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e14560 Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m2, a mean BSA of 1.7 m2, and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

3603 Background: Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Here we report the results of the expansion portion of a Phase 1 study of advanced solid tumors patients (pts) harboring an FGFR1-3 gene fusion. Methods: Pts with advanced refractory solid tumors harboring an FGFR1-3 gene fusion were enrolled. Based on results from the dose escalation portion, pts received Debio1347 80 mg once daily (qd) in 28-day cycles. Pharmacokinetics (PK) and pharmacodynamics were evaluated. The data cut-off was October 8, 2019. Results: Among 18 pts enrolled, 5 had primary brain tumors (PBT), 5 had cholangiocarcinoma, 2 had urothelial cancer, 2 had colon cancer, 1 patient each lung neoplasm, gastric cancer, endometrial cancer and squamous cell carcinoma of the chest wall. Tumors harbored fusions with FGFR1 (n = 1), FGFR2 (n = 8), and FGFR3 (n = 9). All had prior systemic therapy (median 3 lines; range 1-4). The most common treatment emergent adverse events were fatigue (50%), hyperphosphatemia (44.4%), anemia (38.9%), alopecia (33.3%), nausea (33.3%), vomiting (33.3%), constipation (33.3%), and palmar-plantar erythrodysesthesia syndrome (22.2%). Blurred vision was reported in 1 pt. There were no findings on ocular exams compatible with retinal detachment. No grade 3 AE related to study drug were reported. One patient needed dose reduction due to grade 2 nails toxicity. In PK analysis, plasma steady-state was rapidly achieved and serum phosphate increase correlated with Debio 1347 plasma exposure, confirming target engagement at 80 mg qd. Median follow-up was 18 weeks. Partial responses were observed in 3 pts harboring an FGFR2 fusion: 1 out of 2 colon cancer and 2 out 5 cholangiocarcinoma. Median duration of response was 16.1 weeks (range: 8.4-22.8+). Overall disease control was observed in 11 out of 14 pts without PBT (79%). Median PFS was 18.3 weeks. No signs of activity were observed in the 5 patients with PBT, all with an FGFR3-TACC3 fusion. Conclusions: Debio 1347 at the recommended dose of 80 mg qd was generally well tolerated and showed signs of activity in solid tumors harboring an FGFR fusion. The FUZE phase 2 clinical trial of Debio 1347 is recruiting FGFR fusion-positive advanced solid tumors irrespectively of tumor histology, excluding PBT. Clinical trial information: NCT01948297 .

1084 Background: Intravenous (IV) paclitaxel is an effective treatment for breast cancer. Oral administration paclitaxel is preferable to IV regarding minimizing IV injections, anaphylactic reactions to cremaphor, steroid pre-medications, hospital visits, and relevant costs. However, paclitaxel has poor oral absorption due to active excretion by P-glycoprotein (P-gp) in the intestinal cells. Oraxol (Athenex, USA) is an oral paclitaxel and HM30181, a novel oral inhibitor of intestinal P-gp which enables the oral administration of paclitaxel. We report the final results of a pharmacokinetics (PK) study, including clinical response and tolerability of Oraxol in treatment of metastatic breast cancer patients. Methods: Multicenter, single-arm, open-label, PK study of Oraxol (HM30181A at 15mg, plus oral paclitaxel 205mg/m2) administered orally for 3 consecutive days weekly for up to 16 weeks. Paclitaxel PK was assessed at week-1 and week-4. Tumor Response was measured at weeks 8 and 16 using RECIST criteria 1.1. Toxicity was assessed using CTCAE v4.03. Results: Twenty-eight MBC patient were studied with a mean age of 56.6 years (range: 38 - 79 yrs). 26 patients had failed mutiple previous chemotherapies. There were 11 (42.3%) partial response, 12 (46.2%) stable disease and 3 (11.5%) progressive disease in 26 evaluable patients. Three patients had treatment-related SAEs (grade ≥3 neutropenia) and all patients recovered completely. PK results showed that the AUC of oral paclitaxel at week-1 was reproducible at week-4 (3050 to 3594 ng-hr/mL). Conclusions: Oral paclitaxel showed very encouraging anti-cancer activity in MBC patients who failed previous chemotherapies with acceptable toxicity. Weekly oral paclitaxel can achieve paclitaxel exposure similar to that of weekly IV paclitaxel (80mg/m2) reported previously. PK of oral paclitaxel is reproducible. Clinical trial information: NCT03165955.

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

8062 Background: No approved therapy exists for NSCLC patients (pts) who have failed chemotherapy (CT) and the reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), erlotinib (E) or gefitinib (G). The efficacy of BIBW 2992 (Tovok), a potent, irreversible inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) with preclinical activity against the secondary resistance mutation T790M, in pts progressing after initial clinical benefit on E/G is being assessed in this randomized trial. Methods: Pts with advanced adenocarcinoma of the lung (Stage IIIB/IV; ECOG 0–2), who have failed one or two lines of CT (including platinum) and progressed following at least 12 weeks of E or G are randomized in a 2:1 ratio to receive BSC plus either oral BIBW 2992 50 mg qd or placebo until disease progression or unacceptable toxicity. Primary endpoint is overall survival, with progression-free survival, objective response and clinical benefit rate and duration, safety and quality of life being secondary endpoints. Enrollment of 400 pts is planned (HR=0.70, 85% power). An unblinded interim analysis of tumor response and safety by the independent Data Monitoring Committee (DMC) after the first 40 evaluable pts treated with BIBW 2992 will determine continuation to full accrual. Results: From May to November 2008, 145 pts have been randomized and 76 are still on treatment. Demographics (n=145): median age 59 (range: 30–82); female 68%, current/ex-smokers 38%; metastatic disease 91%, ECOG 0–1 92%; Asian origin 68%. 50% had one prior line of CT. Main prior EGFR-TKI was G in Asians (70%) and E in non-Asians (85%). 40% of pts had achieved a PR or CR on previous treatment with E/G. Duration of prior E/G treatment was >24 weeks and >48 weeks in 80% and 40% of pts, respectively. As expected, diarrhea, rash, anorexia, stomatitis, paronychia, nausea and vomiting were the most frequently observed adverse events. Conclusions: The trial is continuing recruitment after DMC review of efficacy and safety and updated demographics and blinded safety data will be reported. [Table: see text]

10688 Background: To determine the overall objective response rate (ORR) of Lipo-Dox plus Gemcitabine in patients with metastatic breast cancer. Patients and Methods: We are conducting an open-label, non-comparative phase II clinical trial in Simon’s 2-stage optimal design to assess the efficacy and the safety of the treatment with Gemcitabine (Gems) plus Liposomal Doxorubicin (Lipo-Dox) in patients with metastatic breast cancer. All eligible subjects received Lipo-Dox 25 mg/m2 intravenous infusion over 1 hr and follow by gemcitabine 800 mg/m2 intravenously (iv) over 30 minutes on day 1, and receive gemcitabine 800 mg/m2 intravenously (iv) over 30 minutes only on day 8 in a 21-day cycle. Results: Between July 2004 and December 2005, a total of 21 patients were enrolled in the study and total of 136 cycles of chemotherapy were delivered with a median of six per patients (range 1–16). 17 patients (80.8%) who had at least one post-treatment evaluation and exposed to at least two cycles of treatment were included in this report. Characteristics of the 17 patients: All females; median age 52 years (range 36 - 68); 16 pts had a performance status (PS) of 0 or 1 and 1 had a PS of 2 (ECOG scale); Histology: All metastatic breast cancer. The response assessment of the 17 patients: Complete response was observed in 2, partial response in 5, stable disease in 8, and progressive disease in 2 patients. Overall response rate was 41.17%. Major grade 3/4 hematological toxicities were neutropenia in 9 pts, thrombocytopenia in 2 pt and leukopenia in 5 pts. Peripheral neuropathy was noted in 1 patient (grade 2). Other toxicities occurred during the treatment cycles were all manageable or tolerable. Patient recruitment, treatment and follow-up are still ongoing. Conclusion: Liposomal Doxorubicin used in the regimen reduces the incidence of alopecia (hair loss) to grade 1 compare to the conventional doxorubicin. This study, with an overall response rate of 41.1% (CR+PR) and a rate of stable disease of 47.05%, has shown a good activity with mild and acceptable toxicities of Gemcitabine (Gems) plus Liposomal Doxorubicin (Lipo-Dox) regimen in patients with metastatic breast cancer. No significant financial relationships to disclose.

4156 Background: To evaluate the response rate and safety of weekly paclitaxel (Taxol) combination chemotherapy with UFT (tegafur, an oral 5-fluorouracil prodrug, and uracil at a 1:4 molar ratio) a...