The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance.

Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC. Statement of significance: Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.

Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study.

PURPOSE: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. RESULTS: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. CONCLUSIONS: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.

T cell-inflamed gene expression profile and PD-L1 expression and pembrolizumab efficacy in advanced esophageal cancer.

Aim: Investigate the relationship between response to pembrolizumab and expression of the 18-gene T cell-inflamed gene expression profile (TcellinfGEP) or PD-L1 combined positive score (CPS) in esophageal cancer. Materials & methods: This analysis included heavily pretreated patients with advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma who received pembrolizumab in the single-arm, phase II study KEYNOTE-180. PD-L1 CPS was evaluated with PD-L1 IHC 22C3 pharmDx. Results: In patients with squamous cell carcinoma, trends toward enrichment for responders were observed for patients with PD-L1 CPS ≥10 tumors. In patients with adenocarcinoma, a trend was observed for TcellinfGEP but not for PD-L1. Conclusion: TcellinfGEP and PD-L1 CPS may enrich for responders to pembrolizumab in patients with esophageal cancer. Clinical trial registration: NCT02559687 (ClinicalTrials.gov).

An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic.

INTRODUCTION: Gastric cancer is common worldwide, and while multiple therapeutic options exist, the prognosis remains poor. Tumors may overexpress HER2. While targeting HER2 with trastuzumab provides a survival benefit, options following progression are limited. Subsequent trials of HER2-targeted agents failed to improve outcomes. Recently, DESTINY-Gastric01 demonstrated a survival benefit utilizing the antibody-drug conjugate (ADC) trastuzumab deruxtecan in gastric cancer patients that progressed on trastuzumab. AREAS COVERED: /The authors give background to gastric cancer/HER2 and discuss prognostic implications of HER2 overexpression. They also describe initial trials of anti-HER2 therapy, resistance mechanisms, and ADC development/optimization. Finally, the authors review DESTINY-Gastric01 and provide future perspectives. EXPERT OPINION: While the 2010 ToGA trial demonstrated efficacy of trastuzumab in HER2 positive gastric cancer, subsequent trials of HER2-directed therapy have disappointed. Downregulation of HER2 after trastuzumab may play a role; however, trastuzumab deruxtecan maintains some efficacy in low-level HER2 expressing tumors. The DESTINY-Gastric01 cohort was from South Korea/Japan; authors have reported differences in gastric cancer risk factors/physiology between Eastern and Western populations. DESTINY-Gastric02 will evaluate trastuzumab deruxtecan in Western patients to confirm generalizability. Pulmonary side effects are notable;physicians must be cognizant of overlapping toxicities with combination therapy.

Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction.

BACKGROUND: Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD). METHODS: Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16. RESULTS: Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26). CONCLUSIONS: RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group. TRIAL REGISTRATION: This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .

Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer.

Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies.

AIM: Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). METHOD: This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. RESULTS: In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. CONCLUSIONS: The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01677559.

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

INTRODUCTION: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. PATIENTS AND METHODS: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. RESULTS: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). CONCLUSIONS: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

The Landscape of Alterations in DNA Damage Response Pathways in Colorectal Cancer.

PURPOSE: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Although the mismatch repair system has been extensively studied, the clinical implications of other mechanisms associated with DDR alterations in patients with colorectal cancer remain unclear. This study aimed to understand DDR pathways alterations and their association with common clinical features in patients with colorectal cancer. EXPERIMENTAL DESIGN: Next-generation sequencing and whole-transcriptome sequencing were conducted using formalin-fixed paraffin-embedded samples submitted to a commercial Clinical Laboratory Improvement Amendments-certified laboratory. Samples with pathogenic or presumed pathogenic mutations in 29 specific DDR-related genes were considered as DDR-mutant (DDR-MT) and the remaining samples as DDR-wild type (DDR-WT). RESULTS: Of 9,321 patients with colorectal cancer, 1,290 (13.8%) were DDR-MT. The frequency of DDR-MT was significantly higher in microsatellite instability-high (MSI-H) cases than in microsatellite stable cases (76.4% vs. 9.5%). The DDR-MT genotype was higher in the right-sided, RAS-wild, BRAF-mutant, and CMS1 subgroups. However, these associations were primarily confounded by the distribution of MSI status. Compared with the DDR-WT tumors, the DDR-MT tumors had a higher mutational burden and gene expression levels in the immune-related pathway, which were independent of MSI status. CONCLUSIONS: We characterized a distinct subgroup of patients with colorectal cancer with tumors harboring mutations in the DDR-related genes. These patients more commonly had MSI-H tumors and exhibited an activated immune signature regardless of their tumor's MSI status. These findings warrant further investigations to develop personalized treatment strategies in this significant subgroup of patients with colorectal cancer.

Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet?

Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1. BACKGROUND: Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors. METHODS: Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle. RESULTS: In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response. CONCLUSION: The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies.

PURPOSE: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients. CONCLUSIONS: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.

Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.

BACKGROUND: Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. METHODS: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m2 twice daily administered as 7 days on and 7 days off, intravenous (IV) bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily. The primary end point was progression free survival (PFS) and secondary endpoints included objective response rate (ORR) and tolerability. An exploratory endpoint included correlation of PFS with cytokine levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To examine cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy and to Arm B where levocetirizine was started 7 days prior to chemotherapy. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). RESULTS: Forty-seven patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 23 patients and Arm B enrolled 24 patients. Fifty percent of patients had progressive disease and 62% of patients had stable disease in each arm as best response. There was no demonstrable difference in PFS between the two arms (log-rank test P=0.83). Median time to progression was 3.4 months in Arm A and 3.5 months in Arm B. CONCLUSIONS: Median PFS in the trial was comparable to and appeared to be better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine measurement with IL-8 levels did not show any correlation with progression free survival but patients with stable disease showed overall lower levels of IL-8 as compared to patients with progressive disease in the cytokine analysis.

First-in-human study to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory renal cell carcinoma.

PURPOSE: This study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC). METHODS: This was an open-label, adaptive dose-exploration study in patients with relapsed/refractory ccRCC. The study was conducted in two parts for dose exploration and dose expansion on a biweekly dosing schedule. AMG 172 doses of 0.15, 0.3, 0.6, 1.2, 1.6, 1.8, and 2.4 mg/kg were studied in the dose-exploration phase. RESULTS: The 1.6 mg/kg dose of AMG 172 was identified as the maximum tolerated dose (MTD). The most common adverse events were thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). The most common dose-limiting toxicity (DLT) was thrombocytopenia. Thrombocytopenia and liver injury constituted DLTs that required discontinuation of treatment. Of the 10 patients treated at the MTD in part 2 of the study, 2 patients had grade 3 hepatocellular injury with aspartate aminotransferase or alanine aminotransferase elevation. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and unconjugated cytotoxin. Dose-proportional increases in plasma exposure were observed over the dose range of 0.3-2.4 mg/kg. Following multiple biweekly doses, plasma accumulation was less than two-fold. Two patients (5.4%) had a partial response, 6 patients (16.2%) had stable disease, and 13 patients (35.1%) had progressive disease. CONCLUSION: AMG 172 exhibited a favorable pharmacokinetic profile in patients with relapsed/refractory ccRCC and showed evidence suggestive of limited antitumor activity. Safety and tolerability were as expected for a maytansinoid antibody-drug conjugate.

Author Correction: HER kinase inhibition in patients with HER2- and HER3-mutant cancers.

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.

Inhibition of AURKA Reduces Proliferation and Survival of Gastrointestinal Cancer Cells With Activated KRAS by Preventing Activation of RPS6KB1.

BACKGROUND & AIMS: Activation of KRAS signaling and overexpression of the aurora kinase A (AURKA) are often detected in luminal gastrointestinal cancers. We investigated regulation of ribosomal protein S6 kinase B1 (RPS6KB1) by AURKA and the effects of alisertib, an AURKA inhibitor, in mice xenograft tumors grown from human gastrointestinal cancer cells with mutant, activated forms of KRAS. METHODS: We tested the effects of alisertib or AURKA overexpression or knockdown in 10 upper gastrointestinal or colon cancer cell lines with KRAS mutations or amplifications using the CellTiter-Glo luminescence and clonogenic cell survival assays. We used the proximity ligation in situ assay to evaluate protein co-localization and immunoprecipitation to study protein interactions. Nude mice with xenograft tumors grown from HCT116, SNU-601, SW480, or SNU-1 cells were given oral alisertib (40 mg/kg, 5 times/wk) for 4 weeks. Tumor samples were collected and analyzed by immunoblots and immunohistochemistry. Tissue microarrays from 151 paraffin-embedded human colon tumors, with adjacent normal and adenoma tissues, were analyzed by immunohistochemistry for levels of AURKA. RESULTS: Alisertib reduced proliferation and survival of the cell lines tested. AURKA knockdown or inhibition with alisertib reduced levels of phosphorylated RPS6KB1 (at T389) and increased levels of proteins that induce apoptosis, including BIM, cleaved PARP, and cleaved caspase 3. AURKA co-localized and interacted with RPS6KB1, mediating RPS6KB1 phosphorylation at T389. We detected AURKA-dependent phosphorylation of RPS6KB1 in cell lines with mutations in KRAS but not in cells with wild-type KRAS. Administration of alisertib to mice with xenograft tumors significantly reduced tumor volumes (P < .001). Alisertib reduced phosphorylation of RPS6KB1 and Ki-67 and increased levels of cleaved caspase 3 in tumor tissues. In analyses of tissue microarrays, we found significant overexpression of AURKA in gastrointestinal tumor tissues compared with non-tumor tissues (P = .0003). CONCLUSION: In studies of gastrointestinal cancer cell lines with activated KRAS, we found AURKA to phosphorylate RPS6KB1, promoting cell proliferation and survival and growth of xenograft tumors in mice. Agents that inhibit AURKA might slow the growth of gastrointestinal tumors with activation of KRAS.

Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer.

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program-approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib "run-in" to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398-407. ©2018 AACR.

HER kinase inhibition in patients with HER2- and HER3-mutant cancers.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.