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hoosieroncologygroup

www.hoosieroncologygroup.org. HOG. The Hoosier Oncology Group currently exists as a non-profit cancer research organization. HOG maintains infrastructure to facilitate research from hypothesis to publication. Purposes of HOG. To conduct cancer research;

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hoosieroncologygroup

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  1. www.hoosieroncologygroup.org

  2. HOG The Hoosier Oncology Group currently exists as a non-profit cancer research organization. HOG maintains infrastructure to facilitate research from hypothesis to publication.

  3. Purposes of HOG • To conduct cancer research; • To foster cooperation between medical center researchers and community practitioners; • To engage in research that will enhance existing practice options or produce benefit to other research activities of the HOG; • To disseminate the knowledge and information obtained through the HOG's research.

  4. HOG’S COLLABORATORS Clinical Investigators Research Sponsors HOG Research Sites

  5. Research Process

  6. Research Supporting Entities Concepts $ $ Concepts Institutional Participants Clinical Trials Committee Concepts Protocols Data Funding Publications Data

  7. FY07-08 HOG Organizational Structure -170(b)(1)(A)(vi) public charity -3 member board Hoosier Oncology Foundation = -509(a)(3) supporting organization to HOF -7 member board appointed by HOF Hoosier Oncology Group = -C corporation owned initially 100% by HOG -5 member board appointed by HOG Bio-Oncology Associates in Research (not yet established) =

  8. Leadership Matrix Dr. Nasser Hanna - Chairman and President Dr. Lawrence Einhorn - Chief Scientific Officer Jake Vinson Executive Director Research Operations Manager Jayme Harvey Research Development Manager Vaishali Rajeev Statistics/Data Core Leader Doug Smidabush Administration Jake Vinson

  9. Scientific Mission and Flow -Correlate clinical and laboratory data with the goal of identifying factors that are associated with response and/or toxicity.-Clinical Trial Working Groups to develop hypothesis.-Target Diseases: -Lung (III NSCLC, IV NSCLC, ED SC, LD SC) -Breast (Metastatic, Adjuvant)-GI (Pancreatic, Met CRC, 2nd line CRC) -GU (TCC, HRPC)-Ovarian -Hematology-Quality of Life/Symptom Control

  10. Core Business Areas -Investigator Initiated Research – traditional HOG research-Industry Sponsored Trials – growing market for BOAR-Biorepository: -samples labs data hypothesis clinical trials -Research Awareness / Advocacy (research site relations)– - Centralized Research Services – -Centralized IRB/Regulatory -Clinical Trial Material (study drugs)

  11. Hoosier Oncology Group Trials: shaping cancer care

  12. Colon Cancer • Platinum active in many malignancies • Platinum highly synergistic with 5FU • Widely tested combination in 1980’s • 1988 • Cisplatin + 5FU vs. 5FU • Demonstrated the lack of efficacy of cisplatin in colon cancer

  13. Melanoma • Dartmouth regimen commonly prescribed and considered standard in 1990’s • Highly toxic and inconvienent • Utilized multiple highly emetic drugs (cisplatin, DTIC, BCNU) • 1999: DTIC vs Dartmouth • No difference in efficacy • Altered what was considered “standard therapy” for metastatic melanoma

  14. Bladder Cancer • Gemcitabine/Paclitaxel • Identified high incidence of ILD with this combination • Activity of Alimta • Cis/Gem/Avastin • Study basis for planned randomized trial

  15. Small Cell Lung Cancer • Defined activity of oral etoposide in refractory SCLC • VIP vs EP: positive phase III trial • VIP +/- oral etoposide: defined the lack of efficacy of prolonged etoposide treatment and role of maintenance chemotherapy • IP vs EP: refuted JCOG trial • Iressa and Alimta in relapsed SCLC: only drugs tested to date which are more active in NSCLC than in SCLC • Only group to evaluate efficacy of Avastin in relapsed SCLC

  16. Stage III NSCLC • XRT +/- Cisplatin: confirmed lack of survival benefit with q3wk cisplatin alone • Carbo/Taxol--->XRT--->Carbo/Taxol • Tested “consolidation” carbo/taxol • Confirmed toxicity/intolerance to consolidation • Reported lack of efficacy with more than 2 cycles of chemotherapy • EP/XRT +/- Docetaxel • Refuted SWOG 9504 trial which shaped clinical practice world-wide in stage III disease

  17. Advanced NSCLC • Cisplatin/Gemcitabine phase II study • Cis/Gem vs Cis phase III study • Established role of gemcitabine in NSCLC • CODE regimen • Lack of efficacy of dose dense therapy • Pemetrexed vs Docetaxel • Established role of pemetrexed in NSCLC

  18. Quality of Life • Prozac vs Placebo • Only study to evaluate placebo-controlled, phase III trial in cancer population • Olanzapine phase I and phase II studies • Established potential of this anti-emetic to control acute and delayed nausea against moderate to highly emetagenic chemotherapy

  19. www.hoosieroncologygroup.org

  20. Cisplatin + 5FU vs 5FU alone in metastatic colorectal cancer Loehrer et al, JCO 1988

  21. DTIC vs Dartmouth Regimen Chapman et al, JCO 1999

  22. HOG LUN 01-24/USO 02-033Hanna et al, ASCO 2007, Abst # 7512 ChemoRT Cisplatin 50 mg/m2 IV d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy (1.8 Gy/fr) • Inclusion: • FEV-1 > 1 L Excluded: • wt loss > 5% in preceding 3 months Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-CR Randomize Observation Docetaxel 75 mg/m2 q 3 wk  3

  23. Observation: Median: 24.1 months (18.0-34.2) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 months (17.-34.8) 3 year survival rate: 27.2% P-value: 0.940 Overall Survival (ITT)Randomized Patients (n=147)

  24. Thoracic Discussion Leader: Nasser Hanna

  25. Open Studies • Phase II Study of Erlotinib with Bevacizumab in Chemotherapy Naive Performance Status (PS) 2 Patients with Advanced Non-Small Cell Lung Cancer - LUN04-77 • A Phase II Trial of Concurrent Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Sorafenib in Patients with Inoperable Stage III NSCLC LUN06-107 • A Randomized Phase 2 Study of Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin versus Pemetrexed + Carboplatin + Bevacizumab + Placebo in Chemonaive Patients with Stage IIIB or IV NSCL - LUN06-116 4. Pilot Study with Cetuximab and Radiation Therapy for Patients with Surgically Resectable Esophageal and GE Junction Carcinomas - GI05-92

  26. A Randomized Double Blind Phase II Trial of Cisplatin plus Etoposide with/without Concurrent ZD6474 in Patients with Previously Untreated Extensive Stage Small Cell Lung Cancer: Hoosier Oncology Group LUN06-113 Primary Objective: • evaluate whether the addition of ZD6474 to EP improves time to disease progression over EP alone. Secondary Objective: • Evaluate the safety and tolerability of this treatment combination • Response rate (CR + PR) in each arm • Disease control rate (CR + PR+ SD) in each arm • Overall survival for each arm Tertiary Objective: • Assess VEGF Polymorphisms and correlate subject response.

  27. Schema REGISTRATION / RANDOMIZATION n=74 Arm A (n=34) Cisplatin 60mg/m2 Etoposide 120mg/m2 Placebo Arm B (n=6+34) Cisplatin 60mg/m2 Etoposide 120mg/m2 ZD6474 100mg PE and toxicity evaluation and disease assessment Patients with non-PD and acceptable toxicity: CONTINUE PROTOCOL THERAPY Progressive disease or excessive toxicity: OFF TREATMENT

  28. A Phase II Study of Sunitinib Maleate (Sutent®) with Paclitaxel (Taxol®) in Patients with Advanced Esophageal Cancer. Hoosier Oncology Group: GI07-112 Primary Objective: • To estimate the rate of non-progressive disease Secondary Objective: • response rate • Safety profile • Survival rates. • Time to progression

  29. GI07-112 Schema Evaluation of Eligibility Criteria Patient Registration Paclitaxel 90 mg/m2 IV on days 1, 8, 15 Sunitinib maleate 37.5 mg po daily Adverse event and toxicity evaluation Disease assessment Progressive disease or excessive toxicity: Discontinue study. Complete remission, partial remission, stable disease, and tolerable toxicity profile: Continue Protocol Therapy

  30. Thoracic Study proposals • Pemetrexed/XRT for poor-risk stage III NSCLC • Amrubicin and cyclophosphamide in relapsed SCLC • Tarceva plus dasatinib • IGF-1 inhibitor study

  31. 2. Small Cell Lung Cancer a) Limited - Previously untreated b) Extensive - Previously untreated - Previously treated 3. Prevention trials 4. Supportive care trials 1. Non-Small Cell Lung Cancer a) Localized surgically resectable trials - Stage IA - Stage IB – IIIA - Correlatives/supportive b) Localized unresectable trials - Inoperable stage III A/B - Correlatives c) Metastatic No prior treatment for metastatic/ recurrent disease Prior treatment for metastatic/recurrent disease Correlatives Treatment for brain metastasis New Ideas/interest in Lung cancer studies

  32. Breast Cancer Discussion Leader: George Sledge

  33. Open Studies • A Phase II Study of Combined VEGF Inhibitor (Bevacizumab + Sorafenib) in Patients With Metastatic Breast Cancer: PI – Robin Zon • A Randomized, Double-Blinded, Phase 2 Trial of Paclitaxel Plus Bevacizumab Plus Enzastaurin versus Paclitaxel Plus Bevacizumab plus Placebo for Locally Recurrent or Metastatic Breast Cancer: PI – Bryan Schneider • Center of Excellence: PI – George Sledge/Kathy Miller • Predicting Response and Toxicity in Patients Receiving Chemotherapy for Breast Cancer • Predicting Response and Toxicity in Patients Receiving Paclitaxel and Avastin for Breast Cancer

  34. Study Proposal – Dr. Harb • To develop effective post surgical intervention management strategies to improve the long-term outcome in breast cancer patients at risk of metastases. • To identify, validate and integrate novel biomarkers of metastasis present in lymph and blood draining directly from the primary tumor, prior to entering the sentinel lymph node in women with breast cancer using genomic, proteomics, and metabolomic techniques to develop a test that is more accurate to detect risk of metastasis.

  35. 1. Neo-adjuvant Adjuvant Correlative studies Imaging studies Pre-surgical/profiling studies 6. Metastatic a) Chemotherapy/ Biotherapy - HER 2+ - HER 2- Hormonal Treatment for Brain Metastasis 7. Supportive care trials New Ideas/interest in breast cancer studies

  36. Gynecology Discussion Leader: Daniela Matei

  37. A Phase I/II Study of Sorafenib in Combination with Topotecan for the Treatment of Platinum-Resistant Recurrent Ovarian Cancer or Primary Peritoneal Carcinomatosis: Hoosier Oncology Group GYN06-111 Primary Objective: Phase I: maximum tolerated dose Phase II: response rate Secondary Objective: • progression-free survival • clinical benefit defined as • a) objective response • b) CA125 response • c) sustained stable disease (>3 months) by clinical and radiographic criteria.

  38. Schema Consent and register for protocol therapy Topotecan: 4mg/m2 weekly, 3 weeks on and one week off. Sorafenib: Phase 1: 400mg po daily Phase 2: MTD as determined in Phase 1 Cycles will consist of 4 weeks (28 days) Non-PD and acceptable toxicity PD and unacceptable toxicity Discontinue protocol therapy Continue protocol therapy

  39. 1. Cervical Metastatic Recurrent (>2 prior) 2. Endometrial Recurrent Correlative 3. Ovarian a) Recurrent < 2 prior < 3 prior Platinum sensitive c) Correlative New Ideas/interest in GYN cancer studies

  40. Gastrointestinal Discussion Leader: Gabriela Chiorean

  41. A Phase II Trial of Preoperative Capecitabine Plus Irinotecan Followed By Combined Modality Capecitabine and Radiation For Locally Advanced Rectal Cancer: Hoosier Oncology Group GI03-53 Primary Objective: • pathological response rate Secondary Objectives: • Toxicity, rates of local and distant disease recurrence • rate of clinical response following induction chemotherapy • thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenate, carboxylesterase expression and proteomic correlations with the objective response rate with this chemotherapy/chemoradiation regimen.

  42. Schema Rectal adenocarcinoma (T3-4 N0- 2 M0) Irinotecan 200 mg/m2 IV, day 1 Capecitabine 1000* mg/m2 PO BID day 1-14 Repeat every three weeks for two cycles Beginning at week 7 or following recovery from chemotherapy: Pelvic XRT 45 Gy/1.8 Gy/fx/qd +5.4 Gy/1.8 Gy/fx/qd for T3 +9 Gy/1.8 Gy/fx/qd for T4 Capecitabine 825* mg/m2 PO BID, 5 days/week, Surgery

  43. Phase I / Randomized Phase II Study of Second Line Therapy with Irinotecan and Cetuximab with or without RAD001, an Oral mTOR Inhibitor for Patients with Metastatic Colorectal Cancer: Hoosier Oncology Group GI05-102 Phase 1: Primary Objective: • MTD of RAD001 in combination with irinotecan and cetuximab. • safety Secondary Objective: • pharmacokinetic (PK) profile for RAD001, biologic markers: p-S6, p-Akt, VEGF, and PTEN, Kras mutations and EGFR gene amplification by FISH, genotypes: UGT1A1, UGT1A7, and UGT1A9 and correlate with objective response (CR or PR) and adverse events

  44. Phase 2: Primary Objective: • objective response Secondary Objective: • TTP, duration of objective response and overall survival • objective response rates, TTP and overall survival of patients treated with third line irinotecan and cetuximab plus RAD001 after progression on irinotecan and cetuximab alone (cross over) • tumor specimens for biologic markers: same as phase I

  45. Schema – Phase 1 Obtain informed consent and HIPAA authorization submit blood sample for genotype analysis INELIGIBLE UGT1A1 *28 7/7 genotype IS present ELIGIBLE UGT1A1 *28 7/7 genotype IS NOT present REGISTER for PHASE I*** Cetuximab** 250 mg/m2 IV days 1, 8, and 15 Irinotecan 125 mg/m2 IV days 1 and 8 RAD001 PO QD (dose determined at the time of registration;

  46. Schema – Phase 2 Obtain informed consent and HIPAA authorization submit blood sample for genotype analysis REGISTER for PHASE II RANDOMIZE (based on 2 strata) (1) UGT1A1 *28 7/7 Genotype: (2) Prior Irinotecan Exposure: (a) Is not present (a) Yes (b) Is present (must begin treatment (b) No at dose level -1 of irinotecan) Arm A Cetuximab** 250 mg/m2 Irinotecan 125 mg/m2 Arm B Cetuximab** 250 mg/m2 Irinotecan 125 mg/m2 RAD001 PO QD (MTD) PROGRESSIVE DISEASE PROGRESSIVE DISEASE Arm B Cetuximab** 250 mg/m2 Irinotecan 125 mg/m2 RAD001 PO QD (MTD) TREATMENT DISCONTINUATION

  47. A Phase II Trial of Erlotinib in Combination with Docetaxel in Advanced Hepatocellular and Biliary Tract Carcinomas: Hoosier Oncology Group GI06-101 Primary Objective: • rate of progression-free survival (PFS) at 16 weeks Secondary Objective: • response rate, duration of response, disease control rate (CR+PR+SD), duration of disease control and overall survival. • Safety • To correlate responses with biologic tumor markers expression including: EGFR gene amplification by FISH, E-cadherin expression and Kras gene mutations.

  48. Schema Consent and HIPPA Erlotinib 150 mg PO daily on days 2-7, 9-14, 16-28 Docetaxel 30 mg/m2 IV over 30 min x 3 weeks on days 1,8, 15. Continue treatment until progression or excessive toxicity

  49. Study Proposals • Colorectal • 1st line FOLFIRI (or FOLFOX or XELOX) + Avastin and with the addition of an Insulin Growth Factor Inhibitor (IGF1R inhibitor) • Refractory after failure to 5-FU, irinotecan, oxaliplatin, bevacizumab, cetuximab: mTOR inhibitor + IGF1R inhibitor B. Pancreatic/Biliary • 1st line Gemcitabine + Erlotinib + IGF1R inhibitor • 2nd line after gemcitabine failure: Xeloda + Sunitinib (Sutent) • SAHA + Bortezomib + Gemcitabine

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