A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas.

Devimistat (CPI-613®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, devimistat inhibits the entry of glucose and glutamine derived carbons, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. In a Phase I study of modified FOLFIRINOX, in combination with devimistat for metastatic pancreatic cancer patients, there was a 61% objective response rate including a 17% complete response rate. This report outlines the rationale and design of the AVENGER 500 study, a Phase III clinical trial of devimistat in combination with modified FOLFIRINOX compared with FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas. Clinical trial registration: NCT03504423.

Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment.

BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 µg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.

Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable, Locally Advanced Pancreatic Adenocarcinoma.

PURPOSE: To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC). MATERIALS AND METHODS: This retrospective study included 50 patients (23 women, 27 men; age range, 46-91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)-guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1-5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3-month intervals thereafter. RESULTS: There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7-32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7-16.2 months) from time of IRE. Patients with tumors ≤ 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis (P = .002) and 16.2 vs 9.9 months from time of IRE (P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis. CONCLUSIONS: Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile.

Proximal Splenic Artery Embolization in Chemotherapy-Induced Thrombocytopenia: A Retrospective Analysis of 13 Patients.

PURPOSE: To determine if proximal splenic artery embolization (PSAE) provides a safe and effective alternative to alleviate chemotherapy-induced thrombocytopenia (CIT), allowing patients with cancer to resume chemotherapy regimens. MATERIALS AND METHODS: Thirteen patients (9 men, 4 women; mean age, 63 y) with underlying malignancy (pancreatic adenocarcinoma, n = 6; cholangiocarcinoma, n = 5; other, n = 2) complicated by CIT underwent PSAE. Mean platelet counts were calculated before the initiation of chemotherapy, at the nadir that resulted in discontinuation of chemotherapy before the PSAE procedure, at peak values after the procedure, and at a mean follow-up of 9.2 months. The time to reinitiation of chemotherapy after PSAE was calculated. RESULTS: Baseline platelet count before initiation of chemotherapy was 162 × 10(9)/L (range, 90-272 × 10(9)/L). The platelet count nadir resulting in cessation of chemotherapy was 45 × 10(9)/L (range, 23-67 × 10(9)/L), and the pre-PSAE platelet count was 88 × 10(9)/L (range, 49-131 × 10(9)/L). The post-PSAE peak platelet count improved significantly (to 209 × 10(9)/L; range, 83-363 × 10(9)/L) compared with the nadir counts and the pre-PSAE counts (P < .01) at a mean short-term follow-up of 35 days (range, 7-91 d). The counts at follow-up to 9.2 months (range, 3-15 mo) were 152 × 10(9)/L (range, 91-241 × 10(9)/L). All patients became eligible to resume chemotherapy. The time to initiation of chemotherapy after PSAE averaged 22 days (range, 4-58 d) in 12 patients; one patient declined chemotherapy. CONCLUSIONS: Proximal splenic artery embolization appears to be safe and effective in alleviating CIT, allowing resumption of systemic chemotherapy. Further studies may help guide patient selection by identifying characteristics that allow a sustained improvement in thrombocytopenia.

Percutaneous irreversible electroporation for the treatment of colorectal cancer liver metastases with a proposal for a new response evaluation system.

PURPOSE: To describe an initial experience with irreversible electroporation (IRE) in patients with colorectal liver metastasis (CLM). MATERIALS AND METHODS: A retrospective analysis of patients undergoing IRE for the management of CLM was performed. Procedures were done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS: Between March 2010 and February 2013, 29 patients underwent percutaneous ablation of 58 tumors in 36 IRE sessions. Most patients (89%) had an absolute or relative contraindication to thermal ablation. The median age was 62 years, and the median time from diagnosis to IRE was 28 months. The median number of lesions treated per patient was two, and the median tumor size was 2.7 cm. Patients had received previous chemotherapy regimens (range, 1-5 per patient). A new Metabolic Imaging And Marker Integration response evaluation criteria was used for response assessment, and was a predictor of progression-free and overall survival. The 2-year progression-free survival rate was 18% (95% confidence interval, 0%-35%), and the 2-year overall survival rate was 62% (95% confidence interval, 37%-87%). Complications included arrhythmias (n = 1) and postprocedure pain (n = 1). Both patients recovered without sequelae. CONCLUSIONS: Percutaneous IRE of CLM is feasible and safe. A new response evaluation system for colorectal cancer appears to be prognostic.

Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.

PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

Pancreatic cancer clusters and arsenic-contaminated drinking water wells in Florida.

BACKGROUND: We sought to identify high-risk areas of pancreatic cancer incidence, and determine if clusters of persons diagnosed with pancreatic cancer were more likely to be located near arsenic-contaminated drinking water wells. METHODS: A total of 5,707 arsenic samples were collected from December 2000 to May 2008 by the Florida Department of Health, representing more than 5,000 individual privately owned wells. During that period, 0.010 ppm (10 ppb) or greater arsenic levels in private well water were considered as the threshold based on standard of United States Environmental Protection Agency (EPA). Spatial modeling was applied to pancreatic cancer cases diagnosed between 1998-2002 in Florida (n = 11,405). Multivariable logistic regression was used to determine if sociodemographic indicators, smoking history, and proximity to arsenic-contaminated well sites were associated with residence at the time of pancreatic cancer diagnosis occurring within versus outside a cluster. RESULTS: Spatial modeling identified 16 clusters in which 22.6% of all pancreatic cancer cases were located. Cases living within 1 mile of known arsenic-contaminated wells were significantly more likely to be diagnosed within a cluster of pancreatic cancers relative to cases living more than 3 miles from known sites (odds ratio = 2.1 [95% CI = 1.9, 2.4]). CONCLUSIONS: Exposure to arsenic-contaminated drinking water wells may be associated with an increased risk of pancreatic cancer. However, case-control studies are needed in order to confirm the findings of this ecological analysis. These cluster areas may be appropriate to evaluate pancreatic cancer risk factors, and to perform targeted screening and prevention studies.

Depressive symptoms among caregivers of colorectal cancer patients during the first year since diagnosis: a longitudinal investigation.

OBJECTIVE: Few studies have examined prospectively and longitudinally depressive symptoms of family caregivers who provide care to colorectal cancer patients, and fewer have addressed ethnic minorities in this regard. This study investigated the relations of social support and caregiving stress with caregivers' depressive symptoms during the first year since the relative's diagnosis, as well as the role of ethnicity in such relations. METHODS: Seventy-nine caregivers provided complete data at 2 months (T1), 6 months (T2), and 12 months (T3) after their relative's cancer diagnosis. Demographics and caregiving experiences were measured at T1. Depressive symptoms were assessed at T1 through T3. RESULTS: Greater caregiving stress and lack of social support were significant predictors of greater depressive symptoms. The adverse effect of caregiving stress was more pronounced among African American caregivers, whereas the beneficial effect of social support was more pronounced among White caregivers. CONCLUSIONS: The findings highlight the importance of both caregiving stress and lack of social support early in caregivership. Findings also suggest that caregivers may benefit from programs tailored for their ethnicity.

A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors.

BACKGROUND: E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids). METHODS: In a phase 1 study, E7974 was given intravenously over a 2- to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT). RESULTS: Twenty-eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m(2) , 0.27 mg/m(2) , 0.36 mg/m(2) , 0.45 mg/m(2) , and 0.56 mg/m(2) ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m(2) , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours). CONCLUSIONS: This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m(2).

Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.

In this multicenter phase Ib study, drozitumab was given in combination with the mFOLFOX6 regimen and bevacizumab in patients with previously untreated, locally advanced recurrent or metastatic colorectal cancer on day 1 of every 14-day cycle. Nine patients were treated at 2 different cohort dose levels of drozitumab. No dose-limiting toxicities occurred at either dose level and the maximum tolerated dose was not reached. Two patients had a partial response of 4.93 and 4.96 months duration. Cohort 2 dose level is the recommended starting dose level for future trials.

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma.

BACKGROUND: 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC). METHODS: In this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate. RESULTS: Eighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22-69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %). CONCLUSIONS: FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

Emerging cell-cycle inhibitors for pancreatic cancer therapy.

INTRODUCTION: Patients with pancreatic cancer (PC) present with advanced disease that is lethal and notoriously difficult to treat. The research focused initially on combining cytotoxic therapies with gemcitabine, and over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth. AREAS COVERED: The cell cycle is a tightly regulated series of events that governs cell replication and division. Deregulation of cell cycle kinases have been implicated in PC tumorigenesis. In this review, we discuss the potential and limitations of current cyclin-kinase inhibitors. We also summarize progress in evaluating other mitotic kinase inhibitors and novel cell-cycle kinase inhibitors as potential therapeutic agents in PC. EXPERT OPINION: While the successful development and approval of cell-cycle inhibitors for PC therapy remains unresolved, pre-clinical identification of resistant mechanisms would help design better early- phase clinical trials where relevant combinations may be evaluated prior to Phase II testing. The authors believe that cell-cycle kinases are important anti-cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted, and complimentary anti-cancer mechanism, expand the available armamentarium against PC.

Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma.

PURPOSE: Treatment of unresectable locally advanced pancreatic cancer (LAPC) usually includes chemotherapy and/or radiation therapy in an attempt to downstage these tumors to the extent of resectability, but outcomes remain poor. Irreversible electroporation (IRE) is an ablative modality that may be useful in this population. The aim of this study was to evaluate the safety of percutaneous IRE in patients with pancreatic adenocarcinoma. MATERIALS AND METHODS: IRE was performed in patients with pancreatic cancer whose tumors remained unresectable after, or who were intolerant of, standard therapy. The procedures were all done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS: Fifteen IRE procedures were performed in 14 patients (one was treated twice). Three patients had metastatic disease and 11 had LAPC. All patients had received chemotherapy previously, and 11 had received radiation. The median tumor size was 3.3 cm (range, 2.5-7 cm). Immediate and 24-hour postprocedural scans demonstrated patent vasculature in the treatment zone in all patients. Two patients underwent surgery 4 and 5 months after IRE, respectively. Both had margin-negative resections, and one had a pathologic complete response; both remain disease-free after 11 and 14 months, respectively. Complications included spontaneous pneumothorax during anesthesia (n = 1) and pancreatitis (n = 1), and both patients recovered completely. There were no deaths directly related to the procedure. All three patients with metastatic disease at IRE died from progression of their disease. CONCLUSIONS: Percutaneous IRE for pancreatic adenocarcinoma is feasible and safe. A prospective trial is being planned.

Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma?

BACKGROUND: It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival. METHODS: Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy ≤ 60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model. RESULTS: Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance. CONCLUSIONS: Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS.

EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video).

BACKGROUND: EUS-guided celiac plexus neurolysis (EUS-CPN) improves pain control in patients with pancreatic cancer. EUS allows visualization of the celiac ganglion. OBJECTIVE: To determine predictors of response to EUS-CPN in a cohort of 64 patients with pancreatic malignancy. DESIGN: Retrospective analysis of prospective database. SETTING: Academic medical center. PATIENTS: Sixty-four patients with pancreatic cancer referred for EUS between March 2008 and January 2010. INTERVENTIONS: EUS-CPN injected directly into celiac ganglia when visible by linear EUS or bilateral injection at the celiac vascular trunk. MAIN OUTCOME MEASUREMENTS: Predictors of pain improvement at week 1 by univariate and multivariate analysis. RESULTS: At week 1, 32 patients (50%) had a symptomatic response. In a multivariate model with 8 potential predictors, visualization of the ganglia was the best predictor of response; patients with visible ganglia were >15 times more likely to respond (odds ratio 15.7; P<.001). Tumors located outside the head of the pancreas and patients with a higher baseline pain level were weakly associated with a good response. LIMITATIONS: Retrospective design and lack of blinding. CONCLUSIONS: Visualization of celiac ganglia with direct injection is the best predictor of response to EUS-CPN in patients with pancreatic malignancy.

EUS-FNA with rescue fluorescence in situ hybridization for the diagnosis of pancreatic carcinoma in patients with inconclusive on-site cytopathology results.

BACKGROUND: Detection of chromosomal abnormalities by fluorescence in situ hybridization (FISH) analysis has not been well-studied in FNA samples of pancreatic masses. Selective use of FISH in patients with inconclusive on-site cytopathology results may improve the sensitivity of EUS for malignancy. OBJECTIVE: To determine the sensitivity and specificity of FISH analysis in patients with inconclusive on-site cytopathology results. DESIGN: Consecutive patients with suspected pancreatic malignancy, nonrandomized cohort study. Final diagnosis was based on either surgical biopsy or disease progression on extended follow-up or death. SETTING: Academic center, tertiary-care referral cancer center. PATIENTS: A total of 212 EUS examinations were performed in 206 patients for solid pancreatic lesions over a 24-month period (January 2009-December 2010). FISH analysis was done for 69 patients with inconclusive or nonavailable on-site cytology results. INTERVENTION: EUS-guided FNA (EUS-FNA) of solid pancreatic masses with cytology and FISH analysis for polysomy of chromosomes 3, 7, and 17 and deletion of 9p21. MAIN OUTCOME MEASUREMENTS: Sensitivity/specificity of cytology, FISH, and a composite of cytology and FISH. RESULTS: Patients with positive on-site cytology (110), neuroendocrine tumors (22), insufficient follow-up (1), FISH not obtained (3), and renal cancer with pancreatic metastasis (1) were excluded. Sixty-nine patients comprised the study cohort, 54 with malignancy and 15 with benign disease. Sensitivity for malignancy of cytology, FISH analysis, and the combination were 61%, 74%, and 85%, respectively (P = .009). FISH detected an additional 13 cases of pancreatic adenocarcinoma missed by cytology. There was no false-positive FISH analysis in 15 patients with benign disease. No major complications occurred from EUS-FNA. LIMITATIONS: Single center, selected patients underwent FISH analysis, limited number of patients with benign disease. CONCLUSION: In patients with suspected pancreatic cancer, FISH analysis can detect additional cases missed by cytology without compromising specificity. FISH analysis to detect polysomy of chromosomes 3, 7, and 17 and deletion of 9p21 should be considered when cytology is negative for malignancy in patients with a known pancreatic mass.

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.

Single-session endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography for evaluation of pancreaticobiliary disorders.

BACKGROUND: Endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) often are required in the evaluation and treatment of patients with pancreaticobiliary disorders. Few reports of single-session EUS-ERCP have raised questions regarding its safety and accuracy or about which procedure should be performed first. METHODS: Data from 2005 to 2009 were reviewed from a prospectively maintained EUS-ERCP database at a single tertiary care cancer center. Sensitivity and specificity of EUS and fine-needle aspiration (FNA), bile duct cannulation rate, duration of procedure, and complications were evaluated. RESULTS: Of the 35 patients (15 men and 20 women) studied, 28 had a final diagnosis of malignancy, and 7 had benign disorders. All the patients underwent ERCP and EUS, with FNA performed for 28 patients (80%). For 22 of the 35 patients (62.8%), EUS was the first procedure performed. The sensitivity of EUS-FNA for malignancy was 96.4%. The bile duct cannulation rate during ERCP was 97.1%. Five patients required a precut sphincterotomy for bile duct access, and one patient with chronic pancreatitis had a failed cannulation despite a EUS-guided rendezvous. A stent was successfully placed in 29 patients (96%). No major complications occurred, and no contrast leak was seen when FNA was performed before the cholangiogram. One patient had periduodenal bleeding after FNA, which was managed conservatively. The mean duration of the procedure was 83.7 min. CONCLUSION: Single-session EUS-ERCP can be performed safely and with efficacy similar to that of the procedures performed separately.

Erlotinib (tarceva) for the treatment of non-small-cell lung cancer and pancreatic cancer.

Erlotinib (Tarceva) is a small-molecule, orally dosed, anti-cancer drug that inhibits the epidermal growth factor receptor. Randomized, controlled clinical studies have demonstrated that erlotinib significantly improved survival in patients with previously treated non-small-cell lung cancer and, in combination with chemotherapy, in patients with untreated pancreatic cancer. In this article, we describe the clinical evidence and value of erlotinib as a therapy for non-small-cell lung cancer and pancreatic cancer and discuss ongoing clinical studies to optimize its use in various settings and to identify appropriate patient populations.

A Phase I/II Open-Label Multicenter Single-Arm Study of FABLOx (Metronomic 5-Fluorouracil Plus nab-Paclitaxel, Bevacizumab, Leucovorin, and Oxaliplatin) in Patients with Metastatic Pancreatic Cancer.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18-65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m2 per day (days 1-14 continuous infusion); nab-paclitaxel 75 mg/m2, leucovorin 20 mg/m2, and oxaliplatin 40 mg/m2 (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7-11.3) and 9.9 (95% CI, 4.4-13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7-40.8) and 38.9% (95% CI, 12.6-65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.