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Background: Surufatinib (S, a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) showed encouraging antitumor activity in solid tumors (Cao YS, 2022). Programmed death ligand 1 (PD-L1) expression is the established biomarker for 1L immune checkpoint inhibitors therapy in advanced NSCLC. We conducted an open-label, multi-cohort, single-arm phase 2 study to evaluate the safety and efficacy of S+T in patients (pts) with advanced solid tumors. Here, we reported the results of advanced NSCLC with PD-L1 positive expression cohort. Methods: Eligible pts had histologically confirmed advanced NSCLC with no prior systemic chemotherapy, PD-L1 positive (defined as PD-L1 TPS expression ≥1% [sp263]), and without EGFR, ALK or ROS1 genetic alteration if non-sq-NSCLC. Enrolled pts received 21-day cycles of S (250 mg orally QD) plus T (240 mg IV, Q3W) until disease progression or intolerable toxicity or the maximum duration of treatment with toripalimab is 24 months. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From July 2020 to September 2021, 55 pts were screened, of whom 23 pts were enrolled and received the treatment of S+T. Median age was 66 years (range: 49-73), 16 (69.6%) were male and 12 (52.2%) had squamous histology. Pts with PD-L1 TPS ≥50% and Conclusion: Surufatinib and toripalimab combination showed a promising antitumor activity in 1L therapy for advanced PD-L1 positive NSCLC with manageable toxicity. This study might represent a potential treatment option for these pts. Clinical trial information: NCT04169672. Citation Format: Ying Cheng, Lin Shen, Zhendong Chen, Feng Ye, Xianjun Yu, Xing Zhang, Dongmei Ji, Baorui Liu, Lijie Song, Chunjiao Wu, Ming Lu, Wei Chen, Jingxun Wu, Heli Gao, Desheng Weng, Weina Shen, Rutian Li, Minjie Yang, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Songhua Fan, Michael Shi, Weiguo Su. Surufatinib plus toripalimab for first-line treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 positive expression: A multicenter, single-arm phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT225.

Introduction: Bruton’s tyrosine kinase (BTK), a member of the Tec family, plays a crucial role in signaling through B-cell receptor (BCR). BTK inhibition blocks BCR signals and prevents B-cell activation and growth. First-generation BTK inhibitors such as ibrutinib covalently binds to a cysteine residue (C481) of BTK. Their most frequent acquired resistance is the development of a serine mutation in the binding site (C481S). Next generation BTK inhibitors such as LOXO-305 and ARQ 531 are being developed to overcome this resistance to first-generation inhibitors. Methods: HMPL-760 was tested in biochemical assays using recombinant human wild type (WT) and C481S mutant BTKs. Its selectivity was carried out using Eurofins Cerep KinaseProfilerTM panel. Cellular activity of HMPL-760 was evaluated in HEK293 cells stably transfected with BTKWT or BTKC481S, and other tumor cell lines, which are either human diffuse large B cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) cell lines. The in vivo antitumor activity and PKPD correlation of HMPL-760 was studied in HBL-1 xenograft mouse models bearing BTKWT or BTKC481S respectively. Results: In biochemical assays, HMPL-760 strongly inhibits BTK kinase activities towards wild-type BTK (BTKWT) and C481S mutant (BTKC481S), and binds to BTK in a reversible way. HMPL-760 demonstrates high selectivity in a panel containing 413 kinases. In cellular assays, HMPL-760 displays strong anti-proliferative activities in B-cell lymphoma cells (TMD-8, OCI-LY10, REC-1, HBL-1 and HBL-1-BTKC481S) harboring either BTKWT or BTKC481S (GI50: 0.0015-0.046 μM). In human whole blood assay, HMPL-760 inhibits activation of B-cells at nanomolar concentrations measured by inhibition of immunoglobulin-induced CD69 expression in CD19+cells. HMPL-760 shows ≥ 10-fold inhibitory potency than ARQ 531 in both BTKWT and BTKC481S cells, and ~3-fold higher inhibitory potency than that of LOXO-305 in BTKC481S cells. In cellular assay by detecting p-BTK after compound washout, HMPL-760 maintains a longer duration of target inhibition than LOXO-305 in both BTK wild type (HBL-1) and BTK mutant (HBL-1-BTKC481S) cell lines. HMPL-760 displays dose-dependent antitumor efficacy in multiple human B cell lymphoma xenograft models in mice when orally administered at 3~50 mg/kg once daily. Complete tumor regression occurs in most of the tested models at the high dose levels. HMPL-760 shows much stronger antitumor efficacy than LOXO-305 and ARQ 531 at similar dose level, which may be associated with HMPL-760’s higher drug exposures and more sustainable inhibition on BTK phosphorylation in the tumor tissues. Conclusion: HMPL-760 is a reversible, selective, highly potent, BTK inhibitor targeting both BTKWT and BTKC481S. The first-in-human Phase 1 clinical trials of HMPL-760 are under way in patients with r/r B-NHL (NCT05190068, NCT05176691). Citation Format: Linfang Wang, Junqing Liang, Zhihu Gao, Jia Hu, Weigang He, Xianwen Yang, Fangfang Mao, Wei Zhang, Ying Yu, Qihang Zhang, Na Yang, Chun Zhang, Jian Wang, Yu Cai, Xiong Li, Weiguo Qing, Guangxiu Dai, Yongxin Ren, Michael Shi, Weiguo Su. HMPL-760 is a highly potent and selective reversible BTK inhibitor, targeting BTK and BTKC481S in B-cell malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4020.

BackgroundMET exon 14 skipping mutation (METex14) is observed in ~3% of non-small cell lung cancer (NSCLC) cases and has been shown to be an independent poor prognostic factor associated with shorter overall disease-specific survival. Broad molecular testing can identify this biomarker in patients with advanced NSCLC (aNSCLC) and allow patients to be matched with the appropriate targeted therapy. This study examines biomarker testing patterns and clinical outcomes of chemotherapy and immuno-oncology (IO) monotherapy in aNSCLC patients with METex14.MethodsA descriptive retrospective study was conducted using the Flatiron Health–Foundation Medicine Inc. (FMI) clinico-genomic database. Patients with METex14 aNSCLC treated with systemic therapies were included in the biomarker testing analysis. The duration from specimen collection to reported results was assessed for PD-L1– and METex14-tested patients. Clinical outcomes were assessed in patients treated with chemotherapy or IO monotherapy. First-line (1L) and second-line (2L) real-world progression-free survival (rw-PFS) were estimated using Kaplan-Meier analysis.ResultsOf 91 METex14 patients eligible for the biomarker testing analysis, 77% and 60% received PD-L1 and FMI next-generation sequencing (NGS) testing within 3 months post aNSCLC diagnosis. Of those assessed for both PD-L1 and METex14 (n=9), the median duration between specimen collection and reporting was 1 week shorter for PD-L1 than for FMI NGS. Median 1L rw-PFS was 5.7 months (95% CI, 4.6-7.1) and 2.4 months (95% CI, 1.4-3.2) in patients receiving 1L chemotherapy (n=59) and IO monotherapy (n=18), with 3-month 1L rw-PFS rates of 78% and 33%. Median 2L rw-PFS was 3.5 months (95% CI, 1.9-11.1) and 4.7 months (95% CI, 2.8-12.9) in patients receiving 2L chemotherapy (n=16) and IO monotherapy (n=23), with 3-month 2L rw-PFS rates of 54% and 67%.ConclusionsThe median time from biopsy to test results appears 1 week shorter for PD-L1 than for FMI NGS. Chemotherapy and IO monotherapy were the most common regimens utilized but with limited PFS.

3023 Background: MSB0254 is a humanized vascular endothelial growth factor receptor 2 (VEGFR-2) monoclonal antibody. MSB0254 inhibits angiogenesis induced by either VEGF-A or –C. This trial is a phase I study to evaluate MSB0254’s safety, tolerability and PK profiles, as well as early anti-cancer activities in Chinese patients with advanced solid tumors. Methods: In this phase I study (NCT04381325), locally advanced or metastatic solid tumor patients failed previous standard treatments were enrolled. In the dose escalation phase, following 3+3 rules, MSB0254 was given intravenously Q2W (every 2 weeks) at 4mg/kg, 8mg/kg, 12mg/kg, 16mg/kg, and Q3W at 20mg/kg. In the dose expansion phase, patients with selected tumor types will be treated with MSB0254 at 16mg/kg Q2W or 20mg/kg Q3W. Primary objectives were to evaluate the safety and tolerability and to identify maximum tolerable dose (MTD) and/or Recommended Phase 2 Dose (RP2D). Secondary objectives included the assessment of pharmacokinetics, immunogenicity, and preliminary efficacy per RECIST1.1. Results: As of 10th Jan, 2022, a total of 22 Chinese patients have been enrolled into the dose escalation phase and treated with MSB0254 at different dose levels from 4-16mg/kg Q2W or 20mg/kg Q3W. MTD was not reached. One DLT was reported in 12mg/kg Q2W dose cohort. A subject with intra-cholangial carcinoma developed G3 (grade 3) upper gastrointestinal hemorrhage on the C1D13. The adverse event was resolved after symptomatic treatment. The most common treatment-emergent adverse events (TEAEs) (>10%) included: hypertension (27.3%), AST increased (27.3%), γ-GGT increased (22.7%), neutrophil count decreased (18.2%), proteinuria (18.2%), WBC count decreased (13.6%), platelet count decreased (13.6%) and anemia (13.6%). Three subjects (13.6%) experienced G3 TEAEs: 1 upper gastrointestinal hemorrhage, 1 anemia and 1 Hypertriglyceridemia. No G4/5 TEAE was observed. And three subjects (13.6%) experienced 3 SAEs: 1 upper gastrointestinal hemorrhage, 1 G2 intestinal obstruction caused hospitalization and 1 G2 fatigue caused hospitalization. MSB0254 displayed a dose proportional pharmacokinetic profile between 4-16 mg/kg Q2W with calculated T1/2 of 6-9 days. Eighteen subjects had at least one tumor assessment per RECIST 1.1 after MSB0254 treatment. Eleven subjects (61.1%) had best response of stable disease (SD). Four of them had stable disease for more than 6 months, including a neuroendocrine tumor (NET), a gastric cancer, an epithelioid hemangioendothelioma (EHE) and a submaxillary gland carcinoma patient. Conclusions: MSB0254 demonstrated a manageable safety profile and preliminary antitumor activity in patients with advanced solid tumors. 16mk/kg Q2W is recommended as RP2D. 20mg/kg Q3W is still under investigation. The study of MSB0254 on the expansion phase in selected tumor patients is ongoing. Clinical trial information: NCT04381325.

TPS375 Background: In normal conditions, Claudin (CLDN)18.2 is a tight junction protein with expression strictly confined to differentiated epithelial cells in gastric mucosa. CLDN18.2 has been found to be upregulated, and involved in tumor development and progression in a variety of tumor types such as gastric, pancreatic, and bile duct cancer (BTC). The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development. IMAB362 is the first anti-CLDN18.2 monoclonal antibody (mAb) of high potency to have been tested in humans and it revealed clinical efficacy in gastric cancer in a phase II study. TST001, a humanized IgG1 mAb, binds to a distinct epitope of CLDN18.2 with higher affinity and mediates CLDN18.2 expressing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) in comparison with IMAB362; Furthermore, TST001 is produced using an optimized glycoengineering process to increase affinity to FcR. The enhanced binding to CLDN18.2 on tumor cells and FcR on NK cells results in more efficient engagement of the tumor cells with NK cells and antibody mediated cellular cytotoxicity. In preclinical xenograft studies, TST001 displayed potent anti-tumor activities in the tumor models with medium to high level of CLDN18.2 expression and synergy anti-cancer effect with checkpoint inhibitor. A mAb specific for CLDN18.2 was also developed as an IHC based biomarker for patient enrollment in the clinical trials. Methods: This is an open-label, multi-center, phase I clinical trial to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK) profile and preliminary anti-cancer effect of TST001 in patients with locally advanced or metastatic solid tumors. (NCT04396821) The study consists of two parts: Part A is a 3+3 dose escalation design with sequential dose cohorts of 1, 3, 6, 10mg/kg in Q2W and Q3W schedules. Based on the emerging safety data, higher doses may be proposed for testing. About 27-54 patients will be enrolled. Dose expansion (Part B) will utilize doses of TST001 based on the emerging data from Part A. In Part B, up to 20 patients with CLDN18.2 overexpression per tumor specific cohort will be enrolled to 3 cohorts: A: TST001 single agent in gastric/gastroesophageal junction (G/GEJ) cancer; B: TST001 + nivolumab in G/GEJ cancer; C: TST001 single agent in pancreatic cancer or BTC. All patients in Part B will be selected by CLDN18.2 expression by central lab testing. The safety, anti-tumor activity, and PK will be further assessed in Part B. Enrolment began in July 2020 in the USA and is ongoing in multiple sites. As of 20 September, 2021, 23 subjects were dosed in Part A and the dose of 10mg/kg is being tested. Another phase I study of TST001 single agent and in combination with chemotherapy in patients with metastatic solid tumor is also ongoing in China (NCT04495296).

e14547 Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated. A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0–24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study. In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0–∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0–24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing. Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

Background Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib—a broad-targeted inhibitor of tyrosine kinases, including FGFR3—were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Methods Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant ( FGFR3 MUT ; n =12), wild-type ( FGFR3 WT ; n =31), or unknown ( n =1) FGFR3 status. Patients received 500mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results Most of the patients were men (75%) and over half of the patients were aged ⩾65years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3 MUT (0%; 95% confidence interval [CI], 0.0–26.5) and FGFR3 WT (3.2%; 95% CI, 0.1–16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.

Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. Experimental Design: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients. Clin Cancer Res; 19(5); 1257–68. ©2012 AACR.

Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that accounts for 3 to 5% of all invasive breast tumors in the United States. IBC possesses an increase of proangiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) as compared with non-IBC. In particular, FGF family receptors play a critical role in tumorigenesis, morphogenesis, and inducers of angiogenesis. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor with in vitro IC50 values of approximately 10 nmol/L against FGFR1-3, VEGFR1-3, and PDGFR. These structurally related receptors are important for the growth and survival of endothelial cells during tumor angiogenesis. Trial Design: This is a single institution, single arm phase II study. Patients receive a single daily oral dose of dovitinib 500 mg for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule). Eligibility: Patients have histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d’orange). Pathological evidence of dermal lymphatic invasion should be noted but is not required for diagnosis. HER2-negative. ECOG PS 0-2. Baseline MUGA or echocardiogram scans with LVEF of > 50%. Normal hematology, liver and kidney function laboratory studies. Patients must have received at least 2 chemotherapy lines for metastatic disease and have relapsed. Research Hypothesis: Dovitinib has antitumor activity in patients with HER2-negative advanced IBC. Specific Aims: Primary objective: to determine the disease control rate (CR, PR, and SD). Secondary objective: to evaluate safety profile. Exploratory biomarkers: circulating tumor cells (CTC), CTC undergoing EMT, and cancer stem cells Statistical Methods: The primary endpoint is the six-month disease control rate (ORR) as defined by RECIST 1.1. A response is anyone who experiences SD, CR or PR in the first 6 months. We will conduct this study with Simon’s two-stage design using the mini-max criterion and the response rate will be estimated accordingly. It is assumed that dovitinib will have a target ORR of 30%. An ORR of 10% or lower is considered a failure based on the typical ORR with a second line regimen for IBC and the new regimen will be rejected under this circumstance. When the probability of accepting a "bad" regimen (i.e. response rate < 10%) is 0.05 and the probability of rejecting a "good" regimen (i.e. response rate > 30%) is also 0.10, Simon’s design to minimize the maximum sample size requires 22 patients in the first stage. If two or less patients respond to the treatment, the trial will be stopped and the regimen will be declared as ineffective. If at least three of the first 22 patients respond to the treatment, 11 additional patients will be entered in the study to reach a total of 33 patients. By the end of the study, the new regimen will be rejected if response rate is less than or equal to 6 out of 33 patients and will be accepted otherwise. Present Accrual and Target Accrual: A total of 22 patients were accrued. Target accrual is 33 patients. Citation Format: Ricardo H Alvarez, Mariana Chavez-MacGregor, Joe Ensor, James L Murray, Kimberly Koenig, Savitri Krishnamurty, Antony Lucci, Gildy V Babiera, Wendy Woodward, Gary J Whitman, Summer A Jackson, Michael Shi, Kenneth Culver, James L Reuben, Naoto T Ueno, Vicente Valero. A phase II study of dovitinib as salvage therapy in patients with stage IV inflammatory breast cancer HER2-negative with local or distant relapse [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-15.

6597 Background: Gan (2013) reported that approximately 27% of 120 randomized phase III trials with a primary endpoint of OS had statistically significant outcomes. Ratain (2005) suggests that the ...

473 Background: In the GOLD trial, Dov did not improve progression-free survival (PFS) or overall survival (OS) over Sor. An exploratory objective of the study was to investigate plasma and tumor biomarkers to predict outcome. Methods: Plasma samples were obtained longitudinally throughout the study, and biomarkers were assessed by immunoassay. Primary archival tumor samples were assessed by immunohistochemistry. Log-rank tests, stratified by baseline MSKCC risk group, for difference in Kaplan-Meier curves between biomarker category (low/high based on

255 Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression. Methods: Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simon’s 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if ≥ 2 responses seen in stage 1). Results: A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in ≥ 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups. Conclusions: Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment. Clinical trial information: NCT00790426.

TPS4683 Background: Standard first- and second-line treatments in metastatic renal cell carcinoma (mRCC) target the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. However, signaling through other pathways, including the fibroblast growth factor receptor (FGFR) pathway, may account for tumor resistance to these standard therapies. Dovitinib (TKI258) is an oral FGF, VEGF, and platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor, with IC50 values of ≈ 10 nM. In a phase II study of 59 RCC patients, many of whom had failed prior VEGF-targeted and mTOR inhibitor therapies, dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) was well tolerated and demonstrated promising anti-tumor effects, with progression-free survival (PFS) of 5.5 months (Angevin et al, ASCO 2011). Methods: Approximately 550 patients from over 26 countries will be randomized 1:1 in this multicenter, open-label, randomized phase III trial (NCT01223027) to receive dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) or sorafenib (400 mg twice daily). Eligible mRCC patients must have failed 1 VEGF-targeted therapy and 1 mTOR inhibitor (disease progression on or within 6 months of stopping the prior treatment). Patients will remain on study until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover is planned. The primary endpoint is PFS as determined by central radiology assessment according to RECIST v1.1, with evaluations performed every 8 weeks. Secondary endpoints include overall survival, overall response rate, safety, patient-reported outcomes, and pharmacokinetics. The pharmacodynamic effects of dovitinib on plasma/serum biomarkers will also be explored. The data monitoring committee last reviewed the trial on 20 December 2011 and recommended that the trial continue as planned. This is the first third-line randomized clinical trial in mRCC to evaluate a multitargeted inhibitor of FGFR.

TPS4147 Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor that may rely on tumor angiogenesis for growth, invasion, and metastasis. Inhibition of the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) pathways temporarily prevents HCC tumor progression. However, because the fibroblast growth factor receptor (FGFR) pathway can serve as an escape pathway for these tumors, simultaneous inhibition of FGFR may be required to provide a sustainable antitumor response. Dovitinib (TKI258) has been shown to be a potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic factors, including FGFR, VEGFR, and PDGFR, with IC50 values of < 20 nM. Preclinical studies in HCC xenograft models have demonstrated that the antitumor effects of dovitinib are superior to those of the kinase inhibitor sorafenib, which is approved for use in advanced HCC. These data support additional testing of dovitinib in advanced HCC patients. Methods: This study (NCT01232296) is an open-label, randomized phase II trial being conducted at multiple centers in the Asia-Pacific region. Adult patients are eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C) with Child-Pugh class A cirrhotic status. Patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and cannot be eligible for (or have had disease progression after) surgical or locoregional therapies. Patients are randomized 1:1 to receive dovitinib (500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400 mg twice daily). Patients will be treated until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover will be permitted. The primary end point of this trial is overall survival. Secondary end points include time to tumor progression, disease control rate, time to definitive deterioration in ECOG status, safety, and pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib on plasma/serum biomarkers will also be explored. As of 30 January 2012, 93 of the planned 150 patients have been enrolled.

2543 Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]

Background: Adenoid Cystic Carcinoma (ACC) is an uncommon cancer of the head and neck which typically originates in the salivary glands. We and others have previously performed preclinical and clinical screens of FDA-approved and investigational agents in an attempt to identify useful therapies for ACC. However, to date no approved standard of care drug therapy exists. Fibroblast growth factors (FGF) and their receptors (FGFR 1–4) are a highly conserved group of functional proteins involved in cell migration, proliferation and survival and have been found important in initiation and progression of certain cancer types. Recently FGFR1 has been found over-expressed and phosphorylated in a majority of ACC tumors and FGF2, a known ligand of FGFR1, is a known downstream target of MYB which is rearranged in most ACC tumors. These data provide the rationale for testing the efficacy of FGFR inhibitors in ACC. Dovitinib (TKI-258) is an orally bioavailable multi-tyrosine kinase inhibitor (TKI) selectively targeting a number of proteins including VEGFR, PDGFR and FGFR. Preclinical and clinical activity of this agent has been demonstrated in solid tumors including breast and renal cancers. However, whether dovitinib is active towards ACC is unclear. Methods: We have developed and characterized a panel of patient-derived ACC tumor models including ACC×5M1, ACC×6, ACC×9, ACC×14 and ACC×16. To evaluate potential activity of dovitinib towards ACC we tested this agent alone and in combination with docetaxel, a taxane previously found active in our preclinical ACC screens, in these five models. Single agent and combination tumor growth inhibition was evaluated with a mean control tumor volume of 1cm3 or seventy-days following treatment initiation as study endpoints. Results: In these studies dovitinib was well tolerated at the evaluated treatment regimens. Dovitinib alone demonstrated statistically significant (p58%) and combination with docetaxel resulted in additive tumor growth inhibition in sensitive models, including partial and compete tumor responses in some models. Dose and schedule-dependent activity was also demonstrated with dovitinib in these studies. Conclusion: These results identify dovitinib as a potential treatment for ACC and suggest combination benefit with docetaxel. Based on these studies and correlative molecular characterization data clinical trials have been initiated to evaluate dovitinib in patients with ACC. These studies further demonstrate the utility of patient derived tumor models as translational tools for improved identification of potential anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B120.

4551 Background: Dovitinib is a potent oral inhibitor of angiogenic factors, including the fibroblast growth factor (FGFR) and vascular endothelial growth factor receptors (VEGFR). Phase (ph) I of ...

TPS186 Background: Dovitinib (TKI258) is an oral investigational drug that inhibits angiogenic factors, including the fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor...

Background: Endometrial carcinoma is the most common gynecological malignancy in the western world. Activating mutations of the fibroblast growth factor receptor 2 (FGFR2) have been described in 12-16% of endometrial cancers. Moreover, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are involved in the neovascularization, invasiveness, and metastatic potential of endometrial cancer. Therefore, suppression of FGFR/VEGFR/PDGFR signaling by TKI258 may represent a novel approach for treatment of endometrial cancer. Experimental Design: The aims of this study were 1.) to assess the effect of TKI258 on tumor cell growth in two-dimensional (2D) and three-dimensional (3D) culture assays using a panel of 20 human endometrial cancer cell lines, 2.) to identify candidate molecular markers predicting sensitivity using baseline gene expression profiling and mutational analyses, and 3.) to determine the in vivo antineoplastic activity of TKI258 in endometrial cancer xenograft models. In addition, we screened 200 fresh frozen endometrial cancer specimens to comprehensively assess the distribution pattern of PI3K, PTEN, and FGFR mutations in endometrial cancer. Results: Concentration-dependent anti-proliferative effects of TKI285 using 2D assays were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.42µM – 3.06 µM). The three most sensitive endometrial cancer cell lines demonstrated activating FGFR2 mutations (MFE296: N549K, IC50 0.42µM; AN3CA: N549K and K310R, IC50 0.50µM; MFE280: S252W, IC50 0.66µM). Assessment of TKI258 responses in 3D assays demonstrated similar results to those observed in 2D culture assays in that the 3 cell lines harboring FGFR2 mutations were the most sensitive to TKI258 achieving 100% growth inhibition at a concentration of 1µM. AN3CA and MFE296 endometrial cancer cells formed xenografts in nude mice and antitumor activity was studied in both models. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, pAKT and p-ERK1/2 were observed. Comprehensive data on the pattern of PI3K, PTEN and FGFR mutations in endometrial cancer will be provided. Conclusion: TKI258 demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations. This study provides a strong rationale for the clinical evaluation of TKI258 in patients with endometrial cancer, specifically in those harboring FGFR2 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2011-3589

3057 Background: TKI258 selectively targets FGFR1-3, in addition to VEGFR, PDGFR and other tyrosine kinases. FGF pathway has been reported as an important escape mechanism of anti-VEGFR therapies. ...

e18035 Background: ASA404 (vadimezan, DMXAA) is a flavonoid, non-tubulin-binding tumor-vascular disrupting agent (Tumor- VDA) that causes irreversible tumor vasculature disruption and extensive hemorrhagic necrosis of the tumor core. In combination with paclitaxel and carboplatin (P/C), ASA404 increased the median overall survival of previously untreated NSCLC patients from 8.8 to 14.0 months in a phase II clinical trial. Methods: A phase I trial assessed the safety profile and tolerability of three dose levels of ASA404 (600, 1,200, and 1,800 mg/m2) administered in combination with P/C (P, 200 mg/m2; C, AUC 6) every 3 weeks in Japanese patients with NSCLC. A panel of plasma biomarkers of angiogenesis and cytokines were evaluated to investigate the pharmacodynamic effect and mechanism of action (MOA) of ASA404. Plasma VEGF and basic FGF (bFGF) were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma IL-8 and macrophage chemotactic protein (MCP)1 were analyzed by Luminex beads plat...

Undifferentiated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and ubiquitously associated with Epstein-Barr virus (EBV) infection. AKT is frequently activated in NPC and PIK3CA amplification can be found in 40% of NPC tissues. BEZ235 is a dual inhibitor of PI3K and mTOR, which results in inhibition of downstream effectors AKT, S6 ribosomal protein and 4EBP1. The preclinical activity of BEZ235 was evaluated in 6 NPC cell lines (Table 1). Western Blot analysis showed all 6 NPC cell lines showed basal activation of AKT and mTOR. The effect of BEZ235 on cell growth was evaluated by exposing NPC cell lines to increasing concentrations of BEZ235 (0.1nM, 0.5nM, 1nM, 10nM, 100nM, 1µM& 10µM) for up to 72 hrs followed by MTT assay. Over 80% of growth inhibition was achieved in all NPC cell lines except C666-1 (∼70% inhibition), with the respective IC50 concentrations in the nanomolar range (Table 1). Two representative cell lines (HONE1-LMP-1 and CNE-2 cells) were selected for assessing the effect of BEZ235 on AKT-mTOR signaling, apoptosis, cell cycle and synergism with chemotherapy. Treatment of HONE1-LMP-1 and CNE-2 cells with BEZ235 at 5nM and 50nM for 24-48 hours, resulted in cell cycle arrest at G1 phase, apoptosis (indicated by the induction of PARP cleavage), and moderate reduction of cyclin D1 expression. After BEZ235 treatment, the expression level of phosphorylated (p-)AKT, pS6K, p4EBP-1 and p-mTOR were reduced, but the level of p-p44/42 MAPK was increased in both HONE1-LMP-1 and CNE-2 cells. No synergistic effect on growth inhibition was observed when HONE1-LMP-1 and CNE-2 cells were treated with concomitant BEZ235 and chemotherapy (cisplatin, or paclitaxel). Our preliminary result suggests that BEZ235 has promising activity in most NPC cells, while the increase in p-p44/42 MAPK observed in some cell lines suggest the presence of compensatory MAPK activation that have been previously described with mTORC1 inhibitors in other cancer types. Further investigations are warranted.Table 1: IC50 (growth)% growth inhibition by BEZ235% cells at G1 arrest after BEZ235 (5nM) treatment for 24hrsEBV-associated NPC cell linesHK1-LMP14.1nM∼85%-HONE-1-LMP14.9nM∼75%62%C666-19.5nM∼70%-Poorly-differentiated NPC cell linesHONE-16.4nM∼85%-CNE-25.7nM∼90%58%Well-differentiated NPC cell lineHK14.7nM∼90%- Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1638.

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]