Palliative radiosurgery for localized pancreatic cancer in the elderly.

583 Background: At least 15% of patients diagnosed with localized pancreatic cancer are medically unfit for surgical resection or systemic therapy. Traditionally, these patients are enrolled in palliative care with symptom management alone. With local progression of their disease, they may experience pain, obstruction, weight loss and nausea. Radiosurgery is a localized high dose conformal therapy allowing for noninvasive treatment of pancreatic cancer. This study retrospectively examines the role of palliative radiosurgery as monotherapy for elderly patients who are not candidates for standard of care therapy. Methods: From 2017-2021, 28 patients over the age of 80 with biopsy confirmed pancreatic adenocarcinoma and localized disease by imaging were retrospectively evaluated. All had been deemed not to be candidates for surgical resection or systemic chemotherapy. Outcomes were reviewed to evaluate patient characteristics, local control, quality of life, ECOG status and survival duration. Results: Median patient age was 84 years (range 80-99). All 28 patients received SBRT radiosurgery to the pancreas with 35-40Gy in 5 fractions with photon LINAC platform. Mean ECOG score was 1.2 at time of treatment. At 6 month follow up, 18 patients were alive with a mean ECOG of 1.4. Four patients reported grade 2 acute GI toxicity in the first three months with no late toxicity reported. Eight patients developed local progression while fourteen patients developed distant metastatic disease. Six patients at least one year out from treatment have no evidence of disease progression. Median overall survival is 10.8 months. Conclusions: Pancreatic radiosurgery is a safe and effective method of palliative therapy for elderly patients who are not candidates for surgical resection or systemic therapy. It can provide durable local control, relief of pain and obstructive symptoms, is well tolerated with minimal toxicity and provides favorable survival when compared to palliative care alone. </jats:p

Prospective study of early detection of malignancies in individuals at risk for developing pancreatic cancer.

TPS500 Background: It is estimated that by 2030 pancreatic cancer will be the second leading cause of cancer deaths in the US. Currently, only 9% of newly diagnosed pancreatic cancer is localized and 5-year survival is 7%. Due to most pancreatic cancers (PC) presenting at a later stage with poor overall survival, early detection methods must be implemented to improve treatment outcomes. Yet, effective early screening guidelines do not exist for pancreatic cancer. Our Early Detection Program (EDP) provides personalized early detection including risk assessment, screening, and genetic testing. We aim to evaluate risk assessment criteria, establish a database to delineate a pattern of characteristics, and utilize a biospecimen repository and molecular based technologies to map novel biomarkers for early detection. Methods: The EDP screens those with a family history or germline mutation consistent with potential increased risk for developing PC. Patients are eligible based on risk assessment and stratified into 3 groups based on the CAPS Consortium criteria (average, moderate, and high risk). Screenings may include genetic testing for germline mutations, blood testing including Hemoglobin A1C (HgBA1C), complete blood count (CBC), complete metabolic profile (CMP), cancer antigen 19-9 (CA 19-9), vitamin D 25-OH, lipid panel, and thyroid stimulating hormone (TSH). Serum and urine collection will be offered for banking for future studies. Patients have yearly screenings including thorough history and physical exam and cases are discussed at a multi-disciplinary pancreatic tumor board. If indicated, patients undergo MRI/MRCP abdomen, GI consult and EUS. Study participants also complete a cancer anxiety index. The EDP is still recruiting patients. Next-generation sequencing and molecular based technologies are being explored for mapping novel biomarkers for early detection. The Institute is expanding to include those at risk for breast and ovarian cancer. We are evaluating risk assessment criteria and are developing a valid and reliable EDP index (EDP-I) anxiety instrument. </jats:p

Phase I dose escalation and pharmokinetic study of a modified schedule of 14-o-phosphonooxymethyltriptolide

TPS472 Background: We are conducting a phase I trial of a modified dosing schedule 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. We have previously presented our results from the initial phase I study of 27 patients using a daily dosing schema. That study demonstrated promising clinical activity with documented reductions in HSP70 levels. The common and dose limiting toxicity was neutropenia, which though cumulative, was also rapidly reversible early in the course of therapy with brief treatment interruptions. Several patients with disease control in the highest dose cohorts (0.67 and 0.8 mg/m2) progressed after dose reductions or prolonged treatment breaks mandated by the study protocol for cytopenias. Because of these observations we have revised the treatment schedule with short, early treatment breaks to allow more sustained therapy, and describe here the new study protocol. 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 5 of 7 days for 3 weeks of a 4 week cycle. The initial dose cohort begins at 0.67mg/m2, above the MTD defined in the prior study and one step below the highest level achieved in our previous study of 0.8 mg/m2. The primary endpoint is toxicity, in order to define the MTD for this dosing schedule. Secondary endpoints being measured include: pharmokinetics of the study drug and its active metabolite triptolide; suppression of HSP70 levels; and tumor response. Cohort 1 at 0.67mg/m2 has been completed without DLT, enrollment to cohort 2 at 0.8mg/m2 is complete without DLT to date, and cohort 3 is anticipated to begin November of 2015. Clinical trial information: NCT01927965

A pilot-blinded randomized feasibility trial comparing an investigational hand therapy intervention (IHT) to a traditional occupational therapy (TOT) intervention to prevent chemotherapy induced peripheral neuropathy (CIPN) of the hands in patients (pts) receiving chemotherapy (CTX).

TPS518 Background: CIPN is an unsolved, common problem for cancer pts. CIPN greatly affects quality of life and may impact quantity of life due to dose reductions and discontinuation of beneficial therapy. No generally accepted evidence-based prevention strategies for CIPN exist. In the discipline of hand therapy (HT), there are effective science-based interventions to treat peripheral neuropathies due to injury and disease. These interventions have not been explored in patients with CIPN. Methods: Study objective is to determine if an IHT intervention based on concepts of neuroplasticity can prevent or delay time to onset of CIPN of the hands as measured by Patient Reported Outcomes &amp; Criteria for Adverse Events, version 4 (CTCAE 4.0), compared to a TOT intervention. Eligible pts have pancreatic cancer and receive nab-paclitaxel + gemcitabine containing combinations; have no prior evidence of peripheral neuropathy (PN) of the hands and are not taking duloxetine or gabapentin. Randomization is 1:1. Patient instructions on the blinded IHT or TOT activities are done by an Occupational Therapist prior to start of CTX, then reinforced at multiple follow-up sessions. Periodic assessments include standardized hand sensibility testing: QuickDASH, upper extremity provocative testing, TEN Test; plus pt reporting of CIPN onset, CTCAE-4, physical examination of peripheral sensory/motor neurologic assessment of the hands, Karnofsky Performance Status, and pain visual analogue scale. Participation in the study with a daily home program continues until onset of CIPN of the hands or if no CIPN then through completion of an 84 day schedule of chemotherapy. The number and proportion of patients without CIPN of the hands at the end of 84 days of CTX will be summarized for both intervention groups. For an 80% powered design with a medium effect size, 40 evaluable pts are needed (95% CI, alpha .05). Planned enrollment is up to 50 pts allowing for pt attrition. Study opened to enrollment 8/2016. </jats:p

Pilot skin microbiome study of patients with pancreatic cancer in comparison to patients with other malignancies as well as those without cancer.

TPS502 Background: The microbiome is a burgeoning field involving the study of the microbial flora in humans and its effect on health. The human microbiome is altered by several environmental factors and may play a great role in inflammation and possibly in the development in several malignancies including pancreatic cancer. The purpose of this study is to characterize the skin microbiomes on the forehead and cheek of people with pancreas cancer compared to people with other forms of cancer and people without cancer by utilizing the ProdermIQ skin profiling platform. Methods: This is a prospective, open-label, pilot study. Sampling will be done as one time collection after informed consent through a skin swab on the forehead and one on the cheek. Subjects with a diagnosis of pancreatic adenocarcinoma, subjects with a diagnosis of malignancy other than pancreatic adenocarcinoma, and subjects without a diagnosis of malignancy will be enrolled for three separate arms of the study. Each study arm is composed of 25 individuals for a total of 75. Key inclusion criteria include subjects at least 18 years of age and a histologically confirmed diagnosis of pancreatic adenocarcinoma in the pancreas arm; a histological confirmed diagnosis of a malignancy other than pancreatic cancer in the other cancer arm; and individuals without cancer. Individuals with a rash or skin disorder will be excluded from the study. Once all swabs are collected they will be batch tested through next generation sequencing to characterize the skin microbiomes. A comprehensive comparison will be constructed of the profiles of each study group. </jats:p

Ibrutinib + durvalumab (MEDI4736) in patients (pts) with relapsed or refractory (R/R) pancreatic adenocarcinoma (PAC): A phase Ib/II multicenter study.

TPS484 Background: PAC is an aggressive disease characterized by poor prognosis and is inadequately treated with available therapies. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase (BTK) that was shown to inhibit mast cell degranulation in the PAC tumor microenvironment with subsequent inhibition of tumor cell proliferation, angiogenesis, and collagen deposition (Chang, 2011; Masso-Valles, 2015). Durvalumab, a human IgG1 monoclonal antibody (mAb), binds PD-L1 with high affinity and prevents interaction with PD-1 and CD80 (IC50values of 0.1 nM and 0.04 nM, respectively), facilitating antitumor T-cell responses (Stewart, 2015). Ibrutinib + anti-PD-L1 mAbs inhibited tumor cell growth and led to enhanced anti-tumor immune responses in mouse models (Sagiv-Barfi, 2015). This trial (PCYC-1135; NCT02403271) evaluates the safety and efficacy of ibrutinib + durvalumab in pts with PAC, breast cancer, and non-small cell lung cancer. Study details presented here focus on the cohort of pts with PAC. Methods: Key inclusion criteria include pathologically confirmed PAC, R/R disease (failed ≥ 1 prior systemic therapy), stage III-IV disease, ≥ 1 measurable lesion by RECIST 1.1 criteria, and adequate hematologic, renal, hepatic function. Key exclusion criteria include any history of central nervous system involvement; prior treatment with ibrutinib/BTK inhibitor or treatment with antibodies targeting PD-1, PD-L1, PD-L2, CD137, or CTLA-4; history of allogeneic organ transplant; or treatment with a strong cytochrome P450 3A inhibitor. Primary objectives are safety, tolerability, and efficacy of the combination; secondary objectives include pharmacokinetics and pharmacodynamic assessments of the combination. The phase 1b portion will assess the dose-limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D). Ibrutinib will be administered at the standard dose with the potential for dose level reductions if DLTs occur in combination with durvalumab. After RP2D determination, enrollment in phase 2 will occur until a total of 130-160 pts (across all 3 disease cohorts) are treated. Enrollment for phase 1b began in March 2015. Clinical trial information: NCT02403271. </jats:p

A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma

Abstract Lessons Learned This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment. Background Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR. Methods A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles. Results Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea. Conclusion PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed. </jats:sec

Mitomycin C in Homologous Recombination Deficient Metastatic Pancreatic Cancer after Disease Progression on Platinum-Based Chemotherapy and Olaparib

Recent efforts to personalize treatment with platinum-based chemotherapy and PARP inhibitors have produced promising results in homologous recombinant deficient (HRD) metastatic pancreatic cancer (MPC). However, new strategies are necessary to overcome resistance. The below case series documents patients treated at the HonorHealth Research Institute with a diagnosis of HRD MPC who received Mitomycin C (MMC) treatment from January 2013 until July 2018. Five HRD MPC patients treated with MMC were evaluated. All patients received at least one course of treatment. Mean age at MMC treatment initiation was 58 years. There were 3 females and 2 males. All patients had tumors that progressed on platinum-based chemotherapy, four patients had previous exposure to Olaparib. The median PFS was 10.1 months, and the median OS was 12.3 months. Responses were observed only in patients harboring BRCA2 mutations, no response was observed in the PALB2 mutation carrier. MMC in this heavily previously treated PC was safe, with overall manageable grade 2 gastrointestinal toxicities including nausea and vomiting, and G3 hematological toxicities including anemia and thrombocytopenia. Pancreatic cancer patients with HRD may benefit from MMC treatment. Further clinical investigation of MMC in pancreatic cancer is warranted

Phase II clinical trial of novel agent PBI-05204 in patients with metastatic pancreatic adenocarcinoma (mPDA).

698 Background: Survival statistics for mPDA are dismal and with limited treatment options novel agents are needed to improve disease outcomes. PBI-05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract’s major cytotoxic component, has demonstrated anti-tumor activity in various tumor cell lines. In a human PDA orthotopic model, this preparation reduced tumor burden as monotherapy. Pharmacodynamic studies suggest that PBI-05204’s mechanism of action is through inhibition of the PI3k/Akt/mTOR pathway. Methods: A phase II single-arm, open-label study to determine the efficacy of PBI-05204 in patients (pts) with mPDA refractory to standard therapy was conducted. The primary endpoint was overall survival (OS) with the hypothesis that 50% of pts would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Pts received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or pt withdrawal. Radiographic response was assessed every two cycles. Results: Forty-one pts were enrolled; two never received treatment and one was found to have a neuroendocrine tumor after pathological re-evaluation, leaving 38 pts for analysis. Median age at time of enrollment was 65.0 years. The median time from initial diagnosis to treatment was 16.9 months. The primary reason for withdrawal was PD (45.2%). Ten pts were alive at 4.5 months (26.3%) with a mPFS of 56 days (corresponding to first restaging). One objective response (2.6%) was observed for 162 days. Grade ≥3 treatment-emergent adverse events occurred in 63.2% of pts with the most common attributed to drug (all grades) being fatigue (36.8%), vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Conclusions: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate an efficacious role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized Phase II trial is currently being designed. Clinical trial information: NCT02329717. </jats:p