Hereditary Pancreatic Cancer

Pancreatic cancer is estimated to surpass breast cancer to become the third leading cause of cancer-related death in the USA in 2016. The 5-year overall survival is 7%, and most individuals are diagnosed with advanced disease. Thus, there is a need to improve the early detection of pancreatic cancer in order to detect and improve survival in the same way that mammograms and colonoscopies have improved survival for individuals with breast and colorectal cancer. This chapter discusses the genetics of hereditary pancreatic cancer, the current available screening options, and the use of biomarkers for early detection of pancreatic cancer

Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

Leukemia inhibitory factor; Safety; Solid tumorsFactor inhibidor de la leucemia; Seguridad; Tumores sólidosFactor inhibidor de la leucèmia; Seguretat; Tumors sòlidsBackground Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors. Materials and methods Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers. Results Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action. Conclusions MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.This work was supported by Northern Biologics (no grant number). Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Carole Mongin-Bulewski, PhD, of Ashfield MedComms (Manchester, UK), an Ashfield Health company, and was funded by AstraZeneca (no grant number)

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy

A preclinical and phase Ib study of palbociclib plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas

Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD. Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2). Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not me

Abstract CT207: Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide

Abstract Introduction: We are conducting a phase I, first-in-human trial of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma. Methods: The study uses a 3+3 dose escalation scheme, enrolling subjects with gastrointestinal malignancies refractory to standard therapies. The drug is administered as a daily, brief IV infusion for 21 days out of a 28 day cycle. The primary endpoint is toxicity, with secondary endpoints of pharmokinetics and response. Results: To date we have enrolled 27 subjects (17 pancreas, 7 colorectal, 3 other GI) at doses from 0.16 to 0.8 mg/m2, with 24 evaluable for toxicity. The therapy has been generally well tolerated with the only common toxicity being hematologic, but one patient experienced reversible cerebellar dysfunction at the highest dose. Pharmokinetics (n = 21) indicate rapid conversion of Minnelide to triptolide, with all Minnelide cleared within 30 minutes and peak triptolide levels achieved within 5 minutes of completion of infusion. Triptolide was rapidly cleared with a half-life of less than 30 minutes, and complete clearance by 6 hours, except in the patient with cerebellar toxicity who demonstrated delayed clearance of the drug. All subjects, except those in the lowest dose cohort, have had a reduction in HSP70 levels. The 9 patients in the first 3 dose cohorts all progressed by the end of cycle two. Tumor response by PET after cycle 1 (n = 19), shows a partial metabolic response in 36%, and stable metabolic disease in 52%. Response after 2 cycles by RECIST criteria (n = 10) shows a 10% PR (gastric) and 60% SD (5 pancreas, 1 rectal) rate with disease control for up to 6 months. 5 patients remain on study, with ongoing enrollment planned. Conclusions: We have seen promising evidence of significant clinical activity in this group of heavily pretreated patients with refractory GI malignancies. The toxicity profile and optimal dosing of Minnelide are being defined. Citation Format: Edward Greeno, Erkut Borazanci, Jon Gockerman, Ronald Korn, Ashok Saluja, Daniel Von Hoff. Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2015-CT207</jats:p

Triptolide and Its Derivatives as Cancer Therapies

Triptolide, a compound isolated from a Chinese medicinal herb, possesses potent antitumor, immunosuppressive, and anti-inflammatory properties, but is clinically limited due to its poor solubility, bioavailability, and toxicity. Recently, Minnelide, a water-soluble prodrug of triptolide, was shown to have potent antitumor activity in various preclinical cancer models. Minnelide is currently in Phase II clinical trials for treatment of advanced pancreatic cancer, which has fueled increased interest in this promising agent. Here, we review the recent advances in the biological activity of triptolide and its analogs, their mechanisms of actions, and their clinical developments. A special emphasis is given to proteins and pathways within the tumor and stromal compartments that are targeted by triptolide and its analogs as well as the ongoing clinical trials. Triptolide exhibits cytotoxicity toward both tumor cells and cancer-associated fibroblasts, and modulates immune microenvironment. Triptolide induces cell death pathways, inhibits inflammation, reduces metastasis, and attenuates extracellular matrix protein production by cancer-associated fibroblasts. Minnelide is a water-soluble prodrug of triptolide that shows potent in vitro and in vivo antitumor activity in a number of tumor types. In a Phase I clinical trial with Minnelide, partial responses by RECIST (Response evaluation criteria in solid tumors) criteria were noted in patients with gastric and pancreatic cancer

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

Immunoteràpia; Teràpies; Biomarcadors tumoralsInmunoterapia; Terapias; Biomarcadores tumoralesImmunotherapy; Therapies; Tumor biomarkersBackground We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens. Methods This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1–14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase. Results The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes. Conclusion Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.This study was funded by Eli Lilly and Company