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3603 Background: PEP503 (aka NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles that increases the energy deposition of radiotherapy. A phase 3 study in soft tissue sarcoma patients has significantly increased pCR and R0 when PEP503 was added to preop radiotherapy. This phase 1b/2 study was conducted with the aim to identify a recommended phase 2 dose (RP2D), and evaluate the efficacy of PEP503 intratumoral injection in combination with concurrent chemoradiation (CCRT) in patients with locally advanced rectal cancer (LARC). Methods: Patients with stage T3-T4 LARC (or with unresectable disease) suitable for neoadjuvant CCRT were enrolled. An intratumoral single administration of PEP503 (multiple punctures) was done 24 to 72 hours prior to IMRT of 50 Gy in 25 fractions of 2 Gy per fraction over 5-6 weeks with concurrent capecitabine or 5-FU. Traditional 3 + 3 design with 4 levels, 5%, 10%, 15%, and 22%, of the baseline GTV as measured by MRI, of PEP503 were assessed in Phase Ib. PEP503 nanoparticles intratumoral dispersion was analyzed by CT-scan. Surgery was performed 8 to 12 weeks after the completion of CCRT for patients with resectable tumors. Body kinetics was evaluated in Phase Ib. (ClinicalTrials.gov, NCT02465593) Results: Thirty-two (32) patients (male/female: 20/12; median age 62 years, range 38 to 76) were enrolled (1 dropped out before starting CCRT). In Phase 1b, 20 patients were treated and dose was escalated to 22%. RP2D was then determined as 22% with 6 patients treated at this dose level without DLT. Twelve (12) patients were included in the Phase 2. One (1) (3.2%) and 19 (61.3%) of evaluable patients (n = 31) had CR and PR, respectively, as the best tumor response across dose levels. No patient progressed as all evaluable patients (n = 31) achieved disease control for a DCR of 100%. Furthermore, twenty-five patients underwent surgery, of which 24 (96%) had microscopically clear resection margins and 5 of them (20%) had pathological complete response (pCR). The G3 AEs were diarrhea, ileus, thrombocytopenia, urosepsis, procedural haemorrhage, wound complication, hypokalaemia, and myalgia (all in 3.1%). No G4 AE were observed. The results of CT scans for nanoparticles dispersion demonstrated PEP503 remained within the tumor without leakage to the surrounding healthy tissues, before and after CCRT. In most patients, hafnium was not detected or below the Lower Limit of Quantification (LLOQ) in the circulation 60 minutes after PEP503 injection and was not found in urine. Conclusions: A single intratumoral injection of PEP503 in locally advanced or unresectable rectal adenocarcinoma undergoing capecitabine or 5-FU based CCRT is feasible and safe. The preliminary observed efficacy results may warrant further examination in larger clinical studies. Clinical trial information: NCT02465593.

66 Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers. Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected. Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed. Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan. Clinical trial information: NCT02465593.

Inflammatory myopathy is characterized by proximal muscle weakness which is highly suspected through an autoimmune pathogenesis. Extramuscular manifestations including fever, arthralgia, and pulmonary complications are common. 1 Diagnosis of both polymyositis (PM) and dermatomyositis (DM) relies on characteristic clinical manifestations, increased serum muscle enzymes, and a standard electromyography (EMG). Periorbital edema is often accompanied by a heliotrope rash. 1 However, subcutaneous edema in limbs is extremely rare. A literature search uncovered 33 cases of limb edema associated with inflammatory myopathy, of whom seven were localized edema, while the remaining were considered generalized edema. All seven patients with localized edema were diagnosed with DM. In this article, we report on a case of PM with localized subcutaneous edema and hepatocellular carcinoma (HCC). To the best of our knowledge, this is the first case of localized edema to be associated with PM.