day 2006. Agenda. Staging for kidney cancer Adjuvant therapy trial: ARISER Advanced kidney cancer trial: Pazopanib (GW786034).

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New directions in advanced kidney cancer: the ARISER and VEG102616 studies

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  1. New directions in advanced kidney cancer: the ARISER and VEG102616 studies Jonathan Rosenberg, MD UCSF Cancer Center Survivor’s Day 2006

  2. Agenda • Staging for kidney cancer • Adjuvant therapy trial: ARISER • Advanced kidney cancer trial: Pazopanib (GW786034)

  3. Clinical Staging and Prognosis in RCC: American Joint Committee on Cancer Criteria Stage I Tumor <7 cm in greatest dimension andlimited to kidney; 5-year survival, ~95% Gerota’s fascia Adrenal gland Aorta Kidney Stage II Tumor >7 cm in greatest dimension andlimited to kidney; 5-year survival, ~88% Inferior vena cava Stage III Tumor in major veins or adrenal gland,tumor within Gerota’s fascia, or 1 regional lymph node involved;5-year survival, ~59% Lymph nodes Stage IV Tumor beyond Gerota’s fascia or>1 regional lymph node involved;5-year survival, ~20% Modified from Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477-2490.

  4. Clinical Staging and Prognosis in RCC: AJCC System Javidian J et al. J Urol 1999;162:1277-1281.

  5. Surgical Management of RCC • Surgery is the primary approach for early-stage (T1–T2), localized kidney cancer • Partial vs radical nephrectomy • Laparoscopic vs open surgery • RFA or cryotherapy are sometimes considered • Surgical removal of locally advanced RCC (T3) is associated with high recurrence • 20%–30% of patients with localized tumors recur, usually within 3 years • Systemic therapy has not been proven to be effective in reducingrisk of relapse • Surveillance (X-ray and CT) is recommended for all patients and should be more frequent for patients with higher stage tumors • Patients should be considered for clinical trial enrollment testing strategies to prevent recurrence

  6. Limited Role of Adjuvant Therapy inRCC BCG=Bacillus Calmette-Guerin; DFS=disease-free survival; IFN-=interferon alpha; IL-2=interleuken 2; MPA=medroxyprogesterone acetate; NS=not significant; PFS=progression-free survival. 1. Jocham D et al. Lancet. 2004;363:597-599;2. Kjaer M et al. Int J Radiat Oncol Biol Phys. 1987;13:665-672; 3. Pizzocaro G et al. J Urol. 1987;138:1379-1381; 4. Galligioni E et al. Cancer. 1996;77:2560-2566; 5. Messing EM et al. J Clin Oncol. 2003;21:1214-1222; 6. Clark JI et al. J Clin Oncol. 2003;21:3133-3140.

  7. Advanced kidney Cancer • Curing kidney cancer once it recurs is very difficult • Prevention of recurrence in patients who have their kidneys removed is a “holy grail” of kidney cancer • “Adjuvant therapy” • Treatment given after the main therapeutic intervention to reduce the risk of recurrence • No therapy yet has proven beneficial in reducing recurrence • Effective new treatments are needed

  8. Rencarex: Wilex G250 antibody • High affinity chimeric antibody • Targets the MN/ carbonic anhydrase IX (CAIX) antigen • 95% of clear cell kidney cancer express this antigen • CAIX not expressed in normal kidney and in other tissues • How does it work? • G250 binds to kidney cancer cells and targets them for destruction by the immune system • “Antibody dependent cell-mediated cytotoxicity”

  9. Rencarex: Wilex G250 antibody • Initially tested in metastatic kidney cancer • Low response rate in metastatic kidney cancer but high rate of stable disease • Patients with clinical benefit (response or stable disease) did better than those who did not • Excellent safety profile • No serious side effects observed • Low toxicity and results from the early testing provide rationale for testing it to prevent or delay recurrence

  10. G250 Adjuvant Study:ARISER Adjuvant Rencarex (WX-G250) Immunotherapy Phase III trial to Study Efficacy in Non-metastatic Renal Cell Carcinoma • Randomized • Double blind • Placebo controlled • Clear cell kidney cancer with high risk of recurrence

  11. ARISER G250 Study • Who can enroll: • T3bN0/NX (into the renal veins or vena cava below the diaphragm) • T3cN0/Nx (into the vena cava above the diaphragm or into the wall of the vena cava) • T4N0/NX (outside the kidney fascia) • Any T stage and Node + • T1bN0/NX (tumor between 4 and 7 cm) or T2N0 (>7cm but limited to the kidney) with microscopic vascular invasion • T3aN0/NX (invades adrenal gland or peri-renal fat) and grade 3 or higher

  12. ARISER G250 Study • Other major eligibility criteria: • No history of prior cancer, immunotherapy, chemotherapy within 5 years • No immunosuppression or corticosteroid therapy • When can they enroll: • Within 8 weeks of nephrectomy

  13. Nephrectomy Screen Randomize G250 antibody infusion weekly x 6 months Placebo infusion weekly x 6 months CT Chest, Abdomen, Pelvis monitoring Follow for 6 years Study Design 612 patients needed Study is designed to answer the question of whether this treatment will be effective in preventing recurrence and improving survival

  14. Advanced kidney cancer • RCC highly resistant to current chemotherapy drugs • Interferon- • 15% objective response rate (ORR) • responses rarely complete or durable • modest survival benefit compared with placebo or ineffective therapies • High-dose interleukin-2 • 15-20% ORR in stage IV patients • only 5% complete responders • No overall benefit to high dose IL-2 compared to low dose therapy • 3-5% of patients have durable responses

  15. VEGF-targeted tyrosine kinase inhibitors (TKI’s) • Approval of 2 new drugs for kidney cancer (sorafenib, sunitinib) represents a major advance • Need to identify the best anti-VEGF tyrosine kinase inhibitor for patients with advanced kidney cancer • The “best” drug has not yet been defined • Goals of current kidney cancer research is to give patients more and better options • Testing of new drugs in this class may find different levels of anti-cancer activity and side effects

  16. What is Pazaponib (GW786034)? • Pazopanib (GW786034) is a potent multi-target tyrosine kinase inhibitor that inhibits VEGFR-1, -2. -3, PDGFR- and -, and c-kit • Selectively inhibits VEGF-mediated endothelial cell proliferation • Once daily dosing of tablets (800mg) • Pazaponib has been given to 200+ patients

  17. Pazopanib (GW786034) Development • The first study (VEG10003) in various advanced solid tumors : • Phase I • Dosed subjects at various levels (50mg to 2000mg) to find the appropriate dose for the oncology program • The appropriate dose turned out to be 800mg • Many other studies in other cancer types being conducted with this drug

  18. Pazopanib (GW786034) Development in RCC • The Phase I study demonstrated activity (stable disease or partial response) in kidney cancer Baseline Post Treatment (Week 21)

  19. VEG10003 Phase I Patient Background • Enrolled • 63 subjects • 2 cohorts (800mg daily or 300 – 400 mg twice daily) • Tumor types enrolled • Kidney - Renal (12 pts) • Colorectal Cancer - CRC (10 pts) • Sarcoma – soft tissue tumors (8 pts) • Lung (7 pts) • Breast (5 pts) • Pancreatic (4 pts) • GIST - Gastrointestinal stromal tumor (4 pts) • Neuroendocrine (3 pts) • Other (10 pts)

  20. Pazaponib (GW786034) Response in Phase I Several VEG10003 study patients had stable disease or partial responses: - kidney cancer - thyroid cancer (on study for 101weeks or ~2 years) - sarcoma - GIST (gastrointestinal) - ovarian cancer - melanoma (skin cancer) - rectal cancer - lung cancer - neuroendrocrine

  21. Pazaponib (GW786034) Response in Phase I VEG10003 study patients with Kidney cancer: • 7 patients in first study who received 800 mg to 2000 mg daily or 300 mg bid had stable disease or tumor reduction • 3 subjects are still on study: • One with a partial response (PR) • Two with stable disease/minimal response (SD/MR) • 1 subject had a partial response

  22. Pazaponib (GW786034) Side Effects Common side effects seen in at least 2 patients dosed at 800mg for the 11 total subjects include : • Elevated blood pressure (Hypertension) (n=8) • Tiredness (Fatigue) (n=7) • Diarrhea (n=6) • Nausea (n=5) • Protein in urine (Proteinuria) (n=4) • Decrease in neutrophils, a type of white blood cell (Neutropenia) (n=2) • Decreased platelets in the blood (Thrombocytopenia) (n=2) • Vomiting (n=2) • Hair changes color to white (Depigmentation) (n=2)

  23. Comparison of Pazopanib with other Anti-angiogenic Agents

  24. Comparison of Treatment-emergent Adverse Events * Data from sorafenib and sunitinib label, respectively

  25. VEG102616 Study Details VEG102616: Randomized Discontinuation Study of GW786034 (pazopanib)

  26. VEG102616: New Phase II study • Study is open in 10 countries around the world • 12 sites in the USA • There are several sites in California recruiting for the study:Jonathan Rosenberg, MD UCSF Comprehensive Cancer Center in San Francisco, CA David Minor, MDCalifornia Kidney Cancer Foundation in San Francisco, CAJohn Fruehauf, MDUniversity of California, Irvine in Orange, CA

  27. VEG102616: A Global Study 60+ study sites N = 160-230 patients First patient enrolled: Oct 2005 Europe UK Belgium Czech Republic Israel Asia China Taiwan Hong Kong Malaysia Singapore North America USA Australia

  28. VEG102616 Phase II Trial Design Screening/ Baseline 3 months(open label drug) Lead-in phase Decision point 4 months Randomized drug (stable disease) Open label drug (tumors are smaller) RandomizationPhase *Pts may switch to open label if they progress on randomized drug All subjects Open label drug: continues until indefinitely (unless progression)

  29. VEG102616 Phase II Trial Key Objectives: Lead-in Phase (3 months of study) • To determine the response to drug after the first 3 months of treatment Randomized Phase (4 months of study) • Primary Objective: • Compare the tumor shrinkage of patients on active drug vs. patients on placebo in a randomized setting • Secondary Objectives: • Safety (all patients) • To determine progression-free survival over a 4 month time period in a randomized population • To determine response rate (in terms of tumor shrinkage)

  30. Study entry criteria for Phase II VEG102616? Inclusion: • Clear Cell Kidney Cancer • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. • Adequate bone marrow function. • Adequate kidney function. Exclusion: • Have had any major surgery, radiotherapy, or immunotherapy within the last 28 days and/or not recovered from prior therapy. • Women who are pregnant or lactating. • Poorly controlled hypertension. • Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with safety or obtaining informed consent.

  31. VEG102616: Study Procedures Basic study procedures include the following: • Review and consent to the trial (informed consent process) • Review of medical history and medication review • Disease assessment (CT scans, MRI or bone scans) • Blood and urine samples • ECGs (monitor heart) • Physical exams • Vitals and blood pressure monitoring

  32. VEG102616: Contacts for study • Jonathan Rosenberg, MD UCSF Comprehensive Cancer Center San Francisco, CA • David Minor, MDCalifornia Kidney Cancer Foundation San Francisco, CA • GlaxoSmithKline Clinical Trial Center: reference on call study: VEG102616Toll free phone number: 1- 877-379-3718 

  33. Summary: GW786034 • Multi-target tyrosine kinase inhibitor of VEGFR, c-Kit and PDGFR • Evidence of anti-tumor activity in advanced RCC and other advanced solid tumors in early programs • Most common side effects • Hypertension • Fatigue • Gastrointestinal • 800 mg once daily is being evaluated in Phase II trials and is the proposed dose for the Phase III trial in RCC

  34. Future directions • Urgent need to improve options for patients to prevent recurrence of their kidney cancer after nephrectomy (ARISER) • Identify the best anti-VEGF agent in advanced kidney cancer • Ultimate goal is to have many more survivors here each year

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