small - cell lung cancer ( sclc ) , which comprises approximately 1015% of all lung cancers , is a neuroendocrine tumor , previously known as oat cell carcinoma , that is closely linked with tobacco smoking   and characterized by an aggressive and rapid pattern of metastases , limited treatment options following progression , and overall poor prognosis .
the disease is traditionally divided into two stages : limited - stage disease ( ld ) , confined to one hemithorax encompassable in a single radiation port , and extensive - stage disease ( ed ) , extending beyond those boundaries , which comprise the vast majority of patients at initial diagnosis [ 5 , 6 ] . for extensive - disease sclc
, the standard first - line regimen is etoposide - platinum ( ep ) doublets followed by topotecan , approved for second - line treatment , since progression is the rule after first - line ep despite the fact that sclc is initially chemosensitive ( with response rates to first - line treatment on the order of 7090% in ls disease and 5060% in ed disease ) . in ed , despite a response rate of 1528%   to topotecan , the median os rarely exceeds 6 months . according to the current nomenclature
sensitive relapsed ( pfs <3 months ) ,  resistant ( pfs <3 months ) and  refractory ( progression through first - line treatment ) . in general ,
subsequent readministration of ep doublets is contraindicated in resistant and refractory disease due to the likelihood of undue toxicities ( myelosuppression and nephrotoxicity , for example ) without benefit , since therapeutic resistance in these contexts is , with exceptions , construed as a stable and immutable trait .
pretreatment or priming with epigenetic inhibitors , like the approved dna demethylators , e.g. , 5-azacitidine ( azacitidine , aza ) and 2-deoxy-5-azacitidine ( decitabine , dac ) and the histone deacetylases , e.g. , vorinostat and romidepsin as well as experimental rrx-001 , has been identified as a nascent strategy , still in its infancy , to attenuate or reverse resistance to chemotherapy and immunotherapy [ 12 , 13 , 14 ] , particularly in non - small cell and ovarian cancers .
rrx-001 , in particular , has demonstrated evidence of episensitization to refractory irinotecan in the context of a phase ii clinical trial entitled rocket in metastatic colorectal cancer [ 16 , 17 , 18 ] .
triple threat ( nct02489903 ) is an ongoing open - label phase ii trial in non - small lung cancer , sclc and high - grade neuroendocrine tumors , which investigates a resensitization strategy to previously administered , but now refractory , platinum doublets following treatment with and progression on ( by recist vs. 1.1 criteria ) single agent rrx-001 mixed ex vivo with 100 ml of autologous blood prior to infusion .
the rationale for this unusual method of administration is related to the red blood cell partitioning of rrx-001 , which binds with high affinity to a cysteine residue in the -chain of hb ( cys 93 ) , displacing nitric oxide ( no ) in the process .
when no is displaced in vivo via standard intravenous infusion , it stimulates venous nociceptors , with a mild to moderate sensation of pain or discomfort for patients ; however , in the infusion bag , mixed with blood , the no is reabsorbed by the red blood cells , which appears to completely abrogate the hyperalgesia , resulting in a well - tolerated and rapid ( ~30 min ) infusion .
herein , we report a case of a patient with extensive refractory ed - sclc who was  episensitized to cisplatin and etoposide , with a partial response , after treatment with weekly intravenous rrx-001 autologous blood mix .
patient 001001 , a 49-year - old male veteran , former smoker , with a diagnosis of extensive - stage sclc , completed six cycles of carboplatin and etoposide in december 2012 . having progressed approximately 6 months later with 
sensitive relapsed ( pfs > 3 months ) disease , he was enrolled on a clinical trial at the nih in july 2013 where he received six cycles of cisplatin and etoposide followed by maintenance with the hdac inhibitor belinostat . approximately 1 year after completion of the nih trial , with symptoms of fatigue and inappetence due to disease progression as well as dyspnea and decreased exercise tolerance from a large unilateral pleural effusion , he enrolled as the first patient ( 001001 ) on the triple threat clinical trial at walter reed in june 2015 .
after the first dose of rrx-001 , and continuing for the next 89 weeks , the patient reported a significantly increased appetite for and consumption of fried foods , specifically pork chops , and desserts , which led to dyspeptic symptoms .
his fatigue , shortness of breath and exercise tolerance also significantly improved to the point that he resumed uphill running and lifting weights . a ct scan at 6 weeks ( fig .
1 ) , correlating with the symptomatic improvement , demonstrated near complete resolution of the unilateral malignant pleural effusion . in addition
unfortunately , nearly 10 weeks after the start of triple threat , patient 001001 developed 
travelers thrombosis and pulmonary embolism presumably from a prolonged ( 10 h ) car ride , which prompted the pi to discontinue rrx-001 on suspicion of symptomatic progression since the patient began to complain of fatigue and inappetence as well as dyspnea associated to pulmonary embolism , even though repeat ct scans did not confirm radiologic progression . at this point , per protocol , since the patient still met all inclusion / exclusion criteria , he was rechallenged for a third time with ep doublets and , despite expected toxicities of fatigue and anorexia , he reported improved performance status . at 6 weeks after reintroduction of therapy , repeat ct scans demonstrated a partial response with an approximate 32% decrease in tumor size ( fig .
one month later , a confirmatory scan showed a 50% decrease in tumor size , indicative of continued cytotoxic activity .
to the best of our knowledge , triple threat is the first and only clinical trial to investigate resensitization or episensitization , since rrx-001 is an epigenetic inhibitor   in sclc as well as nsclc and neuroendocrine tumors . as a highly aggressive tumor with a uniformly dismal prognosis and an unmet need for effective therapeutic options
, sclc is extremely difficult to treat : the median survival time following recurrence rarely exceeds 6 months , the 2-year survival is < 10% , and there are virtually no 5-year survivors , requiring innovative strategies to address the difficult challenge of salvage treatment of relapsed sclc .
dna methyltransferase and hdac inhibitors have demonstrated the potential to reverse therapeutic resistance   in multiple tumor types because epigenetic alterations , an important driver of carcinogenesis and progression , are , in theory , reversible . paradoxically , these alterations are also stably maintained through mitotic cell division , leading to a kind of epigenetic memory , with priming of responses to temporally separate and subsequent , rather than simultaneous , therapy since the induced pattern of gene transcription persists .
the clinical course of this sclc patient ( 001001 ) suggests , with the usual caveats about making generalizations from 
n - of-1 results , that reintroduction of etoposide - platinum after initial treatment with rrx-001 , leading to episensitization , is a safe and effective strategy for solid tumor types previously treated with platinum doublet - based chemotherapy .
the phase ii triple threat clinical trial is ongoing , having enrolled 5 patients to date , none of whom , besides patient 001001 , have progressed on rrx-001 , and their data will also be reported , if episensitization , anticipated here as elsewhere , is demonstrated .
any subjects have given their informed consent in the study and the study protocol has been approved by the relevant institute 's institutional review board , also known as an independent ethics committee , ethical review board , or research ethics board .
the authors disclose that the clinical trial in which this case was observed is funded by epicentrx , inc .
 rrx-001 is a pan - active , systemically nontoxic epigenetic inhibitor under investigation in advanced non - small cell lung cancer , small - cell lung cancer and high - grade neuroendocrine tumors in a phase ii clinical trial entitled triple threat ( nct02489903 ) , which reexposes patients to previously effective but refractory platinum doublets after treatment with rrx-001 . 
 the purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small - cell lung cancer pretreated with rrx-001 , indicating episensitization or resensitization by epigenetic mechanisms , and second to discuss the literature related to small - cell lung cancer and episensitization . 
Introduction
Case Report
Discussion
Statement of Ethics
Disclosure Statement