RRx-001 followed by platinum plus etoposide in patients with previously treated small-cell lung cancer.

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 re-challenge with etoposide 80-100 IV mg/m on days 1, 2 and 3 and cisplatin 60-80 mg/m 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.

Superior Vena Cava Syndrome in a Patient with Small-Cell Lung Cancer: A Case Report.

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.

A Case of Paraneoplastic Cushing Syndrome Presenting as Hyperglycemic Hyperosmolar Nonketotic Syndrome.

Carcinoid tumors are neuroendocrine tumors that mainly arise in the gastrointestinal tract, lungs, and bronchi. Bronchopulmonary carcinoids have been associated with Cushing syndrome, which results from ectopic adrenocorticotrophic hormone (ACTH) secretion. We report the case of a 65-year-old man, a colonel in the US Air Force, with metastatic bronchopulmonary carcinoid tumors treated on a clinical trial who was hospitalized for complaints of increasing thirst, polydipsia, polyuria, weakness, and visual changes.

RRx-001 Priming of PD-1 Inhibition in the Treatment of Small Cell Carcinoma of the Vagina: A Rare Gynecological Tumor.

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.

RRx-001 protects against cisplatin-induced toxicities.

Purpose: RRx-001, a minimally toxic tumor-associated macrophage and neutrophil-repolarizing agent, is under investigation in Phase II clinical trials as a sensitizer/resensitizer to cisplatin and carboplatin. On the basis of anecdotal clinical observations of improved platinum tolerability following a priming period with RRx-001 as well as preclinical studies that have previously demonstrated radioprotection of intestinal stem cells and cardioprotection from doxorubicin, the in vivo cytoprotective potential of RRx-001 pretreatment against cisplatin-induced bone marrow suppression and renal toxicity was investigated.

Methods: BALB/c mice were divided into three groups: (1) no treatment, (2) vehicle and cisplatin only, and (3) RRx-001 and cisplatin.

Minocycline-Induced Hyperpigmentation in a Patient Treated with Erlotinib for Non-Small Cell Lung Adenocarcinoma.

Introduction: While epidermal growth factor receptor (EGFR) inhibitors have improved progression-free survival in patients with non-small cell lung cancer (NSCLC), one of the most common adverse effects is papulopustular skin eruption, which is frequently severe enough to be treated with oral minocycline or doxycycline.

Case: We present a case of an 87-year-old man who developed a severe papulopustular skin eruption secondary to erlotinib therapy for NSCLC. Control of the eruption with 100 mg of minocycline twice daily for 8 months eventually led to blue-gray skin hyperpigmentation.

Conversion of Platinum-Etoposide-Resistant to Sensitive SCLC after Treatment with the Epi-Immunotherapeutic RRx-001: A Case Report.

Background: The response to first-line platinum doublets (cisplatin/etoposide) in small-cell lung cancer (SCLC) predicts the probability of subsequent response to second-line therapy. In general, the longer-lived the responses in first line, the better the outcome in second line, with the opposite prognosis for shorter-lived responses. Resistant SCLC is defined as relapse within 90 days of platinum-doublet treatment, and predictably correlates with shortened survival compared with sensitive disease, defined as relapse after 90 days.

A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient After Priming with RRx-001.

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.

Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets.

Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.

Partial response to carboplatin in an RRx-001 pretreated patient with EGFR-inhibitor-resistance and T790M-negative NSCLC.

Few therapeutic options are available for T790M-negative non-small cell lung cancer (NSCLC) after failure of primary epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. This report presents the case of a 71-year-old Asian female never smoker with EGFR mutated T790M negative non squamous cell lung cancer (NSCLC) pre-treated with the experimental epi-immunotherapeutic agent, RRx-001, that re-responded to single agent carboplatin after failure of platinum doublets, TKIs, pemetrexed and nivolumab. The management of advanced EGFR mutation-positive NSCLC is briefly reviewed herein and the emerging paradigm of episensitization, which contradicts the long-standing and widely accepted tenet about the immutability of resistance and the futility of therapeutic rechallenge, is introduced as a strategy to avert treatment failure and thereby stave off deterioration and death.

RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets.

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.

Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001.

Neuroendocrine tumors (NETs) are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not.

The Case of a Zebra That Was Misdiagnosed as a Horse: Pulmonary Tumor Thrombotic Microangiopathy, a New Paraneoplastic Syndrome, Mimicking PD-1-Induced Pneumonitis.

A case report of a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 is presented. Although initially diagnosed and treated for anti-PD-1-induced pneumonitis, clinical and radiological abnormalities triggered further investigation, leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM). This example highlights the importance of exercising due diligence in determining immune-related adverse events and suggests that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default.

Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization.

RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001.

RRx-001-Induced Tumor Necrosis and Immune Cell Infiltration in an EGFR Mutation-Positive NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors: A Case Report.

We present the case of a 49-year-old male with metastatic epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma of the lung that continues to outlive stage IV diagnosis of non-small cell lung cancer after treatment with RRx-001, an experimental anticancer agent with epigenetic and immunologic activity, in the context of a phase II clinical trial called TRIPLE THREAT. Currently, no adequate treatment options exist for patients with EGFR mutation-positive tumors who have failed a 1st-generation tyrosine kinase inhibitor (erlotinib or gefitinib) treatment and do not develop a resistant mutation. Biopsy of a large pancreatic metastasis after RRx-001 demonstrated extensive necrosis with CD3+ and CD8+ immune cell infiltration that appears to correlate with prolonged survival despite end-stage disease.

Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military.

Background: Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases.

Objectives: Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC.

Design And Participants: We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry.

Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial.

Background: No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor.

Methods: Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours.

Dacomitinib, a new therapy for the treatment of non-small cell lung cancer.

Introduction: Advanced or metastatic non-small cell lung cancer (NSCLC) is characterized by a poor prognosis and few second- or third-line treatments. First-generation reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI) has paved the way for targeted treatment in lung cancer. These drugs result in excellent responses in patients with activating EGFR mutations.