11055 Background: No effective therapy exists for unresectable malignant peripheral nerve sheath tumors (MPNSTs). We previously reported that the combination of PEX and the mTOR inhibitor S synergistically inhibited MPNST growth (CCR 20: 3146, 2014) by depleting M2 TAMs and by inhibiting receptor tyrosine kinases (RTKs), including c-KIT, PDGFR, CSF1R. We characterized the safety, tolerability, recommended phase 2 dose (RP2D) of PEX plus S in all sarcoma sub-types. Methods: Patients (pts) received PEX plus S orally in 28 days cycle as per Table. The RP2D was determined using the time-to-event continual reassessment method (TITE-CRM) in advanced sarcoma who have progressed on standard therapy. DLT was defined as any need for a dose reduction. Results: 24 pts were accrued (Acr) of which 18 were evaluable (MPNST – 6, pigmented villonodular synovitis (PVNS) – 3, leiomyosarcoma – 5, and other – 9). The mean age was 46y, 56% were male, and 67% had greater than 2 prior therapies. Most common ( > 20%) grade 2 or higher TEAEs were anemia (33%), WBC count decrease (28%), fatigue, neutropenia, and lymphopenia (22% each). There were 5 dose limiting toxicities (DLT): 2 for elevated LFTs both of which resolved with dose reduction, 2 for supra-therapeutic S trough levels, and 1 for grade 5 dehydration at dose level (DL) 3. Four subjects experienced a partial response (PR; -44% to -77% by RECIST, 18 – 61 wks on therapy). Seven subjects experienced stable disease (SD; +19.7% to -20.7% by RECIST; 9.4 – 30 wks on therapy). Five subjects progressed on therapy and two subjects experienced early DLTs and did not undergo tumor assessment. The RP2D is DL 3 (S 2mg/PEX 1000mg) with an estimated probability of DLT of 26.7% as determined by TITE-CRM. This recommendation is based on a target DLT rate of 25%. TAMs and immune subtypes from available tissue specimens and historical controls will be presented. Conclusions: 1000mg of PEX in combination with 2mg of S daily has an acceptable safety profile. Objective responses and durable SD was observed in PNVS and MPNST patients justifying proceeding with a multi-center single arm phase 2 study in advanced MPNST. Clinical trial information: NCT02584647. [Table: see text]

313 Background: Salvage intravesical chemotherapy has shown benefit in patients with high-risk non-muscle invasive bladder cancer who fail first line therapy. Our preclinical murine intravesical trial showed a combination therapy was superior to single-agents. Our objective was to investigate the safety of intravesical triple agent salvage chemotherapy consisting of cabazitaxel, gemcitabine and cisplatin (CGC). Methods: Patients with BCG refractory or recurrent high-risk non-muscle invasive bladder cancer who refused radical cystectomy were enrolled. All patients underwent a pre-treatment transurethral resection of bladder tumor and then received a 6-week regimen. All patients received the same dose of gemcitabine (2000mg) while the dose of cisplatin and cabazitaxel were escalated as shown in table 1. Toxicity was categorized according to CTC for Adverse Events v4 and included hematuria, dysuria, bladder spasm, urinary retention or frequency. A complete response (CR) was defined as a negative random bladder biopsy and negative cytology six weeks after treatment. Results: Median age of the 9 patients was 74 years (table 1) and the median number of prior intravesical therapies was 4 (range 2-5). All patients completed 6 weeks of induction CGC. Any local toxicity was found in 7 patients with 5 experiencing at least 1 grade 1 toxicity and 4 experiencing at least 1 grade 2 toxicity. Seven of eight patients were complete responders and initiated maintenance therapy. Conclusions: CGC appears to be a well-tolerated intravesical salvage chemotherapy regimen for the treatment of BCG-refractory NMIBC. Clinical trial information: NCT02202772. [Table: see text]

TPS450 Background: Pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) are aggressive diseases which account for the third and second leading causes of cancer-related death, respectively. Limited progress has been made towards effective treatments or cure. K RAS is mutated or amplified in nearly 30% of all cancers, including up to 95% of PDAC and 45% of CRC. Although no successful KRAS directed therapy has been approved to date, data has emerged demonstrating that inhibition of downstream targets of KRAS, namely MEK/ERK, increases autophagic flux in KRAS-mutated tumors. This catabolic process is used by many tumors to maintain viability and recent preclinical studies have shown that combining MEK/ERK and autophagy inhibitors in KRAS-mutated tumors can synergistically suppress cancer cell proliferation. Inhibition of autophagy has demonstrated an increase in antigen presentation which sensitize tumors to immune checkpoint inhibitors. Presented here is a trial-in-progress that will evaluate combination of cobimetinib (MEK inhibitor), atezolizumab (anti-PDL1), and hydroxychloroquine (autophagy inhibitor) in KRAS-mutated advanced malignancies. Methods: This is a phase 1/2 multicenter, open-label study of combination cobimetinib (40-60mg) orally once daily on days 1-21, hydroxychloroquine (600mg) orally twice daily on days 1-28, and atezolizumab 840 mg IV on days 1 and 15 of each 28 day cycle. Patients with histologically confirmed metastatic or unresectable KRAS-mutant adenocarcinoma for which standard curative or meaningful life-prolonging treatment options do not exist or are no longer effective will be enrolled. The primary objective of the phase I portion of this trial, which seeks to enroll 18 patients, is to estimate the maximum tolerated dose (MTD) of these agents using a two-stage time-to-event continual reassessment method (TITE-CRM). The primary objective of the phase II portion of this trial, which seeks to enroll approximately 66-157 patients, is to evaluate the preliminary efficacy of this combination, based on the objective response by 16 weeks. Secondary endpoints include PFS, OS, and safety. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, reverse phase protein array for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the phase I portion of the study. This study is open with 4 patients enrolled at the time of submission. Clinical trial information: NCT04214418 . This trial is being conducted as part of the imCORE collaboration. Clinical trial information: NCT04214418.