Clinical trial NCT03971214: PD-1 Inhibitors Consolidation in Extensive-stage Small Cell Lung Cancer
Official title: Pilot Study on PD-1 Inhibitors Consolidation After Standard First-line Chemotherapy and Radiotherapy in Extensive-stage Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Extensive-stage Small Cell Lung Cancer
Radiotherapy
Immunotherapy
Keywords: small cell lung cancer
radiotherapy
PD-1 inhibitor
Lead sponsor: ChineseAMS
Sponsor class: UNKNOWN
First posted: 2019-06-03
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The prognosis of extensive-stage small cell lung cancer is still very poor, even for those who received platinum-based chemotherapy and chest radiotherapy. 2-year survival rate of these patients is only about 10%. Therefore, this study aims to explore a comprehensive treatments with low toxicity to further improve the efficacy for these paitents with PD-1 inhibitor.

Detailed description: The study is a prospective pilot trial. The purpose of this study is to evaluate the safety and efficacy of PD-1 inhibitor consolidation in extensive-stage small cell lung cancer paitents who received standard first-line chemotherapy and chest radiotherapy ± SABR for metastasis disease.

The primary endpoint is the safety and objective response rate of treatment. The secondary objectives are progression free survival(PFS), overall survial. The exploratory end point includes the correlation of PD-1 expression on the tumor tissue, and the TMB, Immune Repertoire sequencing derived from the tumor tissue and the blood sample with the efficacy of treatent. The plan for collection of tumor tissue and blood at baseline at different stages during or after treatment was defined in the protocol.

The PICCARE-trial has been designed by National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, and the hypothesis is PD-1 inhibitor consolidation was safe and effective in the treatment of extensive-stage SCLC after sandard first-line chemotherapy and radiotherapy.

Eligibility criteria: Inclusion Criteria:

* Sign written informed consent;
* With extensive small cell lung cancer;
* Previously received first-line standard chemotherapy, with treatment response of CR or PR;
* Can provide at least 5-8 pathological tissue specimens (for detecting PD-L1 expression and infiltrating lymphocytes)
* Can tolerate the radiotherapy process;
* Weight ≥ 40kg;
* Life expectancy ≥ 12 weeks;
* With the Eastern Cancer Cooperative Group (ECOG) score 0-1;
* The interval from the previous chemotherapy is more than 4 weeks, the grade of all adverse events caused by previous treatment have been reduced to grade 1 or less evaluated by CTCAE 4.03;
* Before the administration of the study drug, systemic drugs (such as corticosteroids) applied at an immunosuppressive dose level (prednisone \> 10 mg/d or equivalent) must have been discontinued for at least 2 weeks;
* Major surgery requiring general anesthesia must have been completed for at least 4 weeks before administration of the study drug. Surgery requiring local anesthesia/epidural anesthesia must have been completed for at least 72 hours before administration of the study drug, and the subject must have recovered. Skin biopsy with only local anesthesia has been completed for at least 1 hour before administration of the study drug.
* Other criteria including the laboratory values meets the requirements specified in the protocol.

Exclusion Criteria:

* Subjects with central nervous system (CNS) metastases;
* The subject has cancerous meningitis;
* Subjects with active, known or suspected autoimmune diseases ;
* Previously treated with anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody or anti-CTLA-4 antibody (or any other antibody acting on the T cell stimulation or checkpoint pathway);
* According to chest X-ray examination, sputum examination and clinical examination, it is determined that there is active tuberculosis (TB) infection now or before, even one year before;
* A positive immunodeficiency virus (HIV) test or have acquired immunodeficiency syndrome (AIDS);
* With comorbidity needs to be treated with an immunosuppressive drug;
* Other research drugs were administrated 28 days prior to the start of study drug or although they were more than 28 days apart, still within the 5 half-life of previous study drugs;
* Inoculated with any anti-infective vaccine (such as influenza vaccine, varicella vaccine, etc.) within 4 weeks before starting the study drug;
* In the condition of pregnant or breastfeeding;
* Inability to tolerate venous puncture and/or venous access;
* Any other medical, psychotic, and/or social problems determined by the investigator;
* Subject has interstitial lung disease;
* Use any Chinese medicine with anti-tumor activity within 2 weeks before starting of the study drug;
* Monoclonal antibodies have been used in the past 3 months, except for topical use;
* Subjects who have previously had other malignancies (excluding non-melanoma skin cancer and the following carcinomas in situ: bladder, stomach, colon, endometrium, cervix/dysplasia, melanoma or breast cancer) are not allowed to participate in the study. Unless he/she has been cured at least 2 years prior to enrollment, and does not require additional treatment or other treatments during the study;
* Subjects with chronic hepatitis B (hepatitis B surface antigen positive) or chronic hepatitis C (HCV antibody positive) blood screening positive;
* Previously allergic to macromolecular protein preparations, or to any of the JS001 ingredients.

Primary outcomes:
measure: Adverse events
timeFrame: At least 1 year following the conclusion of immunotherapy
measure: Objective remission rate
timeFrame: 24 weeks following the conclusion of immunotherapy
Secondary outcomes:
measure: Pharmacodynamic indicators
timeFrame: During and 6 weeks after the treatment of immunotherapy
measure: Continuous remission time (DOR)
timeFrame: At least 1 year following the conclusion of immunotherapy
measure: Disease Control Rate (DCR)
timeFrame: At least 1 year following the conclusion of immunotherapy
measure: Time to response (TTR)
timeFrame: 24 weeks following the conclusion of immunotherapy
measure: Progression-free survival (PFS)
timeFrame: At least 1 year following the conclusion of immunotherapy
measure: Overall survival (OS)
timeFrame: At least 1 year following the conclusion of immunotherapy
Other outcomes:
measure: Exploratory end point including biomarkers
timeFrame: At least 1 year following the conclusion of immunotherapy
Locations:
city: Beijing
country: China
facility: Cancer Insititute and Hosiptal of Chinese Academy of Medical Sciences
state: Beijing
Study officials:
affiliation: Cancer Hospital, CAMS and PUMC
name: Nan Bi, MD
role: STUDY_DIRECTOR
References:
citation: Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. doi: 10.3322/caac.21262. Epub 2015 Feb 4.
citation: Chen W, Zheng R, Zhang S, Zeng H, Zuo T, Xia C, Yang Z, He J. Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin J Cancer Res. 2017 Feb;29(1):1-10. doi: 10.21147/j.issn.1000-9604.2017.01.01.
citation: Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, Nishiwaki Y, Watanabe K, Noda K, Tamura T, Fukuda H, Saijo N. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002 Jul 15;20(14):3054-60. doi: 10.1200/JCO.2002.12.071.
citation: Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71. doi: 10.1056/NEJM199901283400403.
citation: Janne PA, Freidlin B, Saxman S, Johnson DH, Livingston RB, Shepherd FA, Johnson BE. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer. 2002 Oct 1;95(7):1528-38. doi: 10.1002/cncr.10841.
citation: Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Piccirillo J. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006 Oct 1;24(28):4539-44. doi: 10.1200/JCO.2005.04.4859.
citation: Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, Blakely J, Serwatowski P, Karaseva NA, Ciuleanu T, Jassem J, Dediu M, Hong S, Visseren-Grul C, Hanauske AR, Obasaju CK, Guba SC, Thatcher N. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009 Oct 1;27(28):4787-92. doi: 10.1200/JCO.2009.23.1548. Epub 2009 Aug 31.
citation: Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009 May 20;27(15):2530-5. doi: 10.1200/JCO.2008.20.1061. Epub 2009 Apr 6.
citation: Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, Fruh M, Qian W, Tamura T, Samantas E, Shibata T, Perrone F, Gallo C, Gridelli C, Martelli O, Lee SM. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012 May 10;30(14):1692-8. doi: 10.1200/JCO.2011.40.4905. Epub 2012 Apr 2.
citation: Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, Keijser A, Faivre-Finn C, Senan S. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385(9962):36-42. doi: 10.1016/S0140-6736(14)61085-0. Epub 2014 Sep 14.
citation: Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, Keijser A, Faivre-Finn C, Senan S. Radiotherapy for extensive stage small-cell lung cancer - Authors' reply. Lancet. 2015 Apr 4;385(9975):1292-3. doi: 10.1016/S0140-6736(15)60679-1. No abstract available.
citation: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239.
citation: Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.
citation: Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol. 1996 May;8(5):773-80. doi: 10.1093/intimm/8.5.773.
citation: Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012 Mar 28;4(127):127ra37. doi: 10.1126/scitranslmed.3003689.
citation: Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7. doi: 10.1073/pnas.192461099. Epub 2002 Sep 6.
citation: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.
citation: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.
citation: Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jager D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin CS, Christensen O, Calvo E. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5. Epub 2016 Jun 4.
citation: Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst. 1979 Nov;63(5):1229-35. No abstract available.
citation: Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013 Feb 20;105(4):256-65. doi: 10.1093/jnci/djs629. Epub 2013 Jan 4.
citation: Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015 Oct;16(13):e498-509. doi: 10.1016/S1470-2045(15)00007-8.
citation: Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, Jones H, Wilkinson RW, Honeychurch J, Illidge TM. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014 Oct 1;74(19):5458-68. doi: 10.1158/0008-5472.CAN-14-1258.
citation: Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95. doi: 10.1172/JCI67313. Epub 2014 Jan 2.
citation: Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, Deweese TL, Drake CG. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol Res. 2015 Apr;3(4):345-55. doi: 10.1158/2326-6066.CIR-14-0196. Epub 2014 Dec 19.
citation: Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, Duret H, Yagita H, Johnstone RW, Smyth MJ, Haynes NM. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012 Jul 1;72(13):3163-74. doi: 10.1158/0008-5472.CAN-12-0210. Epub 2012 May 8.
citation: Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, Albesiano E, Pradilla G, Ford E, Wong J, Hammers HJ, Mathios D, Tyler B, Brem H, Tran PT, Pardoll D, Drake CG, Lim M. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):343-9. doi: 10.1016/j.ijrobp.2012.12.025. Epub 2013 Feb 22.
citation: Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, Yu HH, Etame AB, Weber JS, Gibney GT. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016 Mar;27(3):434-41. doi: 10.1093/annonc/mdv622. Epub 2015 Dec 27.
citation: Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. Epub 2017 May 24.
citation: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.
citation: Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1306-10. doi: 10.1016/j.ijrobp.2011.09.049. Epub 2011 Dec 28.
citation: Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009 Sep 1;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265. Epub 2009 Aug 25.
citation: Finkelstein SE, Timmerman R, McBride WH, Schaue D, Hoffe SE, Mantz CA, Wilson GD. The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol. 2011;2011:439752. doi: 10.1155/2011/439752. Epub 2011 Nov 15.