The Present and Future of Mesothelioma Treatment: Medical Oncologist and Researcher Perspective

Transcription

1 The Present and Future of Mesothelioma Treatment: Medical Oncologist and Researcher Perspective Hedy Lee Kindler, MD Associate Professor of Medicine Director, Mesothelioma Program University of Chicago

2 Present and future of chemotherapy treatment for MM Where are we now? Current standard chemotherapies for MM Key questions about these treatments Where are we going? Novel agents in development Some obstacles for moving forward

3 What is chemotherapy? Chemotherapy is cytotoxic Chemotherapy kills cancer cells indiscriminately, usually by interfering with their DNA Chemotherapy exploits the fact that cancer cells usually grow faster than normal cells This differs from targeted therapy which targets specific growth factors or signaling pathways that may be increased or turned on in the cancer cell

4 Systemic therapy for MM before pemetrexed Many single-agents were evaluated Trials were small The primary endpoint was usually response Assessment criteria were not standardized Monitoring was often done by CXR Minimal to very modest activity was observed for many drugs, including: Capecitabine, carboplatin, cisplatin, DHAC, docetaxel, doxorubicin, edatrexate, epirubicin, gemcitabine, ifosfamide, irinotecan, mitomycin, paclitaxel, topotecan, trimetrexate

5 Chemotherapy for MM in 2010: Where are we now? Cytotoxic drugs with single-agent activity (<25% response rate): pemetrexed, raltitrexed, vinorelbine, vinflunine To prolong survival (by 3 months or less): add pemetrexed or raltitrexed to cisplatin To increase response rate (by about 10-20%): add a platinum to pemetrexed, raltitrexed, irinotecan, vinorelbine, or gemcitabine In preclinical models, many novel agents seem promising few have activity in clinical trials

6 Activity of selected drugs and drug classes in MM Agent # trials # pts Response Alkylating agents % Anthracyclines % Antimetabolites % Carboplatin % Cisplatin % Gemcitabine % Taxanes % Topo I inhibitors % Vinca alkaloids % Adapted from Ellis, JTO 2006 and Fennell, Nat Pract Clin Oncol 2008

7 The anthracyclines: The original gold standard drugs for MM Agent # Trials # Pts Response Doxorubicin % Epirubicin % Mitoxantrone % Liposomal doxorubicin Liposomal daunorubicin Doxorubicin + dexrazoxane % % %

8 The current gold standard for MM: The antifolates Agent # Trials # Pts Response DHAC % Trimetrexate % Edatrexate % Edatrexate/LV % Methotrexate % Pemetrexed % Pralatrexate % Raltitrexed %

9 Pemetrexed (Alimta)

10 Cell membrane transport of folates Reduced folate carrier (RFC) facilitated diffusion Low affinity high capacity PCFT: Pemetrexedselective transporter - high capacity* Lipid soluble drugs - Free diffusion but no concentration Folate Receptor (FRα) podocytosis Pemetrexed: more active in MM than in other tumors: The protoncoupled folate transporter is highly specific for pemetrexed Folate receptor α is highly activated High affinity low capacity Wang, Ca Res2002 Chattopadhyay, Mol Cancer Ther 2007 Efflux by MRP

11 Pemetrexed mechanism of action AMP PRPP + Gln GARFT IMP RNA & DNA synthesis Pemetrexed Cell membrane Folate Carriers (mainly RFC) FPGS Pemetrexed Pemetrexed-Glu N dtmp dump TS DNA synthesis 10-CHO-FH 4 5, 10-CH2-FH4 DHFR FH 2 GMP FH4

12 Phase II trial of pemetrexed (Alimta) in mesothelioma Patients: 64 Dose: 500 mg/m 2 q 21D Partial Response Rate: 14% Median time to progression: 4.7 months Median survival: 10.7 months 1 year survival: 47.8% Grade ¾ neutropenia: 23% Scagliotti, JCO 2003

13 The trial that changed our outlook on the role of chemotherapy for MM Pemetrexed 500 mg/m 2 q 21D Cisplatin 75 mg/m 2 q 21D 456 patients Primary objective: survival (HR=.67) Placebo q 21D Cisplatin 75 mg/m 2 q 21D Stratification: Performance status, histology, gender, WBC, disease measurability, baseline homocysteine Vogelzang, JCO 2003

14 Pemetrexed + cisplatin: The benchmark regimen for mesothelioma PC C p Pts RR 41% 17% <0.001 MST 12.1 M 9.3 M TTP 5.7 M 3.9 M Vogelzang, JCO 2003

15 Alimta/cisplatin improves quality of life in mesothelioma patients p=0.012 p= Pem + Cis Cis 44 % Target AUC Global QoL Symptom distress

16 Alimta/cisplatin improves fatigue, appetite, and activity level % Target AUC p= p= Pem + Cis Cis 43 p= Fatigue Anorexia Activity level *Includes all data up to 18 weeks; 100% = best score

17 Alimta/cisplatin improves shortness of breath in MM patients Pem/Cis Cis n.s. p =0.476 p =0.344 p = Cycle mm

18 Alimta/cisplatin improves lung function in mesothelioma n.s. Pem/Cis Cis n.s. p=0.034 p=0.006 VC (L) Cycle

19 FDA Approval of Pemetrexed (Alimta) On the basis of these data, the FDA approved pemetrexed for the treatment of mesothelioma in 2003 This is the first and only drug ever FDA approved for this disease Pemetrexed with cisplatin is thus a standard treatment option for patients with mesothelioma. There are other drugs with activity, however, which may be more appropriate for an individual patient

20 A few things we don t really know about pemetrexed + cisplatin When to start it: timing of therapy When to stop it: maintenance The optimal dose of folic acid When to give something other than cisplatin: special populations: elderly, frail When to give something other than pemetrexed: after all, other drugs have activity

21 What is the optimal duration of treatment? In the pivotal randomized study, pts received no more than 6 cycles of Pemetrexed-Cisplatin What is the optimal treatment duration: 4-6 cycles? 4-6 cycles Pem-platin then Pem until PD? 4-6 cycles Pem + platin then novel agent? In a small, non-randomized feasibility study: Maintenance pemetrexed following pemetrexed-platin was well-tolerated Responses occurred after 6 cycles The CALGB is running a randomized study to address this question

22 CALGB 30901: A study of pemetrexed maintenance 90 patients Pemetrexed + Cisplatin or Carboplatin X 4 cycles SD PR CR R A N D O M I Z E Pemetrexed until progression Observation until progression Primary endpoint: progression-free survival PI: Arek Dudek Stratification: Cisplatin vs. carboplatin Epithelial vs. other

23 Alimta, Folate and B 12 Supplementation with dietary levels of folate + B 12 significantly decreases side effects of Alimta, including: diarrhea, rash, fatigue, low blood counts (white cells and platelets) and mouth sores allows more chemotherapy cycles to be given In laboratory models, however, too much folic acid blocks the activity of Alimta 1. How much is just right? Folic acid: 350 to 600 mcg orally daily. Most multivitamin pills have 400 mcg B 12 : 1000 mcg shot every 9 weeks 1 Chattopadhyay, Oncologist 2007; 12:80815

24 Special populations: the elderly In the United States, mesothelioma is a disease of the older patient: median age 74 72% of MM pts are > 65 years Many older MM pts have medical comorbidities and cannot tolerate cisplatin (which causes fatigue, and affects the kidneys and hearing)

25 Phase II trials of pemetrexed + carboplatin Author Ceresoli 1 Castagneto 2 Patients Response 19% 25% Survival 12.7 mo 14 mo TTP 6.5 mo 8.0 mo In a pooled subset analysis, the elderly patients in these 2 studies had comparable outcomes to their younger counterparts, although the older patients experienced greater hematologic toxicity 3 1 Ceresoli, JCO Castagneto, Ann Oncol Ceresoli, Br J Ca 2008

26 What if standard Alimta-based chemotherapy stops working, or the patient cannot tolerate it? A clinical trial is optimal, but often these are not readily available What are the other drugs off the shelf the doctor can give? What are their risks and benefits?

27 Gemcitabine (Gemzar)

28 Single-agent Gemcitabine Dose (mg/m 2 ) # Response Survival Gemcitabine % 4.7 mo 1 Gemcitabine % 8.0 mo 2 Gemcitabine % NR 3 1 Kindler Lung Ca 2001; 2 van Meerbeeck Cancer 1999; 3 Bischoff Proc ASCO 1998

29 The activity of gemcitabine + cisplatin varies between trials Author # Gemcitabine Cisplatin RR MS Byrne D1,8, D1 q28d 48% 9.5 Nowak D1,8, D1 q28d 33% 11.2 Castagneto D1,8 75 D1 q21d 26% 12 vanhaarst D1,8 80 D1 q21d 16% 9.6 SWOG D1,8,15 30D1,8,15 q28d 12% 10 1 Byrne, JCO Nowak, Br J Ca Castagneto, Proc ASCO van Haarst, Br J Ca Kalmadi, Lung Ca 2007

30 Other gemcitabine combinations # RR Survival Gemcitabine Carboplatin % 15.1 mo Gemcitabine Oxaliplatin % 13 mo Gemcitabine Pemetrexed % 17% 8.1 mo 10.1 mo Gemcitabine Epirubicin % 12.6 mo *Gemcitabine *Vinorelbine % 10.9 mo *second-line regimen 1 Favaretto, Cancer Schuette, Clin Lung Ca Janne, JCO Portalone, Tumori Zucali, Cancer 2008

31 Which combination is better: Alimta/Cisplatin or Gemcitabine/Cisplatin?

32 Which platinum doublet partner is better: pemetrexed or gemcitabine? C Lee, Proc IASLC 2007 In a retrospective Canadian series, there was no difference in overall survival between platinum doublets of gemcitabine or pemetrexed

33 Vinorelbine (Navelbine)

34 Vinorelbine in mesothelioma # RR Survival First-line Vinorelbine % 10.6 mo Vinorelbine % 9.4 mo Vinorelbine 3 Oxaliplatin 26 23% 8.8 mo Vinorelbine 4 Cisplatin 57 28% 11.6 mo Second-line Vinorelbine % 9.6 mo Vinorelbine 6 Gemcitabine 30 10% 10.9 mo 1 Steele, JCO Muers, Lancet Fennell, Lung Ca Sorensen, Proc JTO Stebbing, Lung Ca Zucali, Cancer 2008

35 Do we really know that chemotherapy is better than just taking care of symptoms?

36 Is chemotherapy better than no treatment? The UK MS01 Trial: A randomized phase III trial of active symptom control with or without chemotherapy Newly-diagnosed malignant pleural mesothelioma Randomization Active Symptom Control (ASC) ASC + 4 cycles of MVP Mitomycin 6 mg/m 2 Vinblastine 6 mg/m 2 Cisplatin 50 mg/m 2 ASC + 12 weekly cycles of Vinorelbine (30 mg/m 2 )

37 Overall Survival (ASC vs. ASC+ chemo) ASC ASC+chemo Pts Median 7.6 mo 8.5 mo 1 yr survival 30% 37% HR = 0.89 ( ) p= Time (months) ASC alone ASC + Chemotherapy

38 Overall survival (3 arms) ASC ASC+MVP ASC+Vin Pts Median 7.6 m 7.8 m 9.5 m 1 yr 30% 31% 42% HR: % CI p-value Time (months) ASC alone ASC + N ASC + MVP

39 What are some of the challenges facing the development of new drugs for this disease?

40 Obstacles to progress Why haven t we done better? What are some of the obstacles we ve encountered in developing new treatments for this disease? Where do we go from here? What interesting, potentially active new agents are being studied?

41 Several factors have hampered the development of effective regimens for mesothelioma Most drugs don t work MM is uncommon MM is heterogeneous Staging is unreliable Response assessment is difficult

42 Most drugs don t work why? We don t understand the biology well enough to find the right drugs to test More research funding is needed The right drugs may be out there, but it is difficult to persuade pharma to test them in an unprofitable disease More funding is needed Drugs may work in the test tube but not in the patient because the drug isn t being delivered properly to the tumor, or is being inactivated in the patient s body More research is needed

43 Several factors have hampered the development of effective regimens for mesothelioma Most drugs don t work MM is uncommon MM is heterogeneous Staging is unreliable Response assessment is difficult

44 MM is uncommon Many clinical trials, by necessity, are small This can lead to false + and results Large trials are difficult to complete May require many sites in many countries Accrual may take years They may close prematurely and be underpowered A finite number of trials can be performed The potential market is small It s not profitable! It is difficult to interest pharmaceutical companies or grant funding agencies

45 In the US, MM is uncommon and regionalized Most community and academic oncologists see very few MM Several academic centers of excellence see high volumes of MM Principal sources of clinical trials in the US: Cooperative groups NCI phase II consortia Pharmaceutical companies In the past, it was easier to open trials that accrued small numbers of pts per site increased regulatory and cost burdens make it more and more difficult to open trials if only a few pts are accrued

46 Slow accrual: Phase III ranpirnase trial took 8 years to accrue 428 patients! 428 pts R A N D O M I Z E Ranpirnase 240 μg/m 2 (480 μg/m 2 ) q wk + Doxorubicin 60 mg/m 2 d1 q3wk X 6 cycles Doxorubicin 60 mg/m 2 d1 q3wk x 6 cycles The standards of care changed in the interim: *Approval of pemetrexed *Diminished role for doxorubicin Completing a definitive trial will be challenging

47 No difference in survival Treatment (N) Median Survival (months) 1 year survival HR 95% CI p value Ranpirnase / Doxorubicin (203) % Doxorubicin (210) % ,

48 MS01 trial: Non-significant survival benefit for vinorelbine likely due to reduced sample size Initial design: 840 pts in 4 yrs, 3 arms, 90% power. Accrual poor. Revised design: 2 arms, 420 pts, chemo arms pooled, 76% power ASC MVP Vin Pts Median 7.6 m 7.8 m 9.5 m 1 yr 29% 31% 42% HR: % CI p-value Time (months) Study conclusion: Vinorelbine may improve MST by ~2 months (p=0.11; NS) ASC alone ASC + N ASC + MVP

49 Several factors have hampered the development of effective regimens for mesothelioma Most drugs don t work MM is uncommon MM is heterogeneous Staging is unreliable Response assessment is difficult

50 MM is heterogeneous There are many prognostic factors, including: 3 pathologic subtypes epithelial, sarcomatoid, and biphasic that produce very different outcomes 4 different sites of disease pleural, peritoneal, tunica vaginalis, pericardial with differing natural histories No prognostic scoring system fully accounts for this heterogeneity

51 MM is heterogeneous It is very difficult to make cross-trial comparisons The same drugs may yield very different outcomes in different trials--which makes it hard to figure out whether a drug is really helpful, or not Author # Gemcitabine Cisplatin RR MS Byrne D1,8, D1 q28d 48% 9.5 Nowak D1,8, D1 q28d 33% 11.2 Castagneto D1,8 75 D1 q21d 26% 12 vanhaarst D1,8 80 D1 q21d 16% 9.6 SWOG D1,8,15 30D1,8,15 q28d 12% 10

52 Several factors have hampered the development of effective regimens for mesothelioma Most drugs don t work MM is uncommon MM is heterogeneous Staging is unreliable Response assessment is difficult

53 Staging is unreliable There are many staging systems for pleural MM All are surgically based While some may predict survival in the resected patient, none accurately selects non-surgical patients with similar prognoses Therefore, chemotherapy trials in MM may include patients with a range of stages, and prognoses We don t put patients with stages I, II, III, and IV NSCLC in the same study why do so in MM?

54 Many staging systems for MM, none satisfactory Butchart (1976) Based on only 29 surgical pts, not TNM Mattson (1982) Chahinian (1983) UICC-TNM Atlas 3 rd Ed. (1992) Boutin (1993) Sugarbaker et al. (1993) Based on 176 pts, single-center, surgical only, not TNM IMIG-TNM System (1995) The most widely used, current standard IASLC-IMIG-MARF (2010) In development (Rusch, Proc IASLC 2009)

55 Several factors have hampered the development of effective regimens for mesothelioma Most drugs don t work MM is uncommon MM is heterogeneous Staging is unreliable Response assessment is difficult

56 Response assessment is difficult Unlike others tumors, MM is not compact, intraparenchymal, or uniformly growing Thus, MM is difficult to measure reproducibly The assessment of MM tumor response demonstrates substantial variability between observers Assessment criteria vary between trials

57 The current standard for measuring MM: Modified RECIST Byrne and Nowak. Annals of Oncology, 2004

58 Despite these problems, there are several advantages in developing new drugs for MM It is relatively easy to get a new drug approved because: Nothing else works very well Survival is short, so trials complete quickly Trials are small, so they require less money Once a drug is approved for this uncommon indication, it can be more readily approved for a more lucrative one (pemetrexed for NSCLC) The incidence is regionalized, as are the centers of excellence

59 How do we select new agents to test in MM? Targets with interesting preclinical data: VEGF, src, c-met, IGF-1R, AKT, aurora kinases, ephrins, mesothelin, WT-1, TRAIL.. Promising preclinical data has led to many disappointing results in patients Choice of drug is based on: Availability of agents for clinical testing against a target of interest Phase I single-agent and combination safety data Willingness of a drug company to test drugs in MM

60 Given all of these hurdles, it s remarkable how many new drugs are being tested in mesothelioma patients: A partial list VEGF inhibitors: AZD2171, Bevacizumab, NGR-hTNF, Pazopanib, Sorafenib, Sunitinib, ZD6474 Src inhibitor: Dasatinib HDAC inhibitors: SAHA, PXD101 Anti-mesothelin agents: MORAb009, SS1P Proteasome inhibitor: Bortezomib PDGF inhibitor: Imatinib mtor inhibitor: RAD001 CDK inhibitor: CBP501 WT-1: WT-1 vaccine TGF-B inhibitor: GC1008 TRAIL receptor-2 agonist: CS-1008 Other targets with interesting preclinical data: c-met, IGF-1R, AKT, aurora kinases, ephrins, hedgehog.

61 Trial design in MM: It s a balance Many questions Agent? Class? Trial design? Primary endpoint? Line of therapy? Patient population? Finite Resources Limited patient numbers Limited Funding

62 Despite substantial pre-clinical data, phase II trials of EGFR and PDGF inhibitors have not demonstrated any activity in MM Drug # RR SD PFS MST Gefitinib % 49% 40% 3 m 6.8 m Gefitinib % 50% 14.1 m Erlotinib % 47% 28% 6 m 39% 1yr Imatinib 800mg % 38% 2 m Imatinib 600mg % 29% 1.8 m 14.3 m Imatinib 400mg % 12% >6 m 2.1m 13 m Imatinib 400mg % 36% 1.8 m 4.6 m 1 Govindan, CCR Lee, Proc ASCO Garland, Proc ASCO Millward, Proc ASCO Villano Proc ASCO 2004; 5 Mathy Lung Ca 2005; 6 Porta CCP 2006

63 Antibodies against VEGF and its receptors significantly decrease proliferation of MM in vitro Control VEGF VEGF inhibition 1 untreated MPP anti-igg1 control Ab 3 + rhvegf 4 + anti-vegf 5 + anti-kdr Ab 6 + anti-flt-1 Ab Strizzi, J Pathol 2001

64 An incomplete list of the VEGF inhibitors evaluated in MM AZD2171 Bevacizumab NGR-hTNF Pazopanib Sorafenib Sunitinib SU5416 Thalidomide ZD6474 Is it a wise use of limited patient resources to perform so many me too trials in this uncommon disease?

65 Phase II studies of VEGF inhibitors: Modest single-agent activity in mesothelioma Drug # RR SD SD > 6 mo TTP mo MST mo SU % 38% mo Thalidomide % 28% 7.5 mo Thalidomide % 50% 25% 2 11 mo Vatalinib % 66% 10.0 mo Sorafenib % 39% 2.3/ /14.3 Sunitinib % 55% Kindler, Proc ASCO Baas, Lung Ca Pavlakis, Proc IASLC Jahan, Proc IASLC Janne, Proc IMIG Nowak, Proc IMIG 2008

66 Randomized phase II trial of gemcitabine/cisplatin +/- bevacizumab 106 pts Gemcitabine Cisplatin Bevacizumab X 6 cycles Gemcitabine Cisplatin Placebo Bevacizumab until progression Placebo Stratification: Performance status: 0 vs. 1 Histology: epithelial vs. other Primary endpoint: Progression-free survival Kindler, Proc IASLC 2007

67 Overall survival Bevacizumab Logrank p= mo Placebo 14.7 mo

68 Overall survival by baseline VEGF level Median VEGF level = 144 pg/ml VEGF Median VEGF > Median Logrank p=0.014

69 Overall survival by treatment: VEGF < median Bevacizumab Placebo Logrank p=0.028 Bevacizumab-treated pts with low baseline VEGF levels had longer overall survival

70 M.A.P.S Phase 2-3 Trial Pleural MM Histologically proven PS: 0-2 Chemo-naive Stratification: Center Histology (epithelioid vs. sarcomatoid) PS (0-1vs 2) Zalcman, Proc ASCO 2010 Pemetrexed Cisplatin Bevacizumab 15 mgkg X 6 cycles Pemetrexed Cisplatin Bevacizumab until progression Primary endpoints Phase 2: 6 mo PFS Phase 3: OS Statistics Phase 2: >25/50 non-progressors at 6 mo to proceed to phase 3 Phase 3: median OS 13 to 17.3 mo, 3 yr survival 14.7 to 23.6% Requires 445 pts

71 Randomized trial of pemetrexed/cisplatin +/- your new drug here Pemetrexed Cisplatin Randomize Pemetrexed Cisplatin Your new drug here Is this the ONLY appropriate paradigm for new drug development in MM?

72 Mesothelin: a target for antibody therapy Mesothelin: a cell surface glycoprotein expressed on normal mesothelial cells of pleura, pericardium and peritoneum Highly expressed in > 90% of mesotheliomas Precursor protein (71 kda) RR GPI GPI MPF (31 kda) Mesothelin (40 kda) Mesothelin processing Membrane Hassan, Clin Cancer Res, 2004

73 Marked synergy between gemcitabine plus SS1P against mesothelin expressing tumor xenografts Control 400 SS1P Mean tumor size (mm3) Gemcitabine Gemcitabine + SS1P 60% CR % CR 80% CR 100% CR 80% CR 60% CR Days after tumor inoculation Despite these data, the phase II trial uses a pem-cis backbone

74 Anti-mesothelin therapies in phase I/II trials Recombinant immunotoxin SS1P Chimeric monoclonal antibody MORAb-009 V L V H II III Anti-mesothelin -S-S- -Toxin- Phase I/II trials of SS1P + pemetrexed/cisplatin and Morab pemetrexed/cisplatin are ongoing

75 Bortezomib for mesothelioma In preclinical models in MM, bortezomib: Induces apoptosis and cell cycle arrest Inhibits constitutive activation and nuclear translocation of NFkB Sensitizes MM cells to chemotherapy Has significant anti-tumor activity in mouse MM xenografts Ongoing phase II clinical trials: Single-agent, first and second-line (ICORG/GIME) In combination with cisplatin (EORTC 8052)

76 Second-line chemotherapy in MM # RR Survival Gemcitabine/vinorelbine % 10.9 mo Imatinib % 14.3 mo Pemetrexed % 8.4 mo Raltitrexed/oxaliplatin % 10.1 mo Sorafenib % 14.3 mo Sunitinib % 8.2 mo Thalidomide % 11 mo Vinorelbine % 9.6 mo ZD % 6.7 mo Ranpirnase % 7.3 mo 1. Zucali, Cancer Villano Proc ASCO Jassem, JCO Fizazi, JCO Janne, Proc IMIG Nowak, Proc IMIG Pavlakis, Proc IASLC Stebbing, Lung Ca Giaccone BJC Mikulski, JCO 2002

77 Phase I trial of SAHA (Vorinostat) Inhibits class I and II HDACs Potent inhibitor of MM in vitro Represses the gene for TS Patients: 13 (10 evaluable) Median # prior chemo tx: 1, range 0-5 Dose: 300 (9 pts) or 400 (2 pts) mg po bid x 3D/wk Response: 2/10 (1 unconfirmed) Median TTP: 3 months All pts w/ PR/SD had dyspnea and/or pain Krug, Clin Lung Ca 2006

78 Phase III trial of SAHA in previously-treated mesothelioma Unresectable MPM 1 or 2 prior regimens Stratify by: histology, PS, # prior regimens 660 pts Vorinostat initially 300mg BID x 14 D q 21D changed to 300mg BID x 3 D Q7D Placebo 1 0 endpoint: Overall survival 1 st interim analysis: after 50 pts enrolled for futility 2 nd interim analysis: after 220 pts enrolled for 2 0 endpoints Correlative studies: genotyping, volumetrics, PFT, symptom and QOL assessment

79 Mesothelioma represents a good potential target disease for gene therapy: Localized to chest cavity until late Easily accessible Current therapies inadequate Some evidence of immune responsiveness

80 HSVtk Suicide Gene Therapy HSVtk Mammalian kinases GC V GCV- P GCV-PPP Incorporates into growing DNA and causes cell death. Has bystander effects by intracellular transport of GCV-PPP? Generates an immune response against the tumor

81 Phase I trials of Ad.IFN-β Single dose trial: Intrapleural Ad.IFN-β was well-tolerated, with acceptable toxicities at the lowest dose levels Clear evidence of intrapleural transgene expression given elevations of soluble IFN-β on ELISA Some anecdotal clinical responses A second trial used 2 doses of vector: Gene transfer was much lower after 2 nd dose Anti-tumor antibodies were induced 4 pts had responses- best responses with low tumor burdens

82 The effect of Ad.IFN-b Is enhanced by combining it with chemotherapy 7.112: AB12 Ad.IFN-beta --> Cis/Gem Experiment 2- AB12- Day Contr ol Cis/ Gem mu.ad.ifnbeta --> Ci s/ Gem DAY 31 mu.ad.in-beta Tumor Size Cubic mm ctl alimta/cis IFNbeta Combo -2 combo+2 Phase I trials are in development to combine Ad.IFN-B with one or both of these regimens

83 A New Approach for MM: Blockade of TGF β TGF-β is a cytokine (growth factor) released by tumors and white blood cells within tumors TGF-β helps tumors grow, primarily by paralyzing the body s own immune reaction against the tumor (TGF-b) is made in much larger amounts by MM than other tumors pg/m l Mesothelioma Breast Cancer NSCLC

84 Anti TGF-β antibody markedly inhibits the growth of mouse mesothelioma tumors Effect of Anti-TGF B on Ab 12 tumor Volume (mm3) Control TGF-ab days

85 Phase II trial of GC1008, an antibody that blocks TGF β A clinical trial of GC1008, a monoclonal antibody that blocks TGF-β (U Penn and U Chicago) This trial is open to patients who have failed 1 or 2 other treatments for their mesothelioma This trial is partly funded by a charitable foundation

86 WT-1 Heteroclitic Peptide Vaccine WT-1 gene is involved in tissue development, cell proliferation and differentiation, and apoptosis Over-expressed in mesothelioma 10 MM pts who have received 0-1 prior regimens and are WT-1 + will be enrolled Dose/schedule: Four WT-1 peptides in given weeks 1, 4, 6, 8, 10, 12. Pts with immune response and no disease progression can get maintenance vaccinations monthly after that Correlative studies: DTH, ELISPOT, T-cell proliferation assays, and PCR for WT-1 levels

87 Where do we go from here with systemic therapy for MM? Better drugs More preclinical investigation Learn to use the drugs we have: maintenance, special populations, multimodality Better choices More selectivity regarding the promising drugs we choose to move from the bench to the clinic Fewer me too trials (why 10+ trials of VEGF inhibitors?) Better designed trials Otherwise we may miss an active agent, or conclude erroneously that an inactive regimen merits further study Appropriately powered, multi-center trials, preferably with randomized phase II screening designs to balance heterogeneity Appropriate endpoints: response, PFS, OS, QOL, correlative studies built in

88 Hope for the future: how can we make progress against this disease? Understanding the biology of MM More funding for basic science research Early detection Learning how to use the new biomarkers and developing new ones Staging Revising how we classify tumors Surgery Integrating chemo and radiation Chemotherapy Better drugs, defining key questions, novel approaches Commitment from pharmaceutical companies

89 Medical Oncology Hedy Kindler Ravi Salgia Michael Maitland Victoria Villaflor Nick Campbell Surgical Oncology Wickii Vigneswaran Radiation Oncology Joseph Salama Nursing Jennifer Shouldis Sylvia Watson The University of Chicago Mesothelioma Program Imaging Samuel Armato Heber MacMahon William Sensakovic Adam Starkey Zac Labby Pulmonary/Highrisk asbestos Kyle Hogarth Pathology Aliya Husain Thomas Krausz Translational Lab Ravi Salgia Rajani Kanteti S. Loganathan S. Krishnaswamy Osvaldo Zumba Rabia Hassan V. Natarajan Data Management Jasmin Patel Julia Melnick Lisa Lipp Statistics Theodore Karrison