Albert C. Lockhart

Organic anion transporting polypeptide 1B3 (OATP1B3) is overexpressed in colorectal tumors and is a predictor of clinical outcome

Background and aims: OATP1B3 is an organic anion transporting polypeptide (OATP) that functions as a multispecific transporter in the normal liver. We examined the expression and clinical significance of OATP1B3 in colon cancers in tissue microarrays. Methods: Immunohistochemistry was used to assess OATP1B3 protein expression in paraffinized colon tumor tissue microarrays. OATP1B3 immunostaining was evaluated by location and intensity. Relationships between OATP1B3 expression, known prognostic variables and clinical outcomes were examined. Results: 278 colon tumor samples of all stages were evaluated for OATP1B3 expression. OATP1B3 immunostaining was detectable in the majority (56%) of the tumor samples. Higher OATP1B3 expression was seen in lower stage tumors (p = 0.003) and lower grade (p = 0.004) tumors, but was not predictive of 5-year survival or tumor recurrence as an independent variable. Within individual tumor grades, OATP1B3 expression was associated with improved 5-year survival, but not recurrence in patients with poorly differentiated tumors. Conclusion: OATP1B3 expression was seen in the majority of colon tumors and may be a marker of lower grade and lower stage tumors and may predict for improved outcome in certain tumors.

Aflibercept in the treatment of metastatic colorectal cancer

Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept.

Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.

Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer.

Objectives:Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer. Methods:SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion. Results:Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease. Conclusions:Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.

Dual blockade of the EGFR and COX-2 pathways: a phase II trial of cetuximab and celecoxib in patients with chemotherapy refractory metastatic colorectal cancer.

ObjectivesThe epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways. MethodsCetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m2 loading dose followed by weekly cetuximab at 250 mg/m2) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-&agr;, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade. ResultsSeventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-&agr; or urinary PGE-M between cycles in responders or nonresponders. ConclusionsThis regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-&agr; or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Purpose: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC. Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivo. Results: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748–59. ©2016 AACR.

Genetics of Gastric Cancer

Gastric cancer represents a major cause of cancer mortality worldwide despite a declining incidence. New molecular classification schemes developed from genomic and molecular analyses of gastric cancer have provided a framework for understanding this heterogenous disease, and early findings suggest these classifications will be relevant for designing and implementing new targeted therapies. The success of targeted therapy and immunotherapy in breast cancer and melanoma, respectively, has not been duplicated in gastric cancer, but trastuzumab and ramucirumab have demonstrated efficacy in select populations. New markers that predict therapeutic response are needed to improve patient selection for both targeted and immunotherapies.

A phase I trial of irinotecan alternating with epirubicin in patients with advanced malignancies.

Objectives:This phase I study was conducted to evaluate the combination of irinotecan, a topoisomerase I inhibitor, with epirubicin, a topoisomerase II inhibitor, when administered sequentially on a once-every-three week basis. Methods:Irinotecan was administered at doses ranging from 100 to 150 mg/m2 intravenously over 90 minutes, 24 hours before epirubicin, in doses from 30 to 60 mg/m2, every 3 weeks. Toxicity assessments were performed weekly. Tumor evaluation by radiographic and physical examination was performed after every 3 cycles using Response Evaluation Criteria in Solid Tumors. Results:Eighteen patients with metastatic solid tumors were enrolled in this study. The maximum tolerated dose and recommended phase II dose was irinotecan 150 mg/m2 and epirubicin 30 mg/m2. Dose-limiting toxicities were primarily neutropenia. Other toxicities at this dose level were mild. Three patients with colon cancer, 1 patient with renal cell cancer and 1 patient with adenosquamous cell carcinoma of the ethmoid sinus had stable disease. No objective responses were observed. Conclusions:The maximum tolerated dose and recommended phase II dose for irinotecan and epirubicin administered 24 hours apart every 3 weeks was 150 mg/m2 and 30 mg/m2, respectively. Higher doses were limited by significant hematologic toxicity and fatigue.

Abstract 5443: A phase 1 evaluation of 64Cu-DOTA-patritumab to assess dosimetry, receptor occupancy, and safety in advanced solid tumors

Background: Patritumab (P) is a HER3-specific human mAB that promotes receptor downregulation, inhibits ligand binding and tumor growth in xenografts models, and is safe in humans. The radioisotope 64Cu conjugated with P with a DOTA chelate, was confirmed by mass spectrometry and stable in serum for 24-hours. A microPET study in a mouse model (BxPC3) revealed significant tumor uptake of 64Cu-DOTA-patritumab (64Cu-DOTA-P) and uptake blockage (>50%) with co-injection of unlabeled P. Clinically administering 64Cu-DOTA-P could identify serum concentrations needed for maximal receptor occupancy. Methods: This Phase 1 study evaluated the safety, dosimetry (Cohort 1) and HER3 receptor occupancy (Cohort 2) of escalating doses of GMP generated intravenously administered 64Cu-DOTA-P in subjects with HER3+, solid tumors. Cohort 1 subjects received 64Cu-DOTA-P (8-15 mCi) on D1, then PET/CT scans at 3, 24, and 48 hours (± 3 hours). Sequential PET/CT scans and time integrated organ activity concentrations were used to compute organ residence times and radiation doses. Cohort 2 subjects received 64Cu-DOTA-P on D1 (tracer only) and D8 (tracer after 9.0 mg/kg of P), each followed by PET/CT scans at 24 hours (± 3 hours). Receptor occupancy was measured by: 1) tracer tumor “uptake” at D1 versus D8; and 2) D1 “uptake” versus tumoral HER3 expression with validated IHC (membrane H-Score). After dosimetry and receptor occupancy studies, subjects received P (18.0 mg/kg loading, then 9.0 mg/kg Q3 weeks) were followed for safety and had PK samples collected. Results: Eleven subjects (mean age 61.7) were evaluated. In Cohort 1 (n=5), the mean tumor uptake (SUV ± SD) at 3, 24 and 48 hours was 5.6 (± 4.5), 3.2 (±1.7), and 2.9 (±1.1), respectively. The mean tumor uptake (Tumor-To-Muscle Uptake Ratio [T/M] ± SD) at 3, 24 and 48 hours was 3.0 (± 2.1), 2.1 (±1.2), and 1.6 (±0.5), respectively. The tracer localized primarily in the blood pool and liver, with modest uptake in tumors. The average effective dose was 0.16 ± 0.016 rem/mCi with largest tracer uptake in the liver (1.61 ± 0.30 rad/mCi). In Cohort 2 (n=6), the mean SUV uptake of 64Cu-DOTA-P after administration of unlabeled P was 3.4 (± 1.1) baseline and 4.1 (± 1.3) after 24 hours (p>NS). T/Ms were 1.6 (± 0.6) and 2.8 (± 1.7), respectively. No correlation existed between SUV, T/M, and HER3 H-Score. After D1 injection, tracer signal was detected primarily in the liver. Following D8 co-injection with unlabeled P, tracer signal was higher in the circulation and unchanged in the tumor. Common AEs were diarrhea (27%); and dizziness, fatigue, headache, hypertension, and weight loss (18% each). Conclusions: 64Cu -DOTA-P administration is safe and feasible in humans. This study was unable to determine HER3 receptor occupancy. Possible reasons include lower tumor HER3 expression versus xenografts, tracer liver accumulation, and target internalization. A modified design should be considered for future studies. Citation Format: Albert C. Lockhart, Yongjian Liu, Farrokh Dehdashti, Richard Laforest, Joel Picus, Andrea Wang-Gillam, Lauren Trull, Stefanie Belanger, Madhuri Desai, Jeanne Mendell, Syed Mahmood, Barry A. Siegel, Michael J. Welch. A phase 1 evaluation of 64Cu-DOTA-patritumab to assess dosimetry, receptor occupancy, and safety in advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2014-5443

Phase I trial of cabazitaxel plus cisplatin in patients with advanced solid tumors.

162 Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer whose disease had progressed during or after a prior docetaxel-containing regimen. Therapeutic synergism of Cbz/cisplatin (Cis) has been demonstrated in tumor-bearing mice. METHODS The primary objective in part 1 of this Phase I study ( NCT00925743 ) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives were safety, pharmacokinetics (PK) and efficacy. The primary objective of part 2 was to determine the antitumor activity at the MTD. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1, with confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation with a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. RESULTS Pts (N = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). 2 of 6 evaluable pts experienced a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed. Eighteen pts were treated at the MTD and 60 cycles were administered (median = 3; range 1-8). The most frequent non-hematologic treatment-related adverse events (all Grade/Grade 3-4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of Grade 3-4 neutropenia was 78% and 1 pt had febrile neutropenia. No PK interactions between Cbz and Cis were observed. Stable disease was seen in 11 pts. No objective responses were reported. CONCLUSIONS The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with that of a platinum/taxane combination. No PK interactions were seen. Further investigations into the combined treatment combination are planned.