Epicentrx

Mountain View, CA, United States

Epicentrx

Mountain View, CA, United States
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Cabrales P.,University of California at San Diego | Caroen S.,EpicentRx | Oronsky A.,InterWest Partners | Carter C.,U.S. National Institutes of Health | And 6 more authors.
Expert Review of Hematology | Year: 2017

Background: RRx-001, a clinical macrophage-stimulating anti-cancer agent that also produces nitric oxide (NO) was studied in a model of ischemia-reperfusion injury. Methods: The production of NO is dependent on the oxygen tension because nitric oxide synthases convert l-arginine to NO and l-citrulline in the presence of O2. Since the P450 enzymes, which metabolize nitrate esters such as nitroglycerin are dependent on oxygen, the generation of ‘exogenous’ NO is also sensitive to alterations in tissue PO2. I/R injury was studied in a hamster chamber window, with compression of the periphery of the window for 1 h to induce ischemia. Animals received RRx-001 (5 mg/kg) 24 h before ischemia and sodium nitrite (10 nmols/kg) was supplemented 10 min after the start of reperfusion. Vessel diameter, blood flow, adherent leukocytes, and functional capillary density were assessed by intravital microscopy at 0.5, 2, and 24 h following the release of the ischemia. Results: The results demonstrated that, compared to control, RRx-001 preconditioning increased blood flow and functional capillary density, and preserved tissue viability in the absence of side effects over a sustained time period. Conclusion: Thus, RRx-001 may serve as a long-lived protective agent during postsurgical restoration of flow and other ischemia-reperfusion associated conditions, increasing blood flow and functional capillary density as well as preserving tissue viability in the absence of side effects. © 2017 Informa UK Limited, trading as Taylor & Francis Group.


Brzezniak C.,U.S. National Institutes of Health | Oronsky B.,EpicentRx | Trepel J.,U.S. National Cancer Institute | Summers T.A.,U.S. National Institutes of Health | And 14 more authors.
Case Reports in Oncology | Year: 2017

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. © 2017 The Author(s). Published by S. Karger AG, Basel.


Reid T.,University of California at San Diego | Oronsky B.,EpicentRx | Scicinski J.,EpicentRx | Scribner C.L.,RRD International | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. Methods: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m2, 16·7 mg/m2, 24·6 mg/m2, 33 mg/m2, 55 mg/m2, and 83 mg/m2) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. Findings: Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m2 cohort, three patients in the 16·7 mg/m2 cohort, three patients in the 24·6 mg/m2 cohort, four patients in the 33 mg/m2 cohort, three patients in the 55 mg/m2, and six patients in the 83 mg/m2 cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m2. Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. Interpretation: RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m2 was recommended as the targeted dose for phase 2 trials. Funding: EpicentRx (formerly RadioRx). © 2015 Elsevier Ltd.


PubMed | University of Michigan, Sarah Cannon Research Institute, Stanford University, U.S. National Institutes of Health and 7 more.
Type: Clinical Trial, Phase I | Journal: The Lancet. Oncology | Year: 2015

Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001.In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 167 mg/m(2), 246 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982.Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 167 mg/m(2) cohort, three patients in the 246 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge.RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 167 mg/m(2) was recommended as the targeted dose for phase 2 trials.EpicentRx (formerly RadioRx).


PubMed | University of Helsinki, EpicentRx, Uniformed Services University of the Health Sciences, InterWest Partners and 4 more.
Type: | Journal: Clinical Medicine Insights. Oncology | Year: 2016

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.


Oronsky B.T.,Epicentrx | Carter C.A.,U.S. National Institutes of Health | Reid T.R.,University of California at San Diego | Scicinski J.,Epicentrx | And 6 more authors.
Neoplasia (United States) | Year: 2015

Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression.However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials.Second, OS captures the impact of subsequent therapies, both beneficial (i.e., active) and detrimental, on survival but it does not take into account the contribution of subsequent therapies by treatment arm; the postprogression period is treated as an unknown black box (no information about the potential influence of next-line therapies on the outcome) under the implicit assumption that the clinical trial treatment is the only clinical variable that matters: What OS explicitly measures is the destination, that is, the elapsed time between the date of randomization (or intention to treat) and the date of death, not the journey, that is, what transpires in-between.In long-term maintenance strategies, patients receive treatment in temporally separated but mutually interdependent and causally linked sequences that exert a " field of influence " akin to action-at-a-distance forces like gravity, electricity, and magnetism on both the tumor and each other.Hence, in this setting, a new end point, PFS2, is required to measure this field of influence.This article reviews the definition and use in clinical trials of PFS2 and makes the case for its potential applicability as a preferred end point to measure the mutual influence of individual regimens in long-term maintenance strategies with resensitizing agents in particular. © 2015 The authors.


PubMed | Los Gatos Pharmaceuticals, EpicentRx, CFLS, InterWest Partners and 2 more.
Type: Journal Article | Journal: Neoplasia (New York, N.Y.) | Year: 2015

Overall survival (OS) has emerged as the definitive regulatory be-all, end-all for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a test of time, OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials. Second, OS captures the impact of subsequent therapies, both beneficial (i.e., active) and detrimental, on survival but it does not take into account the contribution of subsequent therapies by treatment arm; the postprogression period is treated as an unknown black box (no information about the potential influence of next-line therapies on the outcome) under the implicit assumption that the clinical trial treatment is the only clinical variable that matters: what OS explicitly measures is the destination, that is, the elapsed time between the date of randomization (or intention to treat) and the date of death, not the journey, that is, what transpires in-between. In long-term maintenance strategies, patients receive treatment in temporally separated but mutually interdependent and causally linked sequences that exert a field of influence akin to action-at-a-distance forces like gravity, electricity, and magnetism on both the tumor and each other. Hence, in this setting, a new end point, PFS2, is required to measure this field of influence. This article reviews the definition and use in clinical trials of PFS2 and makes the case for its potential applicability as a preferred end point to measure the mutual influence of individual regimens in long-term maintenance strategies with resensitizing agents in particular.

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