Current Chemotherapy and the Future of Targeted Therapies | Mesothelioma Applied Research Foundation
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Current Chemotherapy and the Future of Targeted Therapies | Mesothelioma Applied Research Foundation



Current Chemotherapy and the ...

Current Chemotherapy and the
Future of Targeted Therapies presented by Lee Krug, MD, of Memorial Sloan-Kettering Cancer Center at the Mesothelioma Applied Research Foundation's conference in New York, NY on September 28, 2012.



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    Current Chemotherapy and the Future of Targeted Therapies | Mesothelioma Applied Research Foundation Current Chemotherapy and the Future of Targeted Therapies | Mesothelioma Applied Research Foundation Presentation Transcript

    • Current Chemotherapy Options Standard 1st line regimen pemetrexed plus cisplatin or carboplatin  Improves survival, but only by a few months on average  Improves quality of life Limited data on the efficacy of 2nd line therapy  Rechallenge with pemetrexed if good initial response and significant time since initial treatment  Other option is vinorelbine  16% response rate in one phase II trial  0% response rate, 40% stable disease in MSKCC retrospective series
    • Approaches for Development of NovelMPM Therapies Adjuvant: After surgery or combined modality therapy First-line:  Add new agent in combination with pemetrexed, cisplatin  Develop new regimen Maintenance: After treatment with pemetrexed, cisplatin to maintain response Second-line: At progression after 1st line therapy
    • VANTAGE 014: Vorinostat inPatients With Advanced MalignantPleural Mesothelioma Who HaveFailed Prior Pemetrexed andEither Cisplatin or CarboplatinTherapy: A Phase 3, Randomized,Double-Blind, Placebo-ControlledTrialLee M. Krug,* Hedy L. Kindler, Hilary Calvert,Christian Manegold, Anne S. Tsao, DeanFennell, Gregory M. Lubiniecki, Xing Sun,Margaret Smith, Paul Baas*Memorial-Sloan Kettering Cancer Center, New York City, USA
    • Histone Deacetylase Inhibitors: Mechanism of Action Epigenetic (Histones/Chromatin) Anticancer Effects HAT Decondensed Ac Ac Ac Ac chromatin Ac Ac Ac Ac Decrease Decrease HDAC proliferation angiogenesis HDACi Increase apoptosis HDAC Ac Ac Transcription factors Signaling proteins Chaperone proteins Ac Ac Structural proteins HAT Decrease Increase cell motility differentiation Nonepigenetic (Nonhistone Protein)HAT: histone acetyltransferase; HDAC: histone deacetylase; HDACi: histonedeacetylase inhibitorAdapted from Paik PK, Krug LM. J Thorac Oncol. 2010;5(2):275–279.
    • VANTAGE 014 Study Design R Vorinostat 300 mg A orally, twice per day Stratification N 3 of 7 days in a D 3-week cycle• KPS (>80% vs ≤ 80%) O• Histology (epithelioid vs other) M Placebo orally,• Prior chemo regimens (1 vs 2) I twice per day Z 3 of 7 days in a E 3-week cycle Double blind 330 patients in each arm 125 centers in 23 countries participated identifier: NCT00128102
    • Overall Survival Curves (ITT Population)OS: overall survival; P: placebo; V: vorinostat
    • Overall Survival: At and After Third Interim Analysis (ITT Population) Interim analysis 3 After interim analysis 3■ Test of interaction between survival effect and time of enrollment (before or after interim analysis 3) has a 2-sided P value of 0.019OS: overall survival; V: vorinostat; P: placebo
    • ConclusionsVANTAGE 014 was the largest randomized trial inmalignant pleural mesotheliomaNo survival differenceStatistically significant, but clinically irrelevantbenefit in progression free survivalExcellent correlative data collection• Pulmonary function tests• Lung cancer symptom scale-mesothelioma• Soluble mesothelin-related peptide• Pathologic tissue samples
    • Abstract ID #: 109 Updated results of the Phase II clinical trial of theanti-mesothelin monoclonal antibody Amatuximabin combination with Pemetrexed and Cisplatin for front line therapy of pleural mesothelioma and correlation of clinical outcome with serum mesothelin, MPF and CA-125
    • BackgroundAmatuximab (MORAb-009): Chimeric mAb to mesothelin• Safety demonstrated in phase I clinical trial• In pre-clinical studies synergistic with chemotherapyMesothelin:• Is a cell surface glycoprotein expressed on mesothelialcells of pleura, peritoneum and pericardium• Highly expressed in epithelial mesothelioma Mesothelin processing
    • K-M for Progression Free Survival ---- MORAb-009 + Pemetrexed + Cisplatin ooo MORAb-009 + Pemetrexed + Cisplatin Censored Subjects who progressed or died: 52% Progression-Free Subjects Censored: 25 Time from First MORAb-009 Dose (Months)
    • Summary of Results• No added toxicity of amatuximab aside from hypersensitivity / infusion reactions in about 20%.• Overall response rate and progression free survival as expected.• The median overall survival of 14.8 months compares favorably with historical controls• Currently, 29/89 subjects still alive, and 5 of the 29 are still on amatuximab• Low baseline mesothelin, MPF and CA-125 levels each correlate with improved median overall survival
    • Randomized Phase II Trial of Pemetrexed/Cisplatin with or without CBP501 in Patients with AdvancedMalignant Pleural Mesothelioma (MPM) L.M. Krug, A.J. Wozniak, H.L. Kindler, R. Feld, M. Koczywas, J.L. Morero, C. Rodriguez, H.J. Ross, J.E. Bauman, S.V. Orlov, J.C. Ruckdeschel, A.C. Mita, L. Fein, X. He, R. Hall, T. Kawabe , S. Sharma
    • CBP501 - Background CBP501 is a novel, synthetic drug MPKAP-K2 C-TAK1 CHK1 designed from the peptide sequence of the cell cycle regulator CDC25C.1 CBP501 P CBP501 inhibits several kinases involved in G2 arrest and thereby CDC25C CDC25C affects DNA repair selectively in malignant cells. 1 P CDC2 CDC2 Cyclin B Cyclin B G2 M  CBP501 also enhances DNA damage by increasing platinum concentration and DNA- platinum adduct formation in tumor cells.2 1. Sha SK, et al. Mol Cancer Ther 2007;6:147-53. 2. Mine N, et al. Mol Cancer Ther 2011;10:1929-38.
    • CBP501 Randomized Phase II Trial Study Design Open-label, multicenter, randomized phase II study conducted in USA, Canada, Argentina and Russia Arm A: R Pemetrexed 500 mg/m2 A 2 Cisplatin 75 mg/m2Unresectable MPM N = 42 N CBP501 25 mg/m2Chemo naïve D Q3 weeksStratify by: O Histology M Arm B: Performance Status 1 I Pemetrexed 500 mg/m2 N = 21 Z Cisplatin 75 mg/m2 E Q3 weeks Primary endpoint: Progression free survival at 4 months in Arm A. If ≥ 23 of the 42 patients remain free of progression more than 4 months, the combination will be deemed worthy of further study.
    • CBP501: Response in Evaluable Patients Chemo + CBP501 ChemoInvestigator Assessed N=39 N=20Complete Response (CR), n (%) 0 (0) 1 (5)Partial Response (PR), n (%) 11 (28) 3 (15)Objective Response Rate (ORR), n (%) 11 (28) 4 (20)(95% CI) (.15, .45) (.06, .44)Stable Disease (SD), n (%) 21 (54) 11 (55) Chemo + CBP501 ChemoIndependent Radiology Review N=39 N=20Complete Response (CR), n (%) 0 (0) 0 (0)Partial Response (PR), n (%) 12 (31) 2 (10)Objective Response Rate (ORR), n (%) 12 (31) 2 (10)(95% CI) (.17, .48) (.01, .32)Stable Disease (SD), n (%) 15 (39) 10 (50)Based on modified RECIST and confirmed with f/u scan at least 4 weeks later
    • CBP501: Progression Free Survival Investigator Assessed Independent Radiology Review Chemo + CBP501 Chemo Chemo + Chemo Chemo + Chemo CBP501 CBP501# censored 7 4 # censored 8 6# events 33 19 # events 32 17Median PFS (mo) 5.9 4.6 Median PFS (mo) 5.1 3.4 P=0.24 P=0.42PFS > 4 mo, n (%) 27 (68) 13 (57) PFS > 4 mo, n (%) 25 (63) 9 (39)
    • CBP501: Conclusions1. This trial met its primary endpoint.2. Response rate and progression free survival favored the triplet combination arm, but not significantly.3. No added toxicities were noted with the addition of CBP501 aside from the infusion reactions which were all grade 1-2.4. Results from a randomized phase II trial in NSCLC are anticipated shortly.
    • Evaluation of anti-tumor activity and tolerability of GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced malignant pleural mesothelioma (MPM) Hedy L. Kindler1, Saoirse Dolly2, Johanna Bendell3, Lee M. Krug4, Lawrence Schwartz5, Michael Rabin6, 8, Nina Tunariu7, Tanguy Y. Seiwert1, Marjorie G. Zauderer4, Ann M. Young2, Jennifer Shouldis1, J P. Marcoux6, David Kwiatkowski6, 8, Jennifer O. Lauchle9, Howard Burris3, Andrew J. Wagner6, 8, Johann de Bono2 
1University Of Chicago, 2The Institute of Cancer Research and Royal Marsden Hospital, 3Sarah Cannon Research Institute,4Memorial Sloan-Kettering Cancer Center, 5Columbia University Medical Center, 6Dana Farber Cancer Institute, 7Radiology Department, Royal Marsden Hospital, 8Brigham and Women’s Hospital, 9Exploratory Clinical Development, Genentech
    • PI3K and mTOR: Therapeutic targets in MPM• The PI3K/Akt/mTOR pathway is frequently activated in MPM1• Small molecules that inhibit PI3K signaling1,2, and/or the mTOR pathway,2,3 have activity in preclinical MPM models4• PTEN loss inversely correlates with survival in MPM patients5 Inhibiting both PI3K and mTOR may result in increased efficacy within a tumor and broader efficacy across tumors with diverse molecular mechanisms of PI3K activation 1. Mikami et al, Oncol Rep, 2010 2. Altomare et al, Oncogene, 2005 3. Hoda et al, J. Thoracic Oncology, 2011 4. López-Lago et al, Mol. Cell. Biol, 2009 5. Opitz et al, Eur J Cardiothorac Surg, 2008
    • Tumor Response Per Modified RECIST Modified RECIST measurements per independent radiographic review * * * * * * * PTEN loss * * * * Biomarker analyses performed PIK3CA R88QData cut-off 18 May 2012
    • Conclusions • GDC-0980 has demonstrated encouraging activity in patients with pleural mesothelioma:  Most patients had tumor shrinkage  About 15% had a partial response • Hyperglycemia, pneumonitis, and rash are associated with GDC-0980 dosing, consistent with other PI3K or mTOR inhibitors in clinical trials • Tolerability of GDC-0980 in mesothelioma patients is similar to patients with other solid tumors • PIK3CA mutation and PTEN alterations have been detected in some pleural mesotheliomas  Preliminary data suggests clinical activity is present in tumors independent of these alterations25
    • Ongoing Clinical Trials (Partial List) Drug Line Phase Sponsor Bevacizumab 1st with pem/cis II/III French Intergroup Cediranib 1st with pem/cis RP II SWOG NGR-hTNF 2nd line RP II MolMed Pemetrexed Maintenance RP II Alliance WT-1 vaccine Adjuvant RP II MSKCC, MD Anderson
    • Potential Future Clinical Trials Drug Sponsor BAY 94-9343 Bayer GDC-0980 Genentech MORAb 009 Morphotek Nintedanib Boehringer Ingelheim Tremelimumab MedImmune VS-6063 Verastem
    • Final Thoughts Fortunately, a number of new agents are planned for clinical trials in mesothelioma, particularly targeting the biology of the disease Imperative for patients to participate in these trials Need to develop a Meso Trials Consortium to ensure that trials are done expeditiously and in a scientifically sound manner