Faculty Bibliography

PURPOSE/OBJECTIVE:To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA). PATIENTS AND METHODS/METHODS:once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1. RESULTS:3.8%). CONCLUSION/CONCLUSIONS:The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.

PURPOSE/OBJECTIVE:Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. EXPERIMENTAL DESIGN/METHODS:Harmonic Motion Imaging is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. RESULTS:In mice, we learned that stiffness increased during progression from pre-neoplasia to adenocarcinoma, and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2-mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. CONCLUSIONS:These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in pancreatic ductal adenocarcinoma.

Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,Lalpha- metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC's) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician's choice treatment as third line therapy for patients with metastatic PDAC.
Method(s): This is a multi-center Phase 3 study of patients >=18 years with metastatic PDAC that progressed after 2nd lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG <2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs

Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically, it is measured using the Demoralization-Scale II (DS-II), a validated questionnaire that yields a patientreported quantification (scale 0-32) of demoralization. Previous studies involving patients with progressive disease have uncovered a strong positive correlation between demoralization and depression, respectively measured by the DS-II and Patient Health Questionnaire-9 (PHQ-9) surveys. Here, we aim to characterize demoralization and its relationship to depression in pancreatic cancer patients, a unique patient population in terms of its poor prognosis. We hypothesize that demoralization is highly prevalent in the pancreatic cancer patient population and strongly correlated with depression.
Method(s): Eligible patients with an active pancreatic cancer diagnosis, after consenting to an IRB approved protocol, will be administered the DS-II and PHQ-9 surveys to yield psychometric measurements for analysis. The primary objective of this project is to determine the association between demoralization (DS-II) and depression (PHQ-9) in pancreatic cancer patients. Secondary objectives include associations between demoralization and ethnicity, sexual orientation, suicidal ideation, education, cancer stage, and disease progression. Data will be analyzed via simple linear regression. An ANOVA will also be conducted using DS-II groups as the categorical variable and PHQ-9 scores as the continuous variable, and vice versa. This is a multi-institutional study to be conducted at Cedars- Sinai Medical Center, New York University, University of Washington, UC San Francisco, and Lewis Katz Schools of Medicine

Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Method(s): Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue

Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

Background and aims: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.

PURPOSE/OBJECTIVE:expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. PATIENTS AND METHODS/METHODS:Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS:= not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. CONCLUSIONS:.

OBJECTIVE:attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples. DESIGN/METHODS:We used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts. RESULTS:Our analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes. CONCLUSION/CONCLUSIONS:Our findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.