Pembrolizumab vs Topotecan in Patients With Small Cell Lung Cancer

NCT02963090 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: AFT-17
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief Summary

This is a multi-institutional, randomized, open-label phase II study of pembrolizumab compared to topotecan, administered to patients with SCLC who have progressed or relapsed after first-line treatment with etoposide and platinum. Patients will be randomized in a 2:1 fashion to receive pembrolizumab or topotecan. Participants in the topotecan arm that progress will be allowed to cross-over to the pembrolizumab arm.

Conditions

Small Cell Lung Cancer

Keywords

SCLC; small cell lung cancer; lung cancer; topotecan; pembrolizumab

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival

  This phase II study will determine if there is a benefit in progression free survival (PFS) for SCLC patients receiving pembrolizumab (Experimental arm) as compared to topotecan (Control arm) in the second-line settingSCLC patients receiving pembrolizumab (Experimental arm) as compared to topotecan (Control arm) in the second-line setting. RECIST Version 1.1 was used in this study for assessment for tumor response. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, which also includes any lymph node that was normal at baseline (\< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. b. At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD. In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.

  4.2 months

Secondary Outcomes (2)

• Overall Survival (OS)

  20 months

• Overall Response Percentage

  4.2 months

Study Arms (2)

Topotecan

ACTIVE COMPARATOR

Topotecan IV at 1265mg/m\^2 Days 1-5 of every 21 day cycle

Drug: Topotecan; Drug: Pembrolizumab

Pembrolizumab

EXPERIMENTAL

Pembrolizumab IV 200mg infusion Day 1 of every 21 day cycle

Drug: Pembrolizumab

Interventions

Topotecan DRUG

Topotecan at 1.25mg/m2 on days 1 to 5 every 21-days until progression of disease or unacceptable toxicities. Patients with progression of disease by RECIST 1.1 will be allowed cross over to receive pembrolizumab 200 mg IV every 21-days for up to 1 year until progression of disease or unacceptable toxicities.

Also known as: hycamtin

Topotecan

Pembrolizumab DRUG

200 mg IV every 21-days until progression of disease or unacceptable toxicities.

Also known as: Keytruda, MK-3475

Pembrolizumab; Topotecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible for participation in this trial, the patient must:
• Have histologically or cytologically confirmed small cell lung cancer. Confirmation will be done at each participating site.
• Have relapsed or progressed after only one prior chemotherapy regimen, which must have been an etoposide-platinum doublet. Eligible patients will be defined as follows:
• "Sensitive" Disease: Patients who had one previous line of chemotherapy and relapsed after \> 60 days of completion of treatment.
• "Refractory" Disease: Patients with no response to first-line chemotherapy or progression \>60 days after completing treatment.
• Be ≥ 18 years of age on day of signing informed consent.
• Have a life expectancy of at least 3 months.
• Have a performance status of ≤ 1 on the ECOG Performance Scale.
• Have measurable disease based on RECIST 1.1.
• Have a tumor tissue specimen available from either a core or excisional biopsy. The tumor specimen should be of adequate size and tumor cellularity to perform whole exome sequencing and immunohistochemistry. In subjects for whom newly obtained samples cannot be obtained (e.g. tumor inaccessible or safety concern), archived tissue may be submitted, if it otherwise satisfies all specimen criteria. Archival samples must have been obtained within 42 days prior to signing consent (please refer to section 12.1 of protocol).
• Demonstrate adequate organ function as defined in Table 1.
• Table 1. Adequate Organ Function Laboratory Values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8 g/dL (without transfusion) Renal Serum creatinine
• Glomerular Filtration Rate (GFR) ≤1.5 X upper limit of normal (ULN)
• GFR ≥60 mL/min\* for patient with creatinine levels \> 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN
• Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN

You may not qualify if:

• The patient must be excluded from participating in the trial if the patient:
• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 14 days of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has had a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 14 days earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
• Has undergone major surgery, he/she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment.
• Has known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Has known carcinomatous meningitis.
• Has an active autoimmune disease requiring systemic treatment in the past 2 years or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
• Has evidence of interstitial lung disease, or history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Sponsors & Collaborators

• Alliance Foundation Trials, LLC.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Metro MN Community Oncology Research Consortium

Saint Louis Park, Minnesota, 55416, United States

Location

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (56)

• Viale PH. The American Cancer Society's Facts & Figures: 2020 Edition. J Adv Pract Oncol. 2020 Mar;11(2):135-136. doi: 10.6004/jadpro.2020.11.2.1. Epub 2020 Mar 1. No abstract available.

  PMID: 33532112 BACKGROUND

• Gaspar LE, McNamara EJ, Gay EG, Putnam JB, Crawford J, Herbst RS, Bonner JA. Small-cell lung cancer: prognostic factors and changing treatment over 15 years. Clin Lung Cancer. 2012 Mar;13(2):115-22. doi: 10.1016/j.cllc.2011.05.008. Epub 2011 Oct 14.

  PMID: 22000695 BACKGROUND

• Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, Kris MG, Rekhtman N, Ladanyi M, Wang L, Berger MF, Pietanza MC. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014 Jun;9(6):892-6. doi: 10.1097/JTO.0000000000000142.

  PMID: 24828667 BACKGROUND

• Ou SH, Ziogas A, Zell JA. Prognostic factors for survival in extensive stage small cell lung cancer (ED-SCLC): the importance of smoking history, socioeconomic and marital statuses, and ethnicity. J Thorac Oncol. 2009 Jan;4(1):37-43. doi: 10.1097/JTO.0b013e31819140fb.

  PMID: 19096304 BACKGROUND

• Krug LM, Kris MG, Rosenzweig K, Travis W. Small cell and other neuroendocrine tumors of the lung. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncolology. 8th ed: Lippincott, Williams, and Wilkins; 2008.

  BACKGROUND

• von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67. doi: 10.1200/JCO.1999.17.2.658.

  PMID: 10080612 BACKGROUND

• Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, Giaccone G, Schaefer B, Wanders J, Verweij J. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol. 1997 May;15(5):2090-6. doi: 10.1200/JCO.1997.15.5.2090.

  PMID: 9164222 BACKGROUND

• Eckardt J, Gralla R, Palmer MC, et al. Topotecan as second-line therapy in patients with small cell lung cancer: a phase II study. Ann Oncol 1996;7:107 (abstr 513).

  BACKGROUND

• Depierre A, von Pawel J, Hans L, et al. Evaluation of Topotecan (Hycamtin) in relapsed small-cell lung cancer (SCLC): A multicenter phase II study. Lung Cancer 1997;18:35 (abstract 126).

  BACKGROUND

• Eckardt J, Depierre A, Ardizzoni A, von Pawel J, Fields SZ. Pooled analysis of topotecan in the second-line treatment of patients with sensitive small cell lung cancer. Proc Am Soc Clin Oncol 1997;16:452a (abstr 1624).

  BACKGROUND

• O'Brien M, Eckardt J, Ramlau R. Recent advances with topotecan in the treatment of lung cancer. Oncologist. 2007 Oct;12(10):1194-204. doi: 10.1634/theoncologist.12-10-1194.

  PMID: 17962613 BACKGROUND

• Koschel R, Huber RM, Gatzemeier U, et al. Topotecan in Second-Line Treatment of Small Cell Lung Cancer Reduced Toxicity with Individualized Therapy. Lung Cancer 2000;29:42 (abstract 135).

  BACKGROUND

• Huber RM, Reck M, Gosse H, von Pawel J, Mezger J, Saal JG, Kleinschmidt R, Steppert C, Steppling H. Efficacy of a toxicity-adjusted topotecan therapy in recurrent small cell lung cancer. Eur Respir J. 2006 Jun;27(6):1183-9. doi: 10.1183/09031936.06.00015605. Epub 2006 Feb 15.

  PMID: 16481389 BACKGROUND

• Disis ML. Immune regulation of cancer. J Clin Oncol. 2010 Oct 10;28(29):4531-8. doi: 10.1200/JCO.2009.27.2146. Epub 2010 Jun 1.

  PMID: 20516428 BACKGROUND

• Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug;8(8):793-800. doi: 10.1038/nm730. Epub 2002 Jun 24.

  PMID: 12091876 BACKGROUND

• Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002 Feb;2(2):116-26. doi: 10.1038/nri727.

  PMID: 11910893 BACKGROUND

• Johnson BJ, Costelloe EO, Fitzpatrick DR, Haanen JB, Schumacher TN, Brown LE, Kelso A. Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2657-62. doi: 10.1073/pnas.0538056100. Epub 2003 Feb 24.

  PMID: 12601154 BACKGROUND

• Thompson RH, Dong H, Kwon ED. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):709s-715s. doi: 10.1158/1078-0432.CCR-06-1868.

  PMID: 17255298 BACKGROUND

• Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, Kuriyama H, Tanaka H, Tanaka J, Yoshizawa H, Nakata K, Gejyo F. Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res. 2008 Nov 1;14(21):6770-9. doi: 10.1158/1078-0432.CCR-08-1156.

  PMID: 18980970 BACKGROUND

• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239.

  PMID: 22437870 BACKGROUND

• Terawaki S, Tanaka Y, Nagakura T, Hayashi T, Shibayama S, Muroi K, Okazaki T, Mikami B, Garboczi DN, Honjo T, Minato N. Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function. Int Immunol. 2007 Jul;19(7):881-90. doi: 10.1093/intimm/dxm059. Epub 2007 Jul 2.

  PMID: 17606978 BACKGROUND

• Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004 Mar;20(3):337-47. doi: 10.1016/s1074-7613(04)00051-2.

  PMID: 15030777 BACKGROUND

• Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71. doi: 10.1073/pnas.231486598. Epub 2001 Nov 6.

  PMID: 11698646 BACKGROUND

• Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004 Jul 15;173(2):945-54. doi: 10.4049/jimmunol.173.2.945.

  PMID: 15240681 BACKGROUND

• Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML. PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion. Eur J Immunol. 2005 Dec;35(12):3561-9. doi: 10.1002/eji.200526347.

  PMID: 16278812 BACKGROUND

• Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.

  PMID: 25034862 BACKGROUND

• Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19.

  PMID: 25891174 BACKGROUND

• 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 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Graus F, Dalmou J, Rene R, Tora M, Malats N, Verschuuren JJ, Cardenal F, Vinolas N, Garcia del Muro J, Vadell C, Mason WP, Rosell R, Posner JB, Real FX. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol. 1997 Aug;15(8):2866-72. doi: 10.1200/JCO.1997.15.8.2866.

  PMID: 9256130 BACKGROUND

• Tanio Y, Watanabe M, Osaki T, Tachibana I, Kawase I, Kuritani T, Saito S, Masuno T, Kodama N, Furuse K, et al. High sensitivity to peripheral blood lymphocytes and low HLA-class I antigen expression of small cell lung cancer cell lines with diverse chemo-radiosensitivity. Jpn J Cancer Res. 1992 Jul;83(7):736-45. doi: 10.1111/j.1349-7006.1992.tb01974.x.

  PMID: 1325431 BACKGROUND

• Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokoyama K, Ogata T. Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol. 1999 Jan;187(2):191-9. doi: 10.1002/(SICI)1096-9896(199901)187:23.0.CO;2-3.

  PMID: 10365094 BACKGROUND

• Schultheis AM, Scheel AH, Ozretic L, George J, Thomas RK, Hagemann T, Zander T, Wolf J, Buettner R. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015 Feb;51(3):421-6. doi: 10.1016/j.ejca.2014.12.006. Epub 2015 Jan 9.

  PMID: 25582496 BACKGROUND

• Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. doi: 10.1200/JCO.2011.38.4032. Epub 2012 Apr 30.

  PMID: 22547592 BACKGROUND

• Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. doi: 10.1093/annonc/mds213. Epub 2012 Aug 2.

  PMID: 22858559 BACKGROUND

• Ott PA, Elez E, Hiret S, et al. Pembrolizumab for Extensive Stage Disease SCLC: Efficacy and Relationship with PD-L1 Expression. 16th World Conference on Lung Cancer 2015;Abstract 3285.

  BACKGROUND

• George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G, Muller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Putzer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmuller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castanos-Velez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Kohler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansen S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nurnberg P, Reinhardt C, Perner S, Heukamp L, Buttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.

  PMID: 26168399 BACKGROUND

• Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordonez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, Costa GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes MD, McKernan KJ, Stratton MR, Futreal PA, Campbell PJ. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010 Jan 14;463(7278):184-90. doi: 10.1038/nature08629. Epub 2009 Dec 16.

  PMID: 20016488 BACKGROUND

• Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella-Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna JD, Brock MV, Seshagiri S. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.

  PMID: 22941189 BACKGROUND

• Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Muller C, Di Cerbo V, Schildhaus HU, Altmuller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Bohm D, Ansen S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grutter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sanger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Buttner R, Wolf J, Nurnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012 Oct;44(10):1104-10. doi: 10.1038/ng.2396. Epub 2012 Sep 2.

  PMID: 22941188 BACKGROUND

• Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 Jul 11;499(7457):214-218. doi: 10.1038/nature12213. Epub 2013 Jun 16.

  PMID: 23770567 BACKGROUND

• Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199. doi: 10.1056/NEJMoa1406498. Epub 2014 Nov 19.

  PMID: 25409260 BACKGROUND

• Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.

  PMID: 25765070 BACKGROUND

• Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, Poulin R, Preston AJ, Dane G, Ross G. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007 May 20;25(15):2086-92. doi: 10.1200/JCO.2006.08.3998.

  PMID: 17513814 BACKGROUND

• J-C S, O F, L H, et al. LATE BREAKING ABSTRACT: Efficacy and Safety of Pembrolizumab (Pembro; MK-3475) for Patients (Pts) With Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Enrolled in KEYNOTE-001. European Society of Medical Oncology Annual Meeting 2015:33LBA.

  BACKGROUND

• Hellmann M, Creelan B, Woo K, et al. Smoking history and response to nivolumab in patients with advanced NSCLCs. Ann Oncol 2014;25.

  BACKGROUND

• Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012 Feb 8;482(7385):400-4. doi: 10.1038/nature10755.

  PMID: 22318521 BACKGROUND

• Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N, de Graaf J, Selmi A, Diken M, Boegel S, Paret C, Koslowski M, Kuhn AN, Britten CM, Huber C, Tureci O, Sahin U. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012 Mar 1;72(5):1081-91. doi: 10.1158/0008-5472.CAN-11-3722. Epub 2012 Jan 11.

  PMID: 22237626 BACKGROUND

• Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wolfel C, Huber C, Wolfel T. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16013-8. doi: 10.1073/pnas.0500090102. Epub 2005 Oct 24.

  PMID: 16247014 BACKGROUND

• van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, van Dijk LJ, Behjati S, Hilkmann H, El Atmioui D, Nieuwland M, Stratton MR, Kerkhoven RM, Kesmir C, Haanen JB, Kvistborg P, Schumacher TN. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013 Nov 10;31(32):e439-42. doi: 10.1200/JCO.2012.47.7521. Epub 2013 Sep 16. No abstract available.

  PMID: 24043743 BACKGROUND

• Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641-5. doi: 10.1126/science.1251102.

  PMID: 24812403 BACKGROUND

• Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA, Schreiber H. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell. 2013 Apr 15;23(4):516-26. doi: 10.1016/j.ccr.2013.03.018.

  PMID: 23597565 BACKGROUND

• Lundegaard C, Lund O, Nielsen M. Accurate approximation method for prediction of class I MHC affinities for peptides of length 8, 10 and 11 using prediction tools trained on 9mers. Bioinformatics. 2008 Jun 1;24(11):1397-8. doi: 10.1093/bioinformatics/btn128. Epub 2008 Apr 14.

  PMID: 18413329 BACKGROUND

• Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M. NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W509-12. doi: 10.1093/nar/gkn202. Epub 2008 May 7.

  PMID: 18463140 BACKGROUND

• Andersen RS, Kvistborg P, Frosig TM, Pedersen NW, Lyngaa R, Bakker AH, Shu CJ, Straten Pt, Schumacher TN, Hadrup SR. Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. Nat Protoc. 2012 Apr 12;7(5):891-902. doi: 10.1038/nprot.2012.037.

  PMID: 22498709 BACKGROUND

• Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24.

  PMID: 19934295 BACKGROUND

• Fleming TR and Harrington DP. (1991). Counting Processes and Survival Analysis. New York, NY: John Wiley & Sons.

  BACKGROUND

MeSH Terms

Conditions

Small Cell Lung Carcinoma; Lung Neoplasms

Interventions

Topotecan; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Thomas Stinchcombe, MD
• Organization: Duke Cancer Institute

thomas.stinchcombe@duke.edu

(919) 668-6688

Study Officials

• Monica Bertagnolli, MD

  Alliance Foundation Trials

  PRINCIPAL INVESTIGATOR

• Thomas Stinchcombe, MD

  University of North Carolina, Chapel Hill

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2016
• First Posted: November 15, 2016
• Study Start: May 20, 2017
• Primary Completion: June 20, 2019
• Study Completion: August 20, 2019
• Last Updated: February 15, 2023
• Results First Posted: September 16, 2022

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)