Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design

Trials

Rodolphe Thiébaut²  Geneviève Chêne¹  Yves Lévy⁵  Amel Bouakane³  Véronique Rieux³  Vincent Arnold⁴  Jean-Daniel Lelièvre⁵  Adélaïde Doussau¹  Laura Richert² 

[1] CHU de Bordeaux, Pole de sante publique, Bordeaux, F-33000, France;INRIA SISTM, Talence, F-33405, France;French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS), Paris, F-95013, France;Vaccine Research Institute (VRI), Créteil, F-94010, France;Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, Créteil, F-94010, France

关键词: HIV vaccine;    Safety;    Stopping rule;    Bayes;    Frequentist;    Randomisation;    Phase II;    Phase I;    Design;    Clinical trial;   

Others  :  807364
DOI  :  10.1186/1745-6215-15-68

 received in 2014-01-17, accepted in 2014-02-05,  发布年份 2014

【 摘 要 】

Background

Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic.

Methods

We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial.

Results

We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative.

Conclusions

By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

【 授权许可】

   
2014 Richert et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D: Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010, 329:1168-1174.
• [2]Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, et al.: Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011, 365:493-505.
• [3]Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P, Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ: Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007, 369:657-666.
• [4]Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, et al.: Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012, 367:399-410.
• [5]Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH: Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009, 361:2209-2220.
• [6]Michael N: RV 144 Update: Vaccination with ALVAC and AIDSVAC to prevent HIV-1 infection in Thai adults. San Francisco, CA; 2010. [17th Conference on Retroviruses and Opportunistic Infections]
• [7]Rerks-Ngarm S, Brown AE, Khamboonruang C, Thongcharoen P, Kunasol P: HIV/AIDS preventive vaccine ‘prime-boost’ phase III trial: foundations and initial lessons learned from Thailand. AIDS 2006, 20:1471-1479.
• [8]Baden LR, Dolin R: The road to an effective HIV vaccine. N Engl J Med 2012, 366:1343-1344.
• [9]Gray GE, Allen M, Moodie Z, Churchyard G, Bekker LG, Nchabeleng M, Mlisana K, Metch B, de Bruyn G, Latka MH, Roux S, Mathebula M, Naicker N, Ducar C, Carter DK, Puren A, Eaton N, McElrath MJ, Robertson M, Corey L, Kublin JG: Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect Dis 2011, 11:507-515.
• [10]Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, Dejesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB: Efficacy Trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med 2083–2092, 2013:369.
• [11]Saunders KO, Rudicell RS, Nabel GJ: The design and evaluation of HIV-1 vaccines. AIDS 2012, 26:1293-1302.
• [12]Corey L, Nabel GJ, Dieffenbach C, Gilbert P, Haynes BF, Johnston M, Kublin J, Lane HC, Pantaleo G, Picker LJ, Fauci AS: HIV-1 vaccines and adaptive trial designs. Sci Transl Med 2011, 3:79ps13.
• [13]Nabel GJ: Designing tomorrow’s vaccines. N Engl J Med 2013, 368:551-560.
• [14]Simon RM, Steinberg SM, Hamilton M, Hildesheim A, Khleif S, Kwak LW, Mackall CL, Schlom J, Topalian SL, Berzofsky JA: Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol 1848–1854, 2001:19.
• [15]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [16]Excler JL, Tomaras GD, Russell ND: Novel directions in HIV-1 vaccines revealed from clinical trials. Curr Opin HIV AIDS 2013, 8:421-431.
• [17]Gilbert PB, Grove D, Gabriel E, Huang Y, Gray G, Hammer SM, Buchbinder SP, Kublin J, Corey L, Self SG: A sequential phase 2b trial design for evaluating vaccine efficacy and immune correlates for multiple HIV vaccine regimens. Stat Commun Infect Dis 2011, 3:4.
• [18]Moodie Z, Rossini AJ, Hudgens MG, Gilbert PB, Self SG, Russell ND: Statistical evaluation of HIV vaccines in early clinical trials. Contemp Clin Trials 2006, 27:147-160.
• [19]Streeck H, Frahm N, Walker BD: The role of IFN-gamma Elispot assay in HIV vaccine research. Nat Protoc 2009, 4:461-469.
• [20]Currier JR, Ngauy V, de Souza MS, Ratto-Kim S, Cox JH, Polonis VR, Earl P, Moss B, Peel S, Slike B, Sriplienchan S, Thongcharoen P, Paris RM, Robb ML, Kim J, Michael NL, Marovich MA: Phase I safety and immunogenicity evaluation of MVA-CMDR, a multigenic, recombinant modified vaccinia Ankara-HIV-1 vaccine candidate. PLoS One 2010, 5:e13983.
• [21]Garcia F, Bernaldo de Quiros JC, Gomez CE, Perdiguero B, Najera JL, Jimenez V, Garcia-Arriaza J, Guardo AC, Perez I, Diaz-Brito V, Conde MS, Gonzalez N, Alvarez A, Alcami J, Jimenez JL, Pich J, Arnaiz JA, Maleno MJ, Leon A, Munoz-Fernandez MA, Liljestrom P, Weber J, Pantaleo G, Gatell JM, Plana M, Esteban M: Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: a phase I clinical trial (RISVAC02). Vaccine 2011, 29:8309-8316.
• [22]Greenberg RN, Overton ET, Haas DW, Frank I, Goldman M, von Krempelhuber A, Virgin G, Badeker N, Vollmar J, Chaplin P: Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis 2013, 207:749-758.
• [23]Peters BS, Jaoko W, Vardas E, Panayotakopoulos G, Fast P, Schmidt C, Gilmour J, Bogoshi M, Omosa-Manyonyi G, Dally L, Klavinskis L, Farah B, Tarragona T, Bart PA, Robinson A, Pieterse C, Stevens W, Thomas R, Barin B, McMichael AJ, McIntyre JA, Pantaleo G, Hanke T, Bwayo J: Studies of a prophylactic HIV-1 vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity. Vaccine 2007, 25:2120-2127.
• [24]Sandstrom E, Nilsson C, Hejdeman B, Brave A, Bratt G, Robb M, Cox J, Vancott T, Marovich M, Stout R, Aboud S, Bakari M, Pallangyo K, Ljungberg K, Moss B, Earl P, Michael N, Birx D, Mhalu F, Wahren B, Biberfeld G: Broad immunogenicity of a multigene, multiclade HIV-1 DNA vaccine boosted with heterologous HIV-1 recombinant modified vaccinia virus Ankara. J Infect Dis 2008, 198:1482-1490.
• [25]Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H: Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013, 381:1021-1028.
• [26]Vasan S, Schlesinger SJ, Chen Z, Hurley A, Lombardo A, Than S, Adesanya P, Bunce C, Boaz M, Boyle R, Sayeed E, Clark L, Dugin D, Boente-Carrera M, Schmidt C, Fang Q, LeiBa , Huang Y, Zaharatos GJ, Gardiner DF, Caskey M, Seamons L, Ho M, Dally L, Smith C, Cox J, Gill D, Gilmour J, Keefer MC, Fast P, et al.: Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1 B’/C candidate vaccine. PloS One 2010, 5:e8816.
• [27]von Krempelhuber A, Vollmar J, Pokorny R, Rapp P, Wulff N, Petzold B, Handley A, Mateo L, Siersbol H, Kollaritsch H, Chaplin P: A randomized, double-blind, dose-finding phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE. Vaccine 2010, 28:1209-1216.
• [28]Pathan AA, Minassian AM, Sander CR, Rowland R, Porter DW, Poulton ID, Hill AV, Fletcher HA, McShane H: Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults. Vaccine 2012, 30:5616-5624.
• [29]Ramanathan VD, Kumar M, Mahalingam J, Sathyamoorthy P, Narayanan PR, Solomon S, Panicali D, Chakrabarty S, Cox J, Sayeed E, Ackland J, Verlinde C, Vooijs D, Loughran K, Barin B, Lombardo A, Gilmour J, Stevens G, Smith MS, Tarragona-Fiol T, Hayes P, Kochhar S, Excler JL, Fast P: A phase 1 study to evaluate the safety and immunogenicity of a recombinant HIV type 1 subtype C-modified vaccinia Ankara virus vaccine candidate in Indian volunteers. AIDS Res Hum Retroviruses 2009, 25:1107-1116.
• [30]Durier C, Launay O, Meiffredy V, Saidi Y, Salmon D, Levy Y, Guillet JG, Pialoux G, Aboulker JP: Clinical safety of HIV lipopeptides used as vaccines in healthy volunteers and HIV-infected adults. AIDS 2006, 20:1039-1049.
• [31]Hokey DA, Weiner DB: DNA vaccines for HIV: challenges and opportunities. Springer Semin Immunopathol 2006, 28:267-279.
• [32]Salmon-Ceron D, Durier C, Desaint C, Cuzin L, Surenaud M, Hamouda NB, Lelievre JD, Bonnet B, Pialoux G, Poizot-Martin I, Aboulker JP, Levy Y, Launay O: Immunogenicity and safety of an HIV-1 lipopeptide vaccine in healthy adults: a phase 2 placebo-controlled ANRS trial. AIDS 2010, 24:2211-2223.
• [33]Vardas E, Stanescu I, Leinonen M, Ellefsen K, Pantaleo G, Valtavaara M, Ustav M, Reijonen K: Indicators of therapeutic effect in FIT-06, a phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects. Vaccine 2012, 30:4046-4054.
• [34]O’Connell RJ, Kim JH, Corey L, Michael NL: Human immunodeficiency virus vaccine trials. Cold Spring Harb Perspect Med 2012, 2:a007351.
• [35]Simon R, Wittes RE, Ellenberg SS: Randomized phase II clinical trials. Cancer Treat Rep 1985, 69:1375-1381.
• [36]Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, Keilholz U, Nichol G: A clinical development paradigm for cancer vaccines and related biologics. J Immunother 2007, 30:1-15.
• [37]Gray K, Legg K, Sharp A, Mackie N, Olarinde F, De Souza C, Weber J, Peters B: Participation in two phase II prophylactic HIV vaccine trials in the UK. Vaccine 2008, 26:2919-2924.
• [38]Asmuth DM, Brown EL, DiNubile MJ, Sun X, del Rio C, Harro C, Keefer MC, Kublin JG, Dubey SA, Kierstead LS, Casimiro DR, Shiver JW, Robertson MN, Quirk EK, Mehrotra DV: Comparative cell-mediated immunogenicity of DNA/DNA, DNA/adenovirus type 5 (Ad5), or Ad5/Ad5 HIV-1 clade B gag vaccine prime-boost regimens. J Infect Dis 2010, 201:132-141.
• [39]Churchyard GJ, Morgan C, Adams E, Hural J, Graham BS, Moodie Z, Grove D, Gray G, Bekker LG, McElrath MJ, Tomaras GD, Goepfert P, Kalams S, Baden LR, Lally M, Dolin R, Blattner W, Kalichman A, Figueroa JP, Pape J, Schechter M, Defawe O, De Rosa SC, Montefiori DC, Nabel GJ, Corey L, Keefer MC: A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204). PloS One 2011, 6:e21225.
• [40]Harari A, Bart PA, Stohr W, Tapia G, Garcia M, Medjitna-Rais E, Burnet S, Cellerai C, Erlwein O, Barber T, Moog C, Liljestrom P, Wagner R, Wolf H, Kraehenbuhl JP, Esteban M, Heeney J, Frachette MJ, Tartaglia J, McCormack S, Babiker A, Weber J, Pantaleo G: An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses. J Exp Med 2008, 205:63-77.
• [41]Brown SR, Gregory WM, Twelves CJ, Buyse M, Collinson F, Parmar M, Seymour MT, Brown JM: Designing phase II trials in cancer: a systematic review and guidance. Br J Cancer 2011, 105:194-199.
• [42]Ray HE, Rai SN: Operating characteristics of a Simon two-stage phase II clinical trial design incorporating continuous toxicity monitoring. Pharm Stat 2012, 11:170-176.
• [43]Launay O, Durier C, Desaint C, Silbermann B, Jackson A, Pialoux G, Bonnet B, Poizot-Martin I, Gonzalez-Canali G, Cuzin L, Figuereido S, Surenaud M, BenHamouda N, Gahery H, Choppin J, Salmon D, Guerin C, Bourgault Villada I, Guillet JG, Launay O, Durier C, Desaint C, Silbermann B, Jackson A, Pialoux G, Bonnet B, Poizot-Martin I, Gonzalez-Canali G, Cuzin L, Figuereido S, et al.: Cellular immune responses induced with dose-sparing intradermal administration of HIV vaccine to HIV-uninfected volunteers in the ANRS VAC16 trial. PloS One 2007, 2:e725.
• [44]Levy Y, Ellefssen K, Stoehr W, Bart PA, Lelièvre JD, Launey O, Wolf H, Weber J, Chene G, Pantaleo G: Optimal Priming of Poxvirus Vector-based HIV Vaccine Regimens Requires 3 DNA Injections: Results of the Randomized Multicentre EV03/ANRS Vac20 Phase I/II Trial. San Francisco, CA; 2010. [17th Conference on Retroviruses and Opportunistic Infections]
• [45]McElrath MJ, Haynes BF: Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity 2010, 33:542-554.
• [46]Virgin HW, Walker BD: Immunology and the elusive AIDS vaccine. Nature 2010, 464:224-231.
• [47]McElrath MJ, De Rosa SC, Moodie Z, Dubey S, Kierstead L, Janes H, Defawe OD, Carter DK, Hural J, Akondy R, Buchbinder SP, Robertson MN, Mehrotra DV, Self SG, Corey L, Shiver JW, Casimiro DR: HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 1894–1905, 2008:372.
• [48]Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982, 38:143-151.
• [49]Gray R, Manola J, Saxman S, Wright J, Dutcher J, Atkins M, Carducci M, See W, Sweeney C, Liu G, Stein M, Dreicer R, Wilding G, DiPaola RS: Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group. Clin Cancer Res 1966–1969, 2006:12.
• [50]A’Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 2001, 20:859-866.
• [51]Zohar S, Teramukai S, Zhou Y: Bayesian design and conduct of phase II single-arm clinical trials with binary outcomes: a tutorial. Contemp Clin Trials 2008, 29:608-616.
• [52]Jung SH, Kim KM: On the estimation of the binomial probability in multistage clinical trials. Stat Med 2004, 23:881-896.
• [53]Bryant J, Day R: Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 1995, 51:1372-1383.
• [54]Messer K, Natarajan L, Ball ED, Lane TA: Toxicity-evaluation designs for phase I/II cancer immunotherapy trials. Stat Med 2010, 29:712-720.
• [55]Kramar A, Bascoul-Mollevi C: Early stopping rules in clinical trials based on sequential monitoring of serious adverse events. Med Decis Making 2009, 29:343-350.
• [56]Ivanova A, Qaqish BF, Schell MJ: Continuous toxicity monitoring in phase II trials in oncology. Biometrics 2005, 61:540-545.
• [57]Yu J, Hutson AD, Siddiqui AH, Kedron MA: Group sequential control of overall toxicity incidents in clinical trials - non-Bayesian and Bayesian approaches. 2012 Mar 9 2012. Epub ahead of print
• [58]Gehan EA: The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 1961, 13:346-353.
• [59]Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989, 10:1-10.
• [60]Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA: Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 2005, 23:7199-7206.
• [61]Jennison C, Turnbull BW: Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall/CRC: Boca Raton, FL; 2000.
• [62]Goldman AI, Hannan PJ: Optimal continuous sequential boundaries for monitoring toxicity in clinical trials: a restricted search algorithm. Stat Med 2001, 20:1575-1589.
• [63]Lee JJ, Liu DD: A predictive probability design for phase II cancer clinical trials. Clin Trials 2008, 5:93-106.
• [64]Jin H: Alternative designs of phase II trials considering response and toxicity. Contemp Clin Trials 2007, 28:525-531.
• [65]Thall PF, Cheng SC: Optimal two-stage designs for clinical trials based on safety and efficacy. Stat Med 2001, 20:1023-1032.
• [66]Conaway MR, Petroni GR: Bivariate sequential designs for phase II trials. Biometrics 1995, 51:656-664.
• [67]Brutti P, Gubbiotti S, Sambucini V: An extension of the single threshold design for monitoring efficacy and safety in phase II clinical trials. Stat Med 2011, 30:1648-1664.
• [68]Ray HE, Rai SN: Flexible bivariate phase II clinical trial design incorporating toxicity and response on different schedules. Stat Med 2013, 32:470-485.
• [69]Hoering A, LeBlanc M, Crowley J: Seamless phase I-II trial design for assessing toxicity and efficacy for targeted agents. Clin Cancer Res 2011, 17:640-646.
• [70]Liu PY, LeBlanc M, Desai M: False positive rates of randomized phase II designs. Control Clin Trials 1999, 20:343-352.