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Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea—DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = − 0.74; P = 1.46 × 10–23), representing a previously unidentified mechanism for HFS. This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

Background S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Methods Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). Results Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49–88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%–17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4– 4.5 months) and 7.5 months (95% CI: 3.7–9.3 months). Conclusions AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3–amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

Despite the benefits of high atom economy and low cost, aerobic oxidations have found limited use in the synthesis of active pharmaceutical ingredients (APIs) because of safety concerns and poor se...

Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti-programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data.Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months.A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached.Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.

The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, “in control” versus “at steady state”, lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crysta...

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future.

9616 Background: Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy following SBRT. We hypothesize that SBRT may improve outcomes for patients receiving immunotherapy through both direct cytoreduction and increased immunogenicity. Within this context, we conducted a phase 1 trial designed to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab(N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT (mSBRT) in patients with stage IV NSCLC. Methods: Treatment naïve patients (EGFR/ALK WT) with advanced NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. Brain metastases were allowed on protocol, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Patients on Seq arm received N/Ip between 1-7 days after completion of SBRT. Patients in Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, development of toxicity, or up to 2 years. Patients underwent pre- and post-treatment biopsy of one irradiated lesion. Results: A total of 35 patients (Seq/Con 19/16) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27%. PD-L1 expression: 0% (16), 1-49% (10), >50% (9). Median number of metastases treated with SBRT was 3.2. 6 patients experienced DLT (4 pneumonitis), resulting in dose reduction in central lung Seq cohort of the organs at risk (OAR) by 20%. Median PFS by RECIST (total/Seq/Con) was 5.9 mo, 95% CI: 4.9-13.1/ 6.2 mo, 95% CI: 3.5-12.6/ 5.9 mo, 95% CI: 3.1-18.0. RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. Treatment past first progression was allowed, and time to second line therapy (chemotherapy) by arm (Seq/Con) was NR/17.5 months. Median OS has not been reached with median follow up of 15mo. PDL1 status did not impact PFS (p = 0.64) nor OS (p = 0.77). Conclusions: Multisite SBRT and concurrent N/Ip was well tolerated. Responses appear durable as median OS was not reached. Multimodality therapy with mSBRT and dual checkpoint inhibitor therapy resulted in impressive tumor control and clinical benefit with promising efficacy. Clinical trial information: NCT03223155 .

Purpose Epidermal growth factor receptor (EGFR) –tyrosine kinase inhibitors have proven efficacy in advanced non–small-cell lung cancer (NSCLC). We hypothesized that erlotinib would be efficacious in the adjuvant setting. Patients and Methods An international randomized, double-blind, placebo-controlled study was conducted in patients with completely resected IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization. Patients were assigned 2:1 to erlotinib 150 mg once per day or placebo for 2 years. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country. The primary end point was disease-free survival (DFS); key secondary end points were overall survival (OS) and DFS and OS in patients whose tumors had EGFR-activating mutations (EGFRm-positive). Results A total of 973 patients were randomly assigned (November 26, 2007, to July 7, 2010). There was no statistically significant difference in DFS (median, 50.5 months for erlotinib and 48.2 months for placebo; hazard ratio, 0.90; 95% CI, 0.74 to 1.10; P = .324). Among the 161 patients (16.5%) in the EGFRm-positive subgroup, DFS favored erlotinib (median, 46.4 v 28.5 months; hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .039), but this was not statistically significant because of the hierarchical testing procedure. OS data are immature. Rash and diarrhea were common adverse events occurring in 528 (86.4%) and 319 (52.2%) patients treated with erlotinib, respectively, versus 110 (32.1%) and 54 (15.7%) patients receiving placebo. The most common grade 3 adverse events in patients treated with erlotinib were rash (22.3%) and diarrhea (6.2%). Conclusion Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup. Further evaluation of erlotinib is warranted in the EGFRm-positive subgroup.

This study tested the effectiveness of a facilitated educational program in a museum for promoting family conversations and children's learning about STEM. A sample of 130 families (71 European-American; 33 African-American; and 26 Hispanic-American) with children M age = 6.42 years were observed in a building construction exhibit. Prior to building, families were randomly assigned to conditions that varied in terms of the instructions about a key engineering principle and elaborative question-asking they received. Conversation instruction resulted in adults’ asking double the number of Wh -questions compared to families who did not receive the instruction. The building instruction was important in promoting increases in adults’ STEM-related talk during the building activity, as well as in the children's STEM talk when prompted for information about what they had learned. The effects of the instructions did not vary by families’ ethnic background. Implications for facilitating family conversations and children's learning related to STEM are discussed.

Up to 40% of breast cancers have been shown to express the glucocorticoid receptor (GR), and activation of the GR is associated with poor prognosis in ER-negative breast cancer. We hypothesize that GR activation in breast cancer cells initiates anti-apoptotic signaling contributing to chemotherapy resistance. Based on our compelling preclinical data demonstrating that GR antagonism with mifepristone (mif) increases paclitaxel (pac) induced breast cancer cell death in vitro and in vivo, we conducted the first clinical trial of the combination of anti-GR therapy and chemotherapy in patients (pts) with metastatic breast cancer (MBC). Because the combination of mif and nab-paclitaxel (nab) had not previously been administered to pts, and because nab can result in cumulative neurotoxicity, a randomized, placebo-controlled, phase I design was used. Mif is known to inhibit CYP2C8, an enzyme involved in the metabolism of pac, thus plasma pac levels were monitored to evaluate for significant changes in clearance. A 3+3 dose escalation scheme was planned, with an initial nab dose of 100mg/m2 weekly and a mif dose of 300 mg/d for 2 days (day prior to and of nab infusion). For each dose level (DL), patients were randomized 3:2 to mif:placebo (p) for cycle 1 (C1). After C1, pts randomized to p were crossed over to receive mif at their assigned DL for the duration of study treatment. DL1 was deemed intolerable due to neutropenia, so the nab dose was decreased to 80 mg/m2 for DL2, and dose escalation of mif beyond 300 mg was halted. Serum cortisol and ACTH levels—biomarkers of effective GR blockade—were measured before and after mif treatment. Archival tumor was collected to determine tumor GR expression, and peripheral blood lymphocytes (PBLs) were collected to evaluate GR-target gene expression after mif. 9 pts were enrolled. Median age was 56 yrs (range 47-74). Median number of prior therapies for MBC was 2 (range 0-3). 8 pts had triple-negative breast cancer (TNBC), and 1 had ER+ disease. 8 of 9 pts had recurred after taxane-based therapy. 1 pt had a CR, 4 pts a PR, and 4 pts POD. 4 of 5 pts who responded to nab plus mif had previously relapsed after taxane-based therapy. 4 pts were treated at DL1 (2 mif, 2 p). Both pts randomized to mif experienced a dose-limiting toxicity (DLT) of neutropenia during C1. 5 pts were treated at DL2 (3 mif, 2 p), and 2 of the 3 pts randomized to mif for C1 experienced a DLT (neutropenia). Plasma pac levels were consistent with delayed clearance of nab when co-administered with mif for most pts. All pts were found to have a 2-fold or greater rise in their serum cortisol levels, demonstrating effective adrenal GR inhibition. Mif delays clearance of nab in most pts, and results in DLT. Given the inter-patient variability in delay of nab clearance by mif, co-administration produces unpredictable toxicity. However, given the responses seen in taxane-pretreated TNBC pts, GR antagonism is a promising approach for treating aggressive TNBCs. As neither carboplatin nor gemcitabine are metabolized, mif is unlikely to affect clearance of these agents. As they are widely used for advanced TNBC, both agents represent attractive chemotherapy partners for future clinical investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-21.

The use of personal narratives in research across the field of psychology has dramatically increased in recent years. In studies spanning a wide range of topics, personal event narratives have provided especially valuable insights into the processes and products of cognitive development. This article offers a guide for researchers who might use personal narratives in research currently or in the future. Issues and best practices surrounding collecting, transcribing, and coding personal narratives are presented. Practical challenges, commonly used methods, and recommended guidelines are described. Illustrations of different types of personal narrative coding systems are offered. The article also highlights benefits of and resources for conducting personal narrative research.

Purpose Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-2457-1) contains supplementary material, which is available to authorized users.

Introduction: Outcomes data treating patients with oligometastatic (⩽5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited. Methods: Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT. Lesions that had received prior radiation or had radiographic/metabolic resolution after chemotherapy were not treated with HIGRT. Local control of all treated lesions, distant control, progression-free survival (PFS), overall survival (OS), and control of individual lesions (LeC) were calculated. Results: Twenty-five patients with median of 2 treated oligometastatic lesions were included. Median follow-up was 14 months. Median age was 66 years. Nineteen patients received systemic therapy before HIGRT and 11 had progressive disease after their most recent systemic therapy before HIGRT. Median OS and PFS were 22.7 and 7.6 months. The 18 months local control, distant control, OS, and PFS were 66.1%, 31.7%, 52.9%, and 28.0%. Greater than two sites treated with HIGRT, nonadenocarcinoma histology, prior systemic therapy, and progression after systemic therapy were associated with worse PFS. Sixty-two individual lesions of median size 2.7 cm were treated. For extracranial lesions, median total and fraction dose were 50 and 5 Gy. Median standard equivalent dose in 2 Gy fractions for extracranial lesions was 64.6 Gy yielding 18 months LeC of 70.7%. Standard equivalent dose ≥64.6 Gy increased LeC ( p = 0.04). Two patients experienced grade 3 toxicity. Conclusions: HIGRT for oligometastatic NSCLC provides durable LeC and may provide long-term PFS in some patients. Future HIGRT studies should optimize patient selection and integration with systemic therapy.

Introduction Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies. Methods Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60 Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models. Results We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59 Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p = 0.0452), mediastinal sterilization (90% vs 67%, p = 0.0769), and pCR (60% vs 35%, p = 0.0728). Conclusions In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates.

Lung cancer is a heterogenous group of disorders, and a difficult disease to treat. The traditional approach of surgical resection for early-stage disease, potentially followed by chemotherapy, as well chemotherapy (with or without radiation) in later stages of disease is being supplemented with a personalized approach. The personalized approach has classically been used by the oncologist based on clinical/pathological parameters such as the performance status of the patient and histology of lung cancer. As molecular mechanisms have been explored in lung cancer more recently, the personalized approach also has incorporated molecular abnormalities. In particular, EGFR, K-ras, ALK, MET, CBL, and COX2, have come to the forefront as potential biomarkers and therapeutic targets. Thus, we review the various molecular mechanisms in lung cancer and the role of novel therapeutics.

We performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 were included. Tumor resectability was determined prior to initiation of study. Induction docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) day 1 with prophylactic filgrastim was delivered every 21 days for 3 cycles. Subsequent concomitant chemoradiotherapy (CRT) utilized weekly docetaxel (20 mg/m(2)) and concurrent radiotherapy (2 Gy/day) in resectable/resected patients (50 Gy) and in unresectable patients (66 Gy). A total of 78 patients (15 squamous cell carcinoma, 60 adenocarcinoma, 3 mixed/undifferentiated; 68 men, 10 women; median age 61 years) were accrued. The regimen was administered to 59 (76%) potentially resectable patients and 13 (17%) unresectable patients; 6 patients (8%) received the regimen post-operatively. Response rate in 66 evaluable patients following induction chemotherapy was 30%. Sixty-nine patients underwent CRT. Ten patients had disease progression during CRT. Forty-five out of 59 potentially resectable patients underwent esophagectomy after CRT, and 42 patients had complete tumor resection with negative margins. Eighteen out of 59 patients who were potentially resectable patients had pathologic complete response (pCR-31%). Grade 3/4 toxicity during induction chemotherapy included leucopenia, neutropenia, vomiting, and neuropathy. Esophagitis was the predominant toxicity during CRT. Median overall survival was 11.4 months for unresectable patients, 14.3 months for resectable patients and 10.4 months for patients who received the regimen post-operatively (log-rank P = 0.2492). Docetaxel-based CRT regimen is active and tolerable in esophageal cancer. The observed pCR in the potentially resectable group indicates good local control.

1071Background: Capecitabine is an effective therapy for advanced breast cancer; however, response prediction is imprecise. In this study, we aimed to identify potential SNPs associated with respon...

Autoimmune hemolytic anemia (AIHA) is most often idiopathic. However, in recent years, AIHA has been noted with increased incidence in patients receiving purine nucleoside analogues for hematologic malignancies; it has also been described as a complication of blood transfusion in patients who have also had alloimmunization. As the technology of hematopoietic stem cell transplantation has become more widespread, immune hemolysis in the recipients of ABO-mismatched products has become better recognized. The syndrome is caused by passenger lymphocytes transferred from the donor, and although transient, can be quite severe. A similar syndrome has been observed in recipients of solid organ transplants when there is ABO-incompatibility between donor and recipient. Venous thromboembolism is a little-recognized, though likely common, complication of autoimmune hemolytic anemia (AIHA), and may in some instances be related to coexistent antiphospholipid antibodies. While AIHA is a well-documented complication of malignant lymphoproliferative disorders, lymphoproliferative disorders may also paradoxically appear as a consequence of AIHA. A number of newer options are available for treatment of AIHA in patients refractory to corticosteroids and splenectomy. Newer immunosuppressives such as mycophenolate may have a role in such cases. Considerable experience has been accumulating in the last few years with monoclonal antibody therapy, specifically rituximab, in difficult AIHA cases; it appears to be a safe and effective option.

Background The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. Methods Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m 2 , carboplatin AUC 5, and paclitaxel 175 mg/m 2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. Results Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to ≤ grade 1 absolute neutrophil count by the day of scheduled chemotherapy administration. Dose de-escalation to irinotecan 30 mg/m 2 , paclitaxel 40 mg/m 2 (with omission of carboplatin) delivered on weeks 2, 3, 5, and 6 of radiotherapy was the MTD. After induction chemotherapy, partial responses, stable disease, and progressive disease was observed in 26%, 60%, and 14% of patients, respectively. After chemoradiotherapy, partial responses were attained in 16 (55%) patients, whereas 12 patients (41%) attained disease stabilization. Median overall survival was 21 months for the entire cohort. Resectable patients had a median survival of 24 months, whereas unresectable patients had a median survival of 19 months. Differences in overall and progression-free survival rates between resectable and unresectable patients was not statistically significant ( p = 0.52 and p = 0.90, respectively). Discussion Carboplatin, paclitaxel, and irinotecan with concurrent chemoradiotherapy was poorly tolerated as a result of neutropenia. Although dose de-escalation was required for delivery of the regimen, the response rates and survival outcomes were comparable to other similar regimens.

For locally advanced but technically operable nonsmall cell lung cancer (NSCLC), neoadjuvant chemoradiotherapy is frequently used. Ideal radiotherapy dose in this context is unclear.Twenty-six NSCLC patients with N2 disease were retrospectively reviewed. All received preoperative concurrent platinum-based chemoradiotherapy. Gross tumor volumes received a median of 58 Gy (range, 50-60 Gy).Two patients experienced major complications and died, resulting in a postoperative mortality rate of 7.7%. Three patients (11.5%) had minor complications. Pathologic specimens revealed downstaging in 76.9% of patients. The pathologic complete response (CR) rate was 34.6%. Downstaging of nodes was observed in 20 of 26 patients. With a median follow-up of 18.3 months, the 1- and 3-year actuarial survival rates were 80.2% and 45.7%, respectively. The 1- and 3-year actuarial disease-free survival (DFS) rates were 76.9% and 37.3%, respectively. Patients experiencing mediastinal downstaging had better DFS rates, relative to patients that did not (18-month DFS = 79.2% vs. 0%; P = 0.0001). Differences in RT dose (50-60 Gy) and types of chemotherapeutic regimens did not significantly impact pathologic downstaging rates, CR rates, DFS, or survival.Neoadjuvant chemotherapy with high-dose concurrent RT is well tolerated and results in favorable outcomes.

Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy.Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower).Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6).Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

Purpose Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC. Patients and Methods Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n = 5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC) = 6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n = 4), carboplatin dose was reduced to AUC = 5. In cohort 3 (n = 7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated. Results Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed. Conclusion The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder. The pathogenesis is believed to be mediated by an autoantibody directed against the metalloproteinase responsible for the degradation of the very-high-molecular-weight multimers of the vWF. The syndrome can be precipitated by a variety of conditions, and certain medications also have been implicated. CASE REPORTS: The cases of two patients who took a cephalosporin antibiotic, cephalexin (Keflex, Eli Lilly), and then developed TTP are reported. One patient subsequently received a third-generation cephalosporin, ceftriaxone (Rocephin, Roche), without adverse reaction. Of interest, one patient had taken cefaclor (Ceclor, Eli Lilly) 8 years before and had also developed TTP at that time. The other patient also took cefaclor for approximately 3 weeks before taking cephalexin. In addition, she had had a dose of clarithromycin (Biaxin, Abbott Laboratories) the day before the onset of the TTP symptoms. CONCLUSIONS: To our knowledge, TTP has not been reported previously after administration of cephalosporin antibiotics. Attention is called to the possibility that this syndrome may occur after exposure to some of these drugs, although the incidence is very rare or, alternatively, underdiagnosed.

Background The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. Patients and methods Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m2 as a 1-h infusion on day 1 with carboplatin at an area under the concentration–time curve (AUC) of 6 mg·min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m2 on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m2 on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg·ml/min. Therapy for dose levels I and III included filgrastim support (5 µg/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/µl. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen’s activity and tolerability. Results Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered inthe initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. Conclusions The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.

Background: Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis. Patients and Methods: Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0–2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m 2 on days 1, 8, and 15 along with bryostatin-1 50 μg/m 2 on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled. Results: Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1–4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4–49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-α after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel. Conclusions: This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.

1083 Background: Glucocorticoid receptor (GR) activity inhibits chemotherapy-induced apoptosis, and GR antagonism with m enhances chemotherapy sensitivity in GR+ breast (B) and ovarian cancer (OC) cells. C+G is a commonly used regimen for B and OC. We report the results of a phase I trial of the GR antagonist m plus C+G in patients with advanced B and OC. Methods: A standard “3+3” dose escalation phase I study was performed. Objectives were to assess the safety and tolerability of the regimen, and to determine the recommended phase 2 (RP2D) dose of M+C+G. C+G was administered on days 1 and 8 of a 21 day cycle, and m was administered the day prior to and the day of chemotherapy. The starting dose level (DL) was 1, with additional DLs as follows in the table. Results: 31 patients (pts) with a median age of 54 years (range 32-76) were enrolled. 18 pts had BC (3 ER+, 15 triple-negative), and 13 had high grade serous OC (11 platinum-sensitive, 2 platinum-resistant). The median number of prior therapies for advanced BC was 1 (range 0-5) and for OC was 2 (range 1-3). Dose de-escalation was necessary due to the DLT of neutropenia. After DL -3, prophylactic G-CSF (PGF) was instituted. The RP2D was C AUC 2, G 600 mg/m2, m 300 mg with PGF administered on day 9. Of the BC pts, 2 had a complete response (CR), 2 had a partial response (PR), 8 had stable disease (SD), 4 had progressive disease (PD). Of the OC pts, there was 1 CR (CR2 lasted > 27 mos; CR1 lasted only 8 mos), 1 PR, 6 SD, and 3 PD. 4 pts were inevaluable for response. Conclusions: These data suggest that M+C+G is safe and tolerable, and the most common DLT is neutropenia. This was easily managed with the institution of PGF. Studies correlating tumor GR expression with response are ongoing, and may help identify patients who are most likely to benefit from this combination. Clinical trial information: NCT02046421. [Table: see text]

9055 Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibitor AZD4547 in patients (pts) with FGFR positive chemo-refractory SqNSCLC. Methods: Eligible pts had tumor FGFR alteration and/or mutation by next generation sequencing (Foundation Medicine), measurable disease, Zubrod PS 0-2, progression after 1 line of systemic therapy, and adequate end organ function. Receipt of prior immunotherapy was allowed. Eligible pts received AZD4547 80 mg bid orally. Primary endpoint was overall response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS) and duration of response (DoR). Originally designed as a randomized trial of AZD4547 versus docetaxel, it was redesigned to be a single arm AZD4547 trial with the emergence of immunotherapy as standard 2ndline therapy. Forty pts were required to rule out an ORR of < = 15% if the true ORR was > 35% (90% power, alpha 0.05). Results: 93 pts (13% of pts screened on S1400) were assigned to S1400D; 43 were enrolled with 28 receiving AZD4547. Pt characteristics: median age 66.3 y (49-88), female (n = 8, 29%), & Caucasian (n = 25; 89%). Biomarker profile: FGFR1 amplification (n = 38; 86%); FGFR3 S249C (n = 4; 9%); FGFR3 amplification (n = 3; 7%); and FGFR3 fusion (n = 2; 5%). Nine pts (26%) had more than one biomarker alteration. The study was closed at interim analysis for futility in October 2016. Treatment related Grade 3 AEs were seen in 5 pts (dyspnea, fatigue, hyponatremia, lung infection & retinopathy); 1 pt had Grade 4 sepsis. There were no Grade 5 AEs. Median follow up among alive pts was 4.3 months (mos). Of 25 response evaluable pts, one with FGFR3 S249C had unconfirmed PR (4%, 95% CI 1-20%) with DoR of 1.5 mos. Median PFS was 2.7 mos (95% CI 1.4 - 4.3 mos). Conclusions: This is the first Phase II trial to evaluate AZD4547 as a targeted approach in pts with previously treated FGFR-altered SqNSCLC. AZD4547 had an acceptable safety profile but minimal activity in this biomarker-enriched cohort. Evaluation of other targeted agents in LUNG-MAP is currently ongoing. Clinical trial information: NCT02965378.

3061 Background: Immune checkpoint blockers have demonstrated durable response in many tumor types including lung cancer. This clinical benefit is however restricted to a subset of patients in whom longitudinal assessments of their tumor microenvironment have revealed increase CD8+ T cell infiltration. However detailed characterization of this T cell dynamics at clonal levels in a large population of patients is yet to be reported. Such analyses will provide vital insight into the mechanism of tumor eradication in responders. Methods: We performed next-generation sequencing of T cell receptor β chain in longitudinal tumor and peripheral blood samples obtained from lung cancer patients treated with immunotherapies. We first extracted RNA from these samples and synthesized cDNA with 5’RACE adapter using SMART library construction kit (Clontech). We then amplified TCR β gene products to prepare sequence libraries which were analyzed with MiSeq system (Illumina). Results: Here we report on TCR receptor β chain sequencing data for 29 patients in whom we had 3 or more serial samples. Thirteen (45%) of the selected patients in this cohort had durable response and seven (24%) had radiological complete response. We confirmed that there is concordance between the expanded T cell clone at tumor site and the peripheral blood. In one responder, we found expansion of a dominant T cell clone (20%) at a metastatic site where he had pathological complete response on day 17 of treatment and the same clone remained persistent in his peripheral blood (24%) at week 48 of therapy. Similarly in other responders, there were T cell clonal expansions detected as early as week 2 after only one cycle of treatment and such clones remained at high frequencies several months afterwards. Such pattern of early and sustained clonal expansions were absent among non-responders even while they remained on therapy. Conclusions: We found durable response to immune checkpoint blockade to correlate with early and sustained expansion of one to two dominant T cell clones in this selected patient cohort.

In a previous phase II trial of the synthetic topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), given as a 72-h infusion, we identified modest single agent activity of 9% in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Preclinical studies suggested that a more prolonged continuous infusion of the drug might lead to greater antitumor activity. A phase I study recommended a phase II dose of 25 microg/m2/hr for 120 h (3000 microg/m2 over 5 days), administered for 2 consecutive weeks of a 3-week cycle. We utilized this schedule and enrolled 13 chemotherapy-naïve patients with Stage IIIB and IV NSCLC in this trial: median age 67 (range 57-74); 46% male; 92% stage IV; and median performance status 1. Twelve patients are available for response and toxicity evaluation after 2 cycles of therapy. One patient achieved a partial response. Four patients had stable disease while seven patients had progressive disease. Patients with stable or progressive disease after two cycles received no additional 9-AC, and were offered conventional chemotherapy. The median survival time was 10.2 months and the one-year survival rate 28% (95% confidence interval, 5-58%). Significant toxicities included myelosuppression, fatigue, and anorexia. One patient had grade 4 neutropenia following the first week of cycle 2, and did not receive additional therapy. There were no neutropenia-related infections. These data suggest that this prolonged schedule is unlikely to increase 9-AC's very modest activity in NSCLC above that seen with the simpler 72-h administration schedule. Further evaluation of 9-AC in NSCLC is not recommended.

JM216 is an orally administered platinum analogue. We undertook this study to determine the maximally tolerated dose (MTD) of JM216 when administered with concomitant radiotherapy to the chest (200 cGy daily, 5 x/week) in patients with locoregionally advanced non-small cell lung (NSCLC) or esophageal cancer. Patients were excluded for inadequate bone marrow reserve, prior radiotherapy to the primary tumor or previous treatment with platinum drugs. A dose-limiting toxicity (DLT) was defined using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) and consisted of gradeor = 2 renal, hepatic, cardiac, or pulmonary toxicity or gradeor = 3 hematologic, neurological, or gastrointestinal toxicity. A total of 23 patients were registered; two never received treatment and are excluded from analyses. Six patients were treated at a dose of 30 mg/m2/day for 5 days with two grade 2 DLT's: cough (1 pt) and elevated trans-aminases (1 pt). Seven evaluable patients were treated at 60 mg/m2/day and seven experienced grade 3 or 4 toxicity, five related to myelosuppression. The dose was then reduced to 45 mg/m2/d. Eight patients were evaluable for toxicity, of which 5 experienced DLT: myelosuppression (3 pts), esophagitis (2 pts), dyspnea (1 pt), and elevated creatinine (1 pt). Fourteen patients were evaluable for efficacy, of which 6 had an objective response, including one complete response. The recommended phase II dose of JM216 with concurrent radiation therapy is 30 mg/m2/d for 5 days. The major DLT is myelosuppression with only limited increased toxicity within the field of radiation. This conceivably may limit the use of JM216 as a radiation sensitizer.

Cyclic amegakaryocytic thrombocytopenic purpura is a rare syndrome characterized by periodic failure of megakaryocytopoiesis. In this report we describe a patient with cyclic amegakaryocytic thrombocytopenic purpura associated with a megakaryocyte specific serum IgG antibody, who responded to cyclosporin A therapy. Serial serum thrombopoietin assays during an episode of platelet cycling demonstrated a reciprocal relationship between serum thrombopoietin level and megakaryocyte mass, suggesting that megakaryocytes have an important role in the regulation of thrombopoietin metabolism.

Summary Background 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 μg/m2/day × 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia. Patients and methods Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 μg/m2/d × 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 μg/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression. Results Fifty-eight patients were treated, thirteen at 1416 μg/m2/d and 45 at 1100 μg/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9–28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%–19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 μg/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 μg/m2/d these toxicities were observed in 12 and three of 45 patients, respectively. Conclusion 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

PURPOSE We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination. PATIENTS AND METHODS Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed. RESULTS Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies. CONCLUSION Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.

Background: Patients with lung cancer who develop brain metastases have a poor prognosis. Those patients with progressive brain metastases tend to have a dismal prognosis. Currently, there is no standard of care for the treatment of these patients. Methods: In this manuscript, we present a retrospective evaluation of 10 patients treated at our institution with a combination of temozolomide and / or erlotinib after disease progression in the central nervous system following radiation therapy. Results: Median overall survival was 28 weeks. Median time to progression in the central nervous system was 14 weeks. Median time to progression systemically was 7.5 weeks. Some patients demonstrated prolonged stability of disease. Conclusions: A palliative regimen of temozolomide and / or erlotinib could be considered in progressive central nervous system metastases from lung cancer. doi:10.4021/jnr85w

A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs. Purpose: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types. Methods: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily. Results: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary. Conclusions: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m2 in weeks 1 and 2, IFN 5 million Units (MU)/m2 per day on days 1–5 in week 1, 5-FU 800 mg/m2 per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m2 during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m2 per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m2 per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m2 week 1, and 100 mg/m2 week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m2 per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.