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2044 Background: Management of advanced gliomas including glioblastoma multiforme (GBM) remains as an unmet medical need. Here we report our clinical experience with ACT001, or dimethylamino micheliolide, a synthesized derivative from parthenolide (a natural product of sesquiterpene lactone class), in Han Chinese patients with advanced glioma. Methods: Adult patients were enrolled in a 3+3 dose escalation phase 1 study with the following pre-defined ACT001 cohorts: 100mg, 200mg, 400mg, 600mg and 900mg, twice a day (BID). Pharmacokinetics and adverse events were evaluated during the study. Imaging studies were performed using RANO criteria to assess the therapeutic afficacy. Results: 16 patients with advanced glioma were enrolled in this single agent dose escalation study including 8 primary GBM, 4 astrocytoma (grade 2-3) and 4 other advanced glioma. The median age was 49 years (range: 31-70). Safety evaluation was performed in five cohorts and 13 of the 16 subjecst were evaluable for drug tolerability analysis. ACT001 was tolerated very well and no DLT or MTD was identified. Other than grade 1 adverse reactions (AE) in most cases and grade 2 AEs in other clinical findings, no drug-related grade 3 AE was noted. Pharmacokinetic analysis indicates that there was approximately linear correlate between the drug exposure (Cmax, AUC0-t and AUC0-inf) and study drug dosages evaluated. T1/2 is 4 hours with mean Cmax increased from approximate 300ng/ml to 5000ng/ml in a dose dependent manner with no significant dose accumulation during repeated dosing challenge. Post baseline MRI scans were performed in 11 out of 16 subjects. Among these 11 subjects, 1 GBM patient had a partial response (PR) at end of cycle 2 but had disease progressed at end of cycle 4; two non-GBM patients had a stable disease (SD) lasting for 5 or 6 cycles respectively before being taken off study due to disease pregression (PD) and other 8 patients had a PD. Of note, 9 out of these 11 subjects had stable or even improved clinical performance by the time they were taken off study due to PD. Five other subjects withdrew their consents or were taken off study due to clinical disease progression. Of note, subject S12 with diffusive astrocytoma was taken off study due to PD while still with a stable clinilcal performance and stereotactic biopsies targeting the progressed lesion didn’t reveal viable tumor tissues other than presence of macrophage/microglia. This subject was still alive 666 days after being taken off study. The mode of ACT001 actions is proposed to be at least partially related to its effects on tumor immune microenvironment. Conclusions: ACT001 was safe and tolerated well in patients. Clinical response was observed including a pathologic response in a subset of patients dosed at lower dose cohorts. iRANO criteria will be used in future studies based on its impacts on tumor immune microenvitonment. Clinical trial information: ChiCTR-OIC-17013604.

e15051 Background: Dysregulation of fibroblast growth factor receptor (FGFR) is strongly associated with establishment and progression of cancer. Pemigatinib is a selective FGFR1–3 inhibitor that are active in a targeted manner against cancers with activated FGFR pathway. The study was aimed at evaluating the tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of pemigatinib in Chinese patients (pts) with advanced malignancy. Moreover, potential efficacy of pemigatinib was explored in a broad spectrum of FGFR alteration in variety of cancer types. Methods: In this phase 1 study, Chinese patients with advanced, recurrent or metastatic malignancy that were histologically or cytologically confirmed and harboring FGF/ FGFR 1-3 variation were enrolled. Pemigatinib was self-administered orally at 13.5 mg QD on a 3-week cycle (2-weeks-on/1-week-off schedule). Adverse events and other safety factors were monitored throughout the study. Blood samples were obtained at prespecified time points for PK and PD analysis and efficacy was assessed every 9 weeks per RECIST v1.1 guideline. Results: As of Jan 31, 2021, 12 patients with 5 different cancer types (colorectal cancer (4 pts), gastric and gastroesophageal junction carcinoma (3 pts), cholangiocarcinoma (2 pts), esophageal carcinoma (2 pts) and breast cancer (1pts)) were enrolled. Documented FGF/ FGFR1-3 alterations were FGFR amplification (6), FGFR point mutation (5), FGFR2 fusion (2) and FGF alteration (4) with 2 subjects had more than one alteration types. All the subjects were failed to at least 1 line of prior standard therapy. All patients had at least 1 treatment related adverse events (TRAE) and the most common ones were hyperphosphatemia (100%), decreased appetite (50%) and diarrhea (33.3%). Two patients (16.7%) reported ≥ grade 3 TRAEs, which were hyponatremia (8.3%) and proteinuria (8.3%). There were no TEAEs leading to death or treatment discontinuation. Among 11 efficacy evaluable patients, 2 of them had partial responses (PR) as evaluated by investigators with 1 cholagiocarcinoma harboring FGFR2 point mutation (p.F276C) and the other esophageal carcinoma carrying FGFR1 mutation (p.A354V). 3 patients had a best overall response of stable disease (SD). The objective response rate (ORR) was 16.7% (95%CI: 2–48%) and disease control rate was 41.7% (95%CI: 15–72%). Conclusions: Pemigatinib had an acceptable and manageable toxicity and demonstrated a possible anti-cancer benefit in Chinese patients with advanced malignancy that accompanied with FGF/FGFR1-3 aberrance. A significant implication of the data is that it extended the population that potentially benefit from pemigatinib other than FGFR2 fusion/rearrangement. Clinical trial information: NCT04258527.

Background: CHOP is widely used for untreated PTCL patients (pts), although it has limited efficacy. Chidamide is an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC 1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. A Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in combination with CHOP (CHOP-chidamide) in the first-line treatment for PTCL pts. Results from the study are reported. Methods: This open-label, multicenter study enrolled pts (18~65 years) with previously untreated PTCL. Pts received one dose chidamide as the run-in treatment, and 4 days later the induction treatment of CHOP (6 cycles [each 21 days]) with chidamide on days 1, 4, 8 and 11. Pts who achieved a complete response or unconfirmed complete response (CR/CRu) at end of induction (EOI) received consolidation treatment with chidamide on days 1, 4, 8 and 11 every 21 days for 24 months maximum. A 3+3 design was employed in the chidamide dose-escalation stage with the starting dose at 20 mg. The first 21-day treatment cycle was a dose-limiting toxicities (DLTs) observation period (phase 1b; safety and pharmacokinetics), followed by a phase 2 cohort expansion stage. For pharmacokinetic (PK) evaluation, blood samples were collected at pre-dose and 1,2,4,8,12,24,48 and 72 h after the first dose of chidamide in the run-in period and in the first cycle of CHOP-chidamide. Primary endpoints were safety and tolerability of chidamide in combination with CHOP assessed by the incidence of adverse events (AEs) in both phase 1b and 2 and as DLTs during phase 1b. Secondary endpoint was efficacy as determined by the investigator. Results: Between Nov 15, 2016 and Aug 29, 2018, 30 pts were enrolled and received treatment. Pt demographics and disease characteristics are shown in Table 1. Fifteen pts were in the dose-escalation cohort and 15 in the expansion cohort (Table 2).One DLT with grade (Gr) 3 febrile neutropenia occurred in the first three enrolled pts in the 20 mg group, and 1 DLT with Gr 3 vascular access complication in the 35 mg group. Also, in the 35 mg group, 1 pt occurred Gr 2 neutropenia with sustained temperature >38℃, and the dose-escalation was stopped at this dose level. Serious AEs occurred in 7 (23.3%) of 30 pts during the combination treatment, including neutropenia (3 [10%]), leukopenia (2 [6.7%]), interstitial pneumonia (2 [6.7%]), thrombocytopenia (1 [3.3%]), febrile neutropenia (1 [3.3%]), pneumonia (1 [3.3%]), hyponatremia (1 [3.3%]), appendicitis (1 [3.3%]) and vascular access complication (1 [3.3%]). The most common (≥10%) Gr 3 or 4 treatment-related AEs were leukopenia (90%), neutropenia (83.3%), lymphocytopenia (40%), vomiting (13.3%), thrombocytopenia (10%) and febrile neutropenia (10%).No fatal AEs were reported. There were no apparently remarkable differences in frequency and intensity of AEs in pts between chidamide dose groups of 20 mg, 25 mg and 30 mg. Among 28 pts evaluable for response, 13 pts (46.4%) had a CR/CRu, 10 pts (35.7%) had a partial response, 1 pt (3.6%) had stable disease, and 4 pts (14.3%) had progressive disease (Table 3). Fifteen pts entered the consolidation phase (13 pts with CR/CRu, 1 pt with PR, 1 pt not evaluable), and the median treatment time was 189 days (35, 483). There was no AE leading to consolidation discontinuation. Progression-free survival (PFS) and overall survival (OS) at 12 months were 54.3% and 100%. At the data cutoff (Jan 8, 2019), median PFS was 14 months and median OS was not achieved. A total of 16 pts were evaluated in the PK analysis. Over the dose range from 20 to 35 mg, a linear and dose-dependent PK profile of chidamide was characterized in both monotherapy and combination treatment. In addition, co-administration of chidamide and CHOP did not significantly affect the plasma exposure of chidamide, with geometric mean ratio (combination vs monotherapy) values for Cmax and AUC were 97.6% (73.6%, 129.2%) and 97.9% (78.4%, 122.2%), respectively. Conclusions: The combination of 20mg to 30 mg chidamide to a standard 3-week cycle of CHOP chemotherapy showed a manageable safety profile and favourable antitumour activity in pts with previously untreated PTCL. This combination could be further explored in comparison to CHOP alone in a randomized trial. CHOP-chidamide did not significantly alter the chidamide pharmacokinetics. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Chidamideis an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. This Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in previously untreated PTCL patients.