BACKGROUND: This exploratory single-arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small-cell lung cancer (SCLC). METHODS: Patients were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by rechallenge with etoposide 80-100 IV mg/m 2 on days 1, 2 and 3 and cisplatin 60-80 mg/m 2 IV on day 1 or carboplatin AUC 5-6 IV on day 1, every 21 days. The primary end points were overall survival (OS) and overall response rate to platinum regimen. RESULTS: Twenty-six patients were enroled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, one patient (3.8%) had complete response and six (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrolment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse event from RRx-001 was mild discomfort at the infusion site (23%). CONCLUSIONS: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. CLINICAL TRIAL REGISTRATION: NCT02489903.
Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific “driver” mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, “elephant in the room”, is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and ‘tame the beast of resistance’, thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to “prime” tumors and reverse resistance.
As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT; NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.
Small cell carcinoma of the vagina is rare, so rare in fact that the total number reported in English-language journals is less than 30. Due to this extremely low incidence, no specific treatment guidelines have been established, and most of what is clinically known is derived from a handful of single case reports. However, as befitting its highly aggressive histologic features, which are reminiscent of small cell lung cancer (SCLC), first-line treatment is modeled after SCLC. Herein is reported the case of a 51-year-old African-American patient with metastatic biopsy-proven small cell carcinoma of the vagina that progressed through multiple therapies: first-line cisplatin and etoposide (making it platinum-resistant) and radiotherapy, followed by the tumor macrophage-stimulating agent RRx-001 in a clinical trial called QUADRUPLE THREAT, which per protocol preceded a mandated rechallenge with cisplatin and etoposide. RECIST v.1.1 tumor progression on both RRx-001 and cisplatin/etoposide was accompanied by central necrosis in several of the enlarged lymph nodes and hepatic metastases, which may have been evidence of pseudoprogression, accounting for her ongoing longer-than-expected survival, since the necrotic tissue may have primed the activity of the PD-1 inhibitor. The lack of response to RRx-001 is hypothesized to have correlated with sparse tumor macrophage infiltration, seen on pre- and post-treatment biopsies, since the mechanism of action of RRx-001 relates to stimulation of tumor-associated macrophages.
Superior vena cava (SVC) syndrome, a potential oncologic emergency, is closely associated with malignancy and right-sided lung cancer in particular. A case of SVC syndrome presenting with facial swelling, neck distension, and enlarged veins of the upper chest, which developed over a period of 5 weeks in a 46-year-old patient on a clinical trial with small-cell lung cancer, is reported. Computed tomography scan of the chest revealed slight enlargement of a superior conglomerate mediastinal lymphadenopathy and intramural thrombus of the SVC. The etiology, diagnosis, and treatment of the SVC syndrome are discussed.
Introduction: RRx-001 is a novel systemically non-toxic small molecule macrophage stimulating agent with promising activity in an ongoing clinical trial in small cell and non-small cell lung cancer and in neuroendocrine tumors. In preclinical studies, RRx-001 activated normally immune-suppressive M2-like Tumor Associated Macrophages (TAMs) to express a series of pro-inflammatory cytokines and chemokines such as transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α TNF-α), inducible nitric oxide synthase (iNOS), and interleukins-10 and -12, a profile that resembles the M1 activated macrophage state. Due to its chemotactic activity for macrophages, TGF-β1 was hypothesized to be involved in the antitumor mechanism of RRx-001. We therefore compared expression patterns of TGF-β1 and TGF-βRI in patient-derived biopsy samples obtained at screening and post RRx-001. As TGF-β1 is closely associated with the induction of fibrosis, we also examined key fibrosis markers. Methods: Tumor biopsies before and after treatment with RRx-001 were obtained from consented patients with NSCLC, SCLC, and neuroendocrine tumors in the QUADRUPLE THREAT Phase II clinical trial (NCT02489903). Post treatment biopsies were obtained following 6 weeks of once-weekly RRx-001 treatment co-incidental with the first on-study CT scan. Tumor samples were evaluated immune-histochemically with putative markers for TGFβ pathway activation (TGF-β1, TGF-βR1), fibrosis (alpha-smooth muscle actin [α-SMA], Matrix metallopeptidase-9 [MMP-9], and Collagen III deposition), and macrophage activation. Patients were subsequently followed for tumor progression. Results: Positive immune-histochemical staining for TGF-β1 and TGF-βR1 was seen in all responding patients, and in none of the non-responding patients to date. In responders we also found that MMP-9 and α-SMA activity was down regulated post RRx-001. The down-regulation of these fibrosis markers is suggestive of less invasive malignancy. The number of tumor associated macrophages and their activation was related to the activity of RRx-001. Conclusions: Our pre and post dose patient derived data to date indicate a correlation between TGF-β signaling activation and a response to RRx-001 that may also correlate with increased numbers of macrophages, and their activation status, in the vicinity of the tumor. These data suggest that activation of the TGF-β1 pathway, as evident by expression of TGF-β1 and TGF-βR1 by tumor cells, could be a predictive biomarker for RRx-001 treatment. Citation Format: Saheli Jha, Thomas A. Summers, Karen Zeman, Christine Brzezniak, Corey Carter, Lindsey Ferry, Jan Scicinski, Bryan Oronsky, Scot Caroen, Jane B. Trepel, Pedro Cabrales, Regina Day. Phase II clinical trial patient responses to the macrophage activating agent RRx-001 correlate to TGF- β pathway activation and markers for fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 966. doi:10.1158/1538-7445.AM2017-966
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