Lim, Dean

Abstract Objectives Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7–25 mg/m 2 ) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

125 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m2) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG>2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m2) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.

Abstract Background: Endemic nasopharyngeal carcinoma (NPC) refers to non-keratinizing (NK) subtypes harboring Epstein Barr virus (EBV) that frequently express programmed death-ligand 1 (PD-L1). We recently reported ≥30% of NPC harbor MHC class 1 gene alterations in a whole genome study. Method: We investigated the activity of nivolumab (NIVO) & relationship with PD-L1 & HLA expression (exp) in tumor cells (TC) & tumor infiltrating cells (TIL). Eligible patient (pt)s had to fail ≥ 1 prior line of platinum-based chemo. NIVO (3mg/kg IV, q2 weeks) was given until disease progression (PD). Archived tumors were analyzed for PD-L1 (DAKO) & HLA mutations (indicated by loss of HLA-A &/or B exp). Result: A total of 45 pts were enrolled across 11 sites from Oct 2015 to June 2016. Overall, 43 and 44 pts were evaluable respectively for response rate (RR, RECIST) & adverse events (AE). The median age was 57 years, 77% pts were males & 84% were Asians. The median number of prior chemo was 3 (range 1-9 lines). Of the 43 evaluable pts, there were 8 confirmed (19%, 95% CI: 8-33%) & 1 unconfirmed partial response (PR), 17 PD (40%), 14 stable disease (SD, 33%) & 3 pts were not assessed. One pt (MD015-027) had an unconfirmed clinical CR in an occipital metastasis (met). Pts received a median of 3 cycles of NIVO (range 1 - 14). Median overall survival has not been reached yet. Of the 44 pts evaluable for AE, 8 (18.2%) had grade 3 or higher treatment-related AEs & 1 pt died of sepsis. The most common grade 3 or higher AEs were increase in alanine/aspartate aminotransferase (n=3), & 1 pt respectively for hyponatremia, neutropenia, fatigue & diarrhea. Of the 21 tumor samples analyzed, 11/21 (52%) had >1% PD-L1 expressed mainly in TC. Table 1 outlines relationship between RR & PD-L1 exp. All pts with PR had >5% PD-L1 exp & one pt (34003-022) with CR (nasopharynx) & PR (lung mets) had the highest exp (80%). Majority of pts with PD had <1% PD-L1 exp tumors. One primary progressor (34003-032) had a PD-L1 +ve tumor harboring a complete loss of HLA-B signal (TC), but intact signal in TILs & stromal cells. Conclusion: NIVO is active in this heavily pre-treated group of pts with NK-NPC and longer follow-up is needed for survival endpoints. Preliminary result suggests PD-L1 exp may predict benefit from NIVO. The analytical result of all 45 tumors will be presented. Table 1.PD-L1 exp and RECIST response in 21 ptsPD-L1%espRR%PRSDPD0-11<1%-265%24-10%--120%-1-30%11-80%1--Total498 Citation Format: Brigette B. Ma, Boon Cher Goh, Wan T. Lim, Kwok W. Lo, Edwin P. Hui, Jonathan W. Riess, Mark Agulnik, Alex Y. Chang, Julie A. Kish, Dean W. Lim, Douglas R. Adkins, Kevin J. Cullen, Barbara J. Gitlitz, Nathan R. Foster, Adam M. Pettinger, Sanna Mckinzie, Ka F. To, Brian Costello, Howard Streicher, Anthony T. Chan. Multicenter phase II study of nivolumab in previously treated patients with recurrent and metastatic non-keratinizing nasopharyngeal carcinoma - Mayo clinic Phase 2 Consortium P2C-MN026, NCI9742, NCT02339558 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT076. doi:10.1158/1538-7445.AM2017-CT076