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Background Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1–4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors. Patients and methods Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8–200 mg futibatinib three times a week (t.i.w.) or 4–24 mg once daily (q.d.). Results A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure–response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%). Conclusions Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D. Clinical trial registration FOENIX-101 (ClinicalTrials.gov, NCT02052778).

Background In 2013, the French National Cancer Institute initiated the AcSe program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). Patients and methods Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. Results From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. Conclusions Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. Clinical trial number NCT02034981.

Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.

Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in Phase I trials among patients aged over 75 years with that observed in younger patients. Patients treated from 2007 to 2012 at Institut Gustave Roussy in Phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged >75 years) matched with patients aged

Background Primary brain tumors are highly heterogeneous and current therapy confers only modest clinical benefit. There is a tremendous need for new therapeutic options and genomic profiling could help defining new strategies. Methods Data from patients with advanced primary brain tumors enrolled in the prospective clinical trial MOSCATO at the Drug Development Department (DITEP) at Gustave Roussy Cancer Center were retrospectively reviewed. Multiple high throughput molecular techniques were used to identify genetic mutations: Next Generation Sequencing (NGS), comparative genomic hybridization array (CGHa) and Foundation one CDx (FMI). Matched therapy was decided accordingly for patients who had targeted molecular alterations. Results Between April 2016 and December 2018, 103 patients with primary brain tumors were enrolled. Median age was 48 years (range, 19-75), median number of previous systemic therapies was 2 (range, 0–5), 98% had an ECOG performance status 0 or 1. The most prevalent histology was glioblastoma (70 %). Ten patients were screen failure due to unavailability of tumor tissue and no possibility of new brain biopsy. Eighty-nine molecular analyses were successful (CGH: N = 45, NGS: N = 47, FMI: N = 42). Median time between consent and results was 49 days (range, 18-235). Tumor mutational burden (TMB) was available in 42 pts and was considered low ( Conclusions Molecular profiling in patients with primary brain tumors is feasible and can lead to orientation in clinical trials and/or treatment with targeted therapies. However the reasons for the small number of patients finally treated are currently under investigations and will be presented at the conference. Legal entity responsible for the study Christophe Massard. Funding Institut Gustave Roussy. Disclosure C. Baldini: Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Abbvie; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen; Speaker Bureau / Expert testimony: Sanofi. L. Verlingue: Speaker Bureau / Expert testimony: Adaptherapy; Speaker Bureau / Expert testimony: Pierre Fabre; Research grant / Funding (self): BMS. E. Angevin: Advisory / Consultancy: Merck; Advisory / Consultancy: GSK; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Abbvie; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Pfizer. A. Varga: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Astra Zeeneca; Speaker Bureau / Expert testimony: MSD. S. Postel Vinay: Research grant / Funding (self): Merck; Research grant / Funding (self): Boehringer; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. A. Gazzah: Travel / Accommodation / Expenses: Boehringer; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Novartis. R. Bahleda: Travel / Accommodation / Expenses: Taiho; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Boehringer. A. Marabelle: Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Onxeo; Advisory / Consultancy: EISAI; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Genticel; Advisory / Consultancy: Rigontec; Advisory / Consultancy: Diachii; Advisory / Consultancy: Imaxio; Advisory / Consultancy: Sanofi; Advisory / Consultancy: BioNtech; Advisory / Consultancy: Corvus; Advisory / Consultancy: Deerfield; Advisory / Consultancy: Bioncotech; Research grant / Funding (self): Merus; Research grant / Funding (self): BMS; Research grant / Funding (self): Boehringer; Research grant / Funding (self): Transgene. V. Ribrag: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Nanostring Technologies; Speaker Bureau / Expert testimony: Servier; Honoraria (self): Eisai. S. Champiat: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Janssen. J. Michot: Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Janssen. A. Hollebecque: Advisory / Consultancy: Amgen; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Lilly; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Lilly; Speaker Bureau / Expert testimony: Bayer. J. Soria: Full / Part-time employment: Medimmune. C. Massard: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Beigene; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Debiopharm; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Lilly; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.

This paper presents results from the phase I study of the focal adhesion kinase inhibitor GSK2256098 in patients with advanced solid tumors. The MTD was identified as 1000 mg, oral BID. Treatment with GSK2256098 showed a good tolerability, evidence of target engagement, and clinical activity in patients with recurrent, merlin-negative mesothelioma. Background Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. Patients and methods The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. Results Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21–84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1–2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4–9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (−26%) and three patients with mesothelioma (−13%, −15%, and −17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). Conclusions GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Background Malignant pleural mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase 1 trials appear as a rationale alternative. Materials and methods MPM patients were enrolled in 20 different phase 1 trials between March 2005 and January 2012, and their data analyzed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, overall survival (OS) and progression free survival (PFS). OS and PFS were estimated using Kaplan–Meier and their association with baseline characteristics was investigated through a log-rank test. The drugs described were divided into 5 groups based on their mechanism of action. Results Forty-five patients were analyzed with a median follow up of 20.5 months. The best tumor response was as follows: 4% of patients had a RECIST partial response, 60% had stable disease, 24% had progressive disease and 11% were not evaluable. Grade ≥3 toxicities were observed in 19 (42%) patients. Median OS and PFS were estimated to 6 months (95% CI = [4.2–10.5]) and 2 months (95% CI = [1.3–2.7]), respectively. The cellular motility inhibitors group appeared as the most promising class to be developed in a phase 2 setting. Conclusion Including MPM patients in phase I trials beyond first line of treatment can result in modest clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies need to be tested.

BACKGROUND Participation of glioma patients in early phase clinical trials has recently shown to be safe, although clinical benefits reported in this population were marginal. We aimed to evaluate whether an enrichment strategy based on molecular profiling associates with improved outcome in gliomas patients participating in early phase trials. MATERIAL AND METHODS Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2017 were analyzed for clinicopathological characteristics, toxicity, response, median progression-free survival (PFS) and overall survival (OS). The primary objective was to evaluate the feasibility and benefit of using molecular profiling to guide enrollment. RESULTS Ninety-one patients were enrolled, of whom 47/91 (51.6%) were molecularly oriented. Molecular targets included IDH1/2 (n=15) and BRAF (11) mutations, FGFR1-3 fusions (n= 10) and mutations (n = 4), mismatch repair deficiency (8), and MDM2 amplification (1). Grade 3/4 adverse events were reported in 9/91 (9.9%) patients. In patients with IDH1/2-wild-type high-grade glioma (n=45), the overall response rate (24.0% [95% CI 11.5–43.4] vs 0.0% [95% CI 0.0–16.1], P=0.027) was significantly higher in molecularly-oriented vs non-molecularly-oriented patients. Updated outcome results, and clinical and molecular factors associated with response, PFS and OS in multivariate analyses will be presented at the conference. CONCLUSION Using molecular profiling to guide enrollment in early phase trials is feasible and offers potential benefit to gliomas patients. Further studies are warranted to identify the population most likely to benefit from this approach.

Background The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. Methods This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma. EMD 534085 (starting dose 2 mg/m2/day) was administered intravenously every 3 weeks. Doses were escalated in 100 % steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50 % until the first dose-limiting toxicity (DLT) arose. If

Background The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side-effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). Case presentation We describe four cases of patients with cancer who developed AKI after starting mTOR inhibitor therapy. A kidney biopsy showed acute tubular necrosis (ATN) with prominent tubular dysfunction. Withdrawal of the drug leads to a rapid recovery in two cases. However, a fixed renal dysfunction was noted in the other two cases, one of which will remain dialysis-dependent. Such patients lead to a broad differential diagnosis of AKI including prerenal AKI, ATN, cancer-related GN, and drug-induced acute interstitial nephritis. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. Conclusions ATN have not been reported with mTOR inhibitor use. These cases demonstrated a potentially new and serious adverse consequence occurring with the use of an mTOR inhibitor, of which physicians need to be aware.

Aim: To analyze the clinical features and outcomes of advanced non-small cell lung cancer (NSCLC) patients treated in phase I trials. Patients and Methods: The clinical characteristics, efficacy and toxicity data of 70 pretreated NSCLC patients enrolled in 17 phase I trials between January 2005 and June 2010 were analyzed at our institution. Results: The histological types were: adenocarcinoma (79%), squamous cell carcinoma (13%), and others. Patients received a median number of 3 prior lines of treatment before inclusion. 1 complete response (CR), 11 (16%) partial responses (PRs), and 29 (41%) stable diseases (SDs) were observed (according to Response Evaluation Criteria in Solid Tumors (RECIST)). The median overall survival (OS) time was 18 months and the median progression-free survival (PFS) time was 4.1 months. The median PFS of these patients within their prior therapy line before phase I inclusion was 4.3 months. A performance status score of 0 and the number of prior lines of treatment were significant for OS and PFS in multivariate analysis, respectively. Grade 3/4 toxicities were observed in 20 (27%) patients, and there was 1 treatment-related death. Conclusion: Patients in good general condition and with limited pretreatment derived an improved benefit, suggesting that phase I studies may be a valid option for pretreated NSCLC patients.

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.

Background Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. Patients and methods From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. Results Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridizartion array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. Conclusions In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

Objectives Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options. The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients with TEN enrolled in Phase I trials. Materials and methods We reviewed retrospectively patients with advanced TEN enrolled in Phase I trials at Gustave Roussy (DITEP) between 1994 and 2012. Efficacy was assessed using RECIST version 1.1. Results Twenty-two treated patients were enrolled (15 with thymic carcinoma, 7 with thymoma). The median number of prior systemic therapies was 2 (0–8). The median age was 50 years (range 23–72), and 4 females were treated. Treatments received encompassed mTOR inhibitor (mTORi) in 4 of patients, antiangiogenic agents (AA) in 11 patients, and other targeted therapies in 7 patients. 18% had grade 3-4 toxicity, 85% all grade toxicity and no toxic death was reported. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 patients had stable disease (median 6.6 months; range 1.0–30.7) and 2 had a progressive disease. The median overall survival was 54.5 months (95% CI 25–75.50). The median progression free survival (PFS) was 6.6 months (95% CI 1.35–11.59). Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. Conclusion Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response and warrant further investigation.

Author Summary Background. This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods. In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50–600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results. Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion. Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.

Background Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. Methods This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). Results Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31–40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. Conclusion Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.

The oncology community usually perceives phase I oncology trials as associated with poor or limited benefits and substantial risks. There is scarce data concerning outcome and survival of patients enrolled in current phase I oncology trials.We reviewed all phase I oncology trials conducted by investigators from the Adult Phase I Unit at Institut Gustave Roussy from 2003 to 2006. We report data concerning patient demographics, treatment outcome, toxicity, survival and type of care after trial exit.We analyzed 10 trials involving 180 participants. The overall response rate was 7.2%. Disease control (objective response plus stable disease) was achieved in 48.2% of patients. The rate of toxic death was 0.5%. In all, 38% of patients had at least one episode of grade 3 or 4 toxic events. The median progression-free survival and the median overall survival (OS) were 2.3 and 8.7 months, respectively. On multivariate analysis, a time between diagnosis of disease and inclusion in the phase I trial > or =24 months and evidence of disease control were statistically significant predictors of improved OS.Current phase I oncology trials are safe and are associated with clinical benefit in a substantial proportion of patients.

Background: Treating relapsed/refractory lymphoma remains a challenge. While phase 1 trials classically aim to determine the recommended phase 2 dose (RP2D), the search of anti-tumor activity is increasingly evaluated. We aimed to assess the tolerance and efficacy of phase 1 trial and to determine a simple scoring system to identify patients who will prematurely discontinue phase 1 studies (before six weeks), in a large cohort of patients with relapsed/refractory lymphoma. Patients and Methods: Data from 105 consecutive patients with relapsed/refractory lymphoma treated within a panel of 17 phase 1 trials were collected, between 2008 and 2014. At inclusion, median age was 66 years [range: 23-83]. Lymphoma histological patient's types were: 58 (55%) aggressive non-Hodgkin lymphoma (34 diffuse large B-cell lymphoma, 7 T-cell lymphoma and 17 Mantle cell lymphoma), 31 (30%) indolent non-Hodgkin lymphoma and 16 (15%) Hodgkin lymphoma. The predefined Gustave Roussy (GR) score combined two simple variables, PS and baseline serum albumin (+1 if PS = 0, +1 if albumin ≤ 35g/l). Results: Grade 3 or 4 adverse events were experienced by 40/105 (38%) patients. With a median follow-up of 10 months, median OS and progression free survival (PFS) were respectively 19 (CI95%: 12-37) and 4 (CI95%: 2-5) months. Best overall response rate and disease control rate were 22% and 56%, respectively. Histological type's analysis shown median OS was 10, 45 and 47 months in aggressive-NHL, Hodgkin and indolent-NHL, respectively (p 0, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L were significantly associated with poorer OS. Patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months vs 17 months vs 9 months; p = 0.007). A premature study discontinuation was recorded in 28/105 patients (27%). The GR score distinguishes patients most likely to remain on study for more than 6 weeks. Conclusion: The three parameters WHO performance status (PS) > 0, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L are associated with OS and premature withdrew of study. Both PFS and OS survival curves demonstrates a plateau, in favor of therapeutic effect potentially maintained.

Background Amplification of the FGFR1 gene occurs in subsets of tumors, notably breast cancer (BC), where the altered FGF pathway may be clinically relevant. Methods E-3810 is a kinase inhibitor targeting FGFR1 and VEGFR1, 2, 3. Its safety and activity, at the daily oral dose of 20 or 15 mg on a continuous schedule, are being assessed in patients with solid tumors and FGFR1 amplification or potentially sensitive to antiangiogenic agents. The study is an open label non comparative extension of the first in man dose-escalation trial; the efficacy threshold, set for the FGFR1+ cohort only, requires 3/14 confirmed objective RECIST responses or non-progressive disease ≥ 6 cycles (one-stage Fleming design: H0 5%, H1 30%, power 80%). Results 46 patients with various tumor types (including 13 FGFR1+) were recruited. 8 patients (4/13 and 4/33 treated respectively at 20 and 15 mg; none in the FGFR1+ cohort) were withdrawn for toxicity including: G3 proteinuria (5), headache and vomiting (2), pancreatic enzymes increase (1), recovered in all cases. Hypertension G2-3, proteinuria G2, GI intolerance, asthenia and weight loss led to dose reduction in 20 patients; frequent TSH increase required supplementation. Tolerability was better in the FGFR1+ cohort, in line with a limited prior exposure to antiangiogenic treatments. Antitumor activity is shown in the table: Antiangiogenic Sensitive FGF-amplified (1) Evaluable PR SD PD Evaluable PR SD PD Breast cancer 1 1 9 4** 3 2 Other 23 3*** 13 7 2 1* 1 Total 24 3 14 7 11 4 4 3 (1) incl. the two BC patients with 11q amplification; * SD ≥ 24 weeks; ** 1 PET response (bone lesions); ***2 thyroid; 1 thymic carcinoma. 12 women with BC were recruited (9 HR + , 1 HER2 + /HR + , 2 TN); 8 were FGFR1 + , 2 more had 11q amplification (CGH). They were treated with a median of 5 prior chemotherapy lines; 9, 10 and 5 patients also received ≥ 1 endocrine, antiangiogenic and experimental therapies, respectively. There were 4 PRs sustained over 4-6 courses (3 FGFR1 and one FGF4 amplification), with 3 responders still on treatment. Conclusions E-3810 has shown significant activity in heavily pretreated BC, with durable responses in patients with altered FGF pathway. Further studies are planned in this population. Disclosure R. Cereda: Currently an employee and stock holder at EOS SpA. M.G. Camboni: Currently an employee and stock holder at EOS SpA. All other authors have declared no conflicts of interest.

Background: S 49076 is a novel ATP-competitive tyrosine kinase inhibitor which displays a unique profile targeting MET, AXL and FGFR-1/2/3 (IC50 for inhibition of pathway activation was Methods: Pts are enrolled on dose-escalation cohorts, using a “3+3” design. Two dosing regimens of S 49076 administration (once a day, QD, or twice a day, BID) are tested in this study, in which pts receive oral capsule(s) of S 49076 during a continuous 21-day cycle. The PK measurements are performed at D1 and at steady state. Tumor biopsies for genomic and proteomic analyses are taken predose and on treatment. Tumor response is measured once every 2 cycles. Results: To date 49 pts have been treated at doses ranging from 15 to 270 mg QD or 7.5 to 225 mg BID. Median age is 59 years, and the most common tumor types are colorectal, NSCLC and uveal melanoma. The most frequent adverse events reported as treatment-related by the investigator have been hypomagnesemia, peripheral edema and hypoalbuminemia mostly grade (G) 1-2. Three DLTs were observed, including failure to restart S 49076 within 1 week due to G2 asymptomatic ejection fraction decrease in 30 mg QD and 225 mg BID cohorts and G3 hypotension in the 180 mg BID cohort. MTD has not been reached and the dose escalation is ongoing. Among 37 evaluable pts, 20 pts had stable disease (SD) ranging from 6 to 36 weeks of whom 3 pts with uveal melanoma had prolonged SD from 12 to 24 weeks. Preliminary PK analyses showed that the maximal plasma concentration (Cmax) occurred between 2h and 6h after oral administration. The bioavailability was estimated to be around 30% and the effective half-life around 15h. There was no evidence of non-linearity since Cmax and AUC24h increased proportionally over the range of doses tested and no evidence of time dependent PK. Based on PK data, the plasma concentrations reached in human at the higher doses are consistent with inhibition of the S 49076 targets MET, AXL and FGFR. Conclusions: The general safety profile of oral treatment with S 49076 is good at the doses tested. PK data suggest dose proportionality in exposure without marked drug accumulation. S 49076 has demonstrated preliminary anti-tumor activity, especially in uveal melanoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C65. Citation Format: Antoine Hollebecque, Jean-Charles Soria, Ratislav Bahleda, Natividad Lopez-Busto, Anne Jacquet-Bescond, Mike F. Burbridge, Cattan Valérie, Jeanne Pauly, Maria Herranz, Analia Azaro, Stéphane Depil, Jordi Rodon. First-in-human Phase I dose-escalation study of a MET/AXL/FGFR inhibitor, S 49076, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C65.

4574 Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a recent VEGFR inhibitor P with B in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This double center trial was conducted with 3+3+3 escalation doses of P + B. The maximum tolerated dose (MTD) was the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. After preliminary DLT results, an approved by IDSMB extension cohort was enrolled and treated at MTD level.The effect of B on steady-state pharmacokinetic (PK) of P was also investigated by comparing PK at day 1 (D1) and D15 (day of B infusion). Results: 25 pts were enrolled with mRCC (n=7) or other advanced refractory solid tumors (n=18). Median age is 62 (41-79), 14 pts are male. At DL2 (n=10) 3 nephrectomized and 2 non-nephrectomized pts experienced DLT, as presented in the Table. In the 6-non-nephrectomized-pt extension cohort at DL1, 3 additional DLT were observed. Mean P AUC at D1 was higher than previously described in phase I P monotherapy (Clin Cancer Res 2009;15:4220). Mean P AUC at steady-state (D15) at both P dose levels was also significantly higher, though without being influenced by B infusion. Conclusions: The MTD of the P + B combination is respectively 400 mg/d and 7.5mg/kg (DL1) in all patients. Final PK analysis showed that there is no influence of B on P PK and that P AUC is higher than previously reported. Clinical trial information: NCT01202032. [Table: see text]

Background Inhibiting multiple signalling pathways with the combination of afatinib, an oral irreversible ErbB Family Blocker, and nintedanib, an oral triple angiokinase inhibitor of VEGFR, PDGFR and FGFR, may lead to better efficacy. Methods This Phase I study used a modified 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib, with dose escalating from 10 to 40 mg qd given in 2 schedules: continuous (C) or intermittent (I) (every other week), in combination with fixed-dose nintedanib (200 mg bid reduced to 150 mg bid after protocol amendment) in a 28-day cycle. Secondary endpoints were safety, efficacy, pharmacokinetics (PK), and circulating tumour cells (CTC) analysis. Treatment continued until disease progression or intolerability. Results 45 pts with heavily pretreated advanced solid tumours were included: 26 men; median age 56 years (range 37–73); main cancer types: lung (NSCLC), colorectal, breast, melanoma and ovary. Main adverse events were diarrhoea, asthenia, nausea, vomiting and transaminase elevation. Two MTDs were established: afatinib 40 mg qd (I) plus nintedanib 150 mg bid and afatinib 30 mg qd (C) plus nintedanib 150 mg bid (Table). Efficacy data showed evidence of antitumour activity with partial responses (RECIST) observed in 2 pts (HER2-negative breast cancer, and head & neck squamous cell carcinoma) and stable disease in 27 pts (lasting >3 months in 8 pts). Preliminary PK data showed no drug–drug interaction. CTC analysis will be presented. Afatinib (C or I) (mg qd) Nintedanib (mg bid) Evaluable pts/dose-limiting toxicity (DLT) DLT/Grade (G) 10 C 200 3/0 20 C 200 3/0 30 C 200 7/2 diarrhoea G3, transaminase elevation G3 40 C 200 3/3 diarrhoea G3, transaminase elevation G3; creatinine increase G2 30 I 200 6/2 diarrhoea G3, transaminase elevation G3, creatinine increase G2 40 I 200 6/2 dehydration G3, transaminase elevation G4 40 C 150 3/2 diarrhoea G3, renal failure G3 40 I 150 6/0 MTD 30 C 150 6/0 MTD Conclusion At MTD, the combination of afatinib with nintedanib showed a manageable safety profile and evidence of activity in different heavily pretreated tumour types. Disclosure J. Soria: Honoraria from Boehringer Ingelheim and Roche. N. Morsli: Employee of Boehringer Ingelheim. M. Ould Kaci: Employee of Boehringer Ingelheim. H. Staines: Employee of Boehringer Ingelheim. K. Marzin: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background Malignant Pleural Mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase I trials appear as a rationale alternative. The results of such an approach have been evaluated.Materials and methods: MPM patients, were enrolled in 20 different phase I trials between March 2005 and January 2012, and their data analysed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, Overall Survival (OS) and Progression Free Survival (PFS). Median follow-up of patients was estimated through Schemper's method. The cut-off date for the analysis was April 2012. Adverse events were assessed by NCI-CTC v.3.0 and response rate according to RECIST 1.1 criteria. Results Forty-six patients with a confirmed histology of MPM were included in the analysis with a median follow up of 20 months. The median age and the sex ratio (M/F) were 61 years old and 2.29 respectively. Radiological disease progression was observed in 50% of pts, clinical progression in 28%, and dose limiting toxicity in 22%. The best tumour response was as follows: 7% of pts had a RECIST partial response, 59% had stable disease for a median duration of 2.8 months and 24% had progressive disease. The median treatment duration in the phase I was 1.9 months. Median OS and PFS were 6 months (95% CI= [4.3-10.7]) and 2.1 months (95% CI= [1.3-2.8]), respectively. The most common grade 3/4 adverse events (41%) were haematological (11%), gastro-intestinal (4%), cutaneous (7%), renal (4%) and hepatic (4%). All adverse events were reversible and no death due to toxicity was reported. Conclusion Including MPM pts in phase I trials beyond first line of treatment can result in clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies might be tested in a phase I setting in a biology-oriented approach rather than a stochastical one. We are currently offering a tumour molecular profiling in our pts (MOSCATO trial) for a better selection of phase I trial. Disclosure All authors have declared no conflicts of interest.

3063 Background: PHA-848125 (PHA) is a dual CDK/TRKA oral inhibitor showing significant single agent antitumor activity in several tumor models including pancreas (tumor growth inhibition range 65-74% in 3 pancreatic ca. xenograft models), prostate, lung, ovarian and glioma. In combination with gemcitabine (G), PHA exhibits synergistic effects in vitro and additive activity in the BX-PC3 human pancreatic ca. xenograft, at well tolerated doses. Methods: Phase I study to determine safety, pharmacokinetics (PK) and recommended dose for phase II (RP2D) of PHA/G combination in patients (pts) with advanced solid tumors. Cohorts of 3-6 pts received iv G on d1, 8, 15 and oral PHA once daily 7 days on/ 7 days off, in 4-week cycles (cy). At the fixed G dose of 1,000 mg/m2, PHA doses investigated were: 45 mg/m2 (3 pts), 60 mg/m2 (3 pts) and 80 mg/m2, the RP2D as a single agent (10 pts). Results: Sixteen pts (lung 5, mesothelioma 3, pancreas, prostate, colorectal 2 each, thymoma 1, thyroid 1) were treated for a total...

e13109 Background: Few clinical trials are conducted in patients with rare types of cancer. Phase I clinical trials could be a great opportunity for patients with advanced rare tumors who fail to r...

Background: Aflibercept (AF) is a recombinant fusion protein of the human vascular endothelial growth factor (VEGF) receptor combining the Fc portion of human IgG1 with the extracellular ligand-binding domains of human VEGFR1 and VEGFR2. AF binds and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to assess the safety, dose-limiting toxicities (DLTs)/ recommended dose (RD), and PK of AF + DCF. Methods: This phase I combination trial explored escalating IV doses of AF given on day 1 followed by DCF (fixed dose of D 75mg/m2, C 75mg/m2 both on day 1 and F 750 mg/m2/day from day 1 to 5), every 3 weeks. G-CSF and fluoroquinolone were given as primary prophylaxis. Patient characteristics: 44 pts (M/F 29/15, median age 53 [range: 33–74], baseline ECOG-PS 0/1/2: 16/27/1) were enrolled in 3 AF dose cohorts: 2 (n = 9), 4 (n = 14) and 6 (n = 21) mg/kg. Primary tumors were mostly gastro-intestinal (28, including 22 gastro-esophageal, 3 pancreas, 2 liver, 1 cholangiocarcinoma), 4 breast, 3 lung, 3 utero-vaginal, 2 thyroid, and 4 others. Sixteen (36%) pts received prior chemotherapy, median number of lines 2 (range 1–6). Preliminary Results: Pts received a median number of 6, 4, and 7 cycles respectively for each dose group of 2, 4, and 6 mg/kg (range 1–19). One AF-related DLT of pulmonary embolism was observed at the 6 mg/kg AF dose level. Most common Gr ≥ 3 adverse events included: fatigue/asthenia (46%), mucosal inflammation/stomatitis (41%), anorexia (18%), and febrile neutropenia (16%). Mild to moderate arterial hypertension and proteinuria were reported. Grade 1 or 2 epistaxis (61%) and dysphonia (41%) also were reported. Two fatal events were observed: gastrointestinal haemorrhage after C2 (cholangiocarcinoma, AF 6 mg/kg), pulmonary haemorrhage with bronchial necrosis after C12 (NSCL cancer, AF 6 mg/kg). Thirteen (35%) partial responses (PR) in various tumor types, and 20 stable disease (SD) including 14 pts with SD≥2 months were noted. PK analysis will be presented once available. Conclusions: AF 6 mg/kg combined with DCF q3wks was selected for further investigation, based on DLTs and overall safety profile. This dose is consistent with results from other aflibercept phase 1 studies. Encouraging signs of anti-tumor activity and disease control have been seen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B10.

Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical xenograft models, the oral selective Class I PI3K inhibitor XL147 augments the anti-tumor efficacy of EGFR inhibitors, including erlotinib. Methods: Patients (pts) with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL147 in combination with erlotinib. Erlotinib is dosed qd, and XL147 is dosed once daily on Days 1–21 of each 28-day cycle. Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated every 8 weeks. Results: As of 01 Aug2009, 18 pts with advanced solid tumors have been enrolled: NSCLC (7), CRC (5), HCC, HNSCC, biliary tract, carcinoid, ethmoid, and esophageal cancer (1 each). Pts have been treated at 6 dose levels up to 400 mg XL147/150 mg erlotinib. No DLTs or study treatment-related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs were rash (40%), fatigue (30%), diarrhea, nausea, and vomiting (each 20%). Two events of Grade 3 thrombosis (both unrelated) were reported. Based on preliminary data, the PK of XL147 in combination with erlotinib is consistent with that observed for XL147 given alone (Exelixis Study XL147-001). Likewise, XL147 does not appear to alter the PK of erlotinib as the PK parameters of erlotinib are similar to published single agent values. Modulation of PI3K pathway and EGFR signaling by XL147/erlotinib has been demonstrated in PBMCs by reductions in phosphorylation of AKT, the AKT substrates PRAS40 and GSK3 , and ERK. In skin and tumor biopsies, robust post-dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, ERK, and EGFR. For example, in tumor biopsies from a subject with an ethmoid tumor (400 mg XL147/150 mg erlotinib), reductions in pAKT-T308 (43%), p4EBP1 (44%), pERK (43%), and pEGFR (40%) were evident at Day 15 post-dose, with a corresponding reduction in Ki67 (47%) and induction of apoptosis (2.7-fold). One EGFR inhibitor-naïve NSCLC pt (no EGFR mutations detected in archival tumor sample, 200 mg XL147/150 mg erlotinib) had a confirmed PR with a 59% reduction in the sum of target lesions. Nine pts continued on study ≥ 12 weeks, including 2 pts who remained on study ≥ 24 weeks. Conclusions: The combination of XL147 and erlotinib is generally well tolerated at doses up to 400 mg XL147/150 mg erlotinib, with no apparent drug-drug PK interaction or emergent toxicities, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C197.

8098 Background: BMS-690514 is an oral selective inhibitor of EGFR, HER2, and VEGFR1–3. Previous results from the phase I portion of this phase I/II study established 200 mg/day as safe and tolerable (ASCO 2008; abstr 2564). Methods: Erlotinib-naïve and erlotinib-resistant adult patients with advanced/metastatic, measurable NSCLC received BMS-690514 200 mg/d. Eligible patients had an ECOG PS ≤1 and adequate organ function. Objectives were to assess disease control rate (DCR; CR, PR, SD ≥4 months), safety, PK and potential predictive and PD biomarkers of BMS-690514. Response was assessed every 8 weeks (modified WHO criteria). Predictive biomarkers included EGFR copy number, and EGFR and KRAS mutations. PD biomarkers included immunohistochemistry of EGFR signaling proteins in skin biopsies, circulating sVEGFR2, blood pressure, skin rash and diarrhea. Results: For 60 patients treated, DCR were 11/28 (39%) and 7/32 (22%) for erlotinib-naive and -resistant patients, respectively. DCR was significantly higher among patients harboring an EGFR mutation (6/8) than those with WT EGFR (5/18). One erlotinib-naive patient had PR (57 wks) and subsequent surgical removal of remaining tumor. Regression (48%) was seen in one erlotinib-naive patient harboring a KRAS G13D mutation. One erlotinib-resistant patient had PR (66%, 31 wks). Two erlotinib-resistant patients with EGFR T790M mutations had SD with 6% and 31% decrease in tumor burden. Most frequent treatment-related AES were diarrhea (90%), skin rash (31%), asthenia (29%), anorexia (27%), hypertension (26%), and reversible acute renal insufficiency (11%). sVEGFR2 (14% decrease from baseline, n=14) and decreased pMAPK levels from skin biopsies (14 of 18 pts) were consistent with EGFR and VEGFR2 inhibition. Conclusions: BMS-690514 200 mg/d showed evidence of anti-tumor activity and disease control in patients with NSCLC, including erlotinib-resistant and those with WT EGFR, EGFR T790M or KRAS mutations. Predictive and PD clinical biomarkers confirmed inhibition of both EGFR and VEGFR signaling pathways by BMS-690514. A randomized phase II trial versus erlotinib in NSCLC is underway. [Table: see text]

2564 Background: BMS-690514 is an oral selective pan-HER and VEGFR2 inhibitor with activity in a wide range of tumor cell lines dependent on ErbB signaling. Methods: This is a dose-escalation study to define the MTD and to characterize the pharmacokinetics, pharmacodynamics and safety profile of BMS-690514 in patients with advanced tumors. Patients≥ 18 years with advanced or metastatic measurable tumors, refractory to standard therapies, ECOG ≤ 1, and adequate cardiovascular, bone marrow, renal and hepatic functions. Biomarkers of ErbB and VEGFR signaling include tumor tissue for ErbB pathway gene amplification and mutations, single nucleotide polymorphism, skin biopsies, circulating proteins, and DCE-MRI. Dosing initiated at 40 mg/d with dose escalation based on a modified Fibonacci scheme. At the MTD, an expansion cohort (n=60) enrolled patients with erlotinib-naive and erlotinib-resistant NSCLC. Results: The study has treated 65 patients (39 M/ 26 F), median age 56.2 years (range 27–77) between Oct 200...