BackgroundThe anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsPhase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME).ResultsOverall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME.ConclusionsIsa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

CyPep-1 is a synthetic tumor membrane targeting 27-D-aminoacid alpha-helical peptide. Preclinical studies with CyPep-1 have demonstrated immunogenic cell death and synergism with anti-PD1 antibodies. The dose-escalation part of this study assessed safety and determined the recommended dose for further development (RP2D). Patients with assessable and injectable non-ulcerating cutaneous or subcutaneous tumor deposits were eligible. Three predefined dose levels (DL) of CyPep-1 were studied: 0.5, 2 and 5 mg/mL. CyPep-1 was administered intratumorally (IT) every 14 days for 3 doses in volumes up to 4 mL per administration, depending on tumor size. Preferentially IT administration was pursued in a single lesion, but up to 3 lesions could be injected. PK Blood samples were collected pre-dose and 15, 30, 60 & 240 min. post-dose after the first IT administration. Cytokines, TCR clonality & blood cell immunophenotyping were assessed pre-dose and on days 15 & 36 post-dose. Pre- and post-treatment biopsies from an injected lesion were analyzed. The DLT observation period was 6 weeks. Response assessment was performed every 8 weeks. Fourteen pts were enrolled, twelve completed the DLT period: 3 DL1, 3 DL2, 6 in DL3. All pts had exhausted SoC therapy. No DLT was observed. One pt discontinued treatment after three IT administrations due to ulceration of the injected lesion. Injection site reactions were noted in 79% (11/14), mainly mild pain (related to IT administration). No grade 3 or higher treatment related AEs were observed. PK: Concentrations below limit of quantification in 5 pts (10 ng/mL). Six pts had detectable levels that peaked at 15 minutes. Highest concentration observed in 1 pt was 226 ng/mL. Tumor biopsy analysis revealed increased cell death and necrosis (range 10-80%) in 5 of 6 pts at DL3. TCR clonality: increased clonality in peripheral blood after treatment. Two patients had iRECIST SD lasting > 8 months. CyPep-1 IT is well tolerated at the RP2D of 5.0 mg/mL. PK data showed minimal systemic exposure with IT injection. Histopathologic examination showed local oncolytic effect, and TCR clonal changes were consistent with systemic immune activation.

Introduction: Patients with locally advanced pancreatic cancer (LAPC) rarely undergo resection with curative intent and controlling disease progression should be the goal of the treatment. We conducted a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT02292745) to investigate the efficacy and feasibility of combining FOLFIRINOX and Stereotactic Radiotherapy (SBRT) for patients with LAPC (LAPC-1 trial). Methods: All eligible patients with biopsy-proven LAPC were included between January 2015 and June 2017. These patients underwent a staging laparoscopy to exclude occult metastasis and were treated with FOLFIRINOX (8 cycles) followed by SBRT (5 fractions/8 Gy) if there was no tumor progression on imaging. Primary outcome was overall survival (OS). Secondary outcomes were progression free survival (PFS), treatment-related toxicity, and resection rates. Results: In total, 53 patients were included in the study. The preliminary survival data showed a median OS of 18 months (95% CI 16-19) and median PFS of 12 months (95% CI 11-13). Thirty (60%) events of a grade 3 or 4 adverse event occurred during FOLFIRINOX. Thirty-nine (74%) patients had no tumor progression after the chemotherapy andreceived the full dose of SBRT. One (3%) patient had a grade 5 adverse event three months after SBRT, while no grade 3 or 4 adverse event occurred after SBRT. Seven (14%) patients underwent a resection, all being a radical resection. Conclusion: FOLFIRINOX combined with SBRT in patients with inoperable LAPC is feasible and effecitve. Forteen percent of the patients became operable and 6% had a complete response.

Background: It remains challenging to predict outcomes in patients with advanced HCC. Small and non-European studies have associated low muscle mass (sarcopenia) and visceral adiposity with impaired survival and increased treatment toxicity. However, large studies in European patients are lacking. Methods: A retrospective analysis was performed in HCC patients treated with sorafenib at two tertiary referral centers between 2007-2016. Muscle mass and density and adipose tissue areas were measured at baseline by computed tomography (CT) at the third lumbar vertebra (L3) level. Sarcopenia and low muscle density were defined using published cut-off points. Body composition parameters were correlated with overall survival (OS), time-to-progression (TTP), response rate, and toxicity. Results: In total, 278 patients were included (79% male, median age 66) with a median OS of 9.5 (95%CI;8.1-11.0) months. At baseline, 52% had sarcopenia and 41% had low muscle density. Sarcopenia showed an independent association with TTP (HR 1.36;95%CI 1.03-1.77;p=0.04), whereas low total adipose tissue index (TATI) was associated with reduced OS. Combined presence of sarcopenia and low total adipose tissue index (TATI) was associated with reduced treatment duration (16 vs 11 weeks, p=0.029) and independently associated with poorer OS (HR 1.68;95%CI 1.24-2.27;p=0.001). None of the body composition parameters was independently associated with response rate or treatment toxicity. Conclusion: In European patients with HCC treated with sorafenib, low TATI and presence of sarcopenia are independent prognostic factors of poorer OS and TTP respectively. Combined presence impairs survival to a greater extent. CT-assessed body composition provided prognostic information prior to sorafenib treatment.

Background: Efforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate definite overall survival benefit. This may partly be due to the fact that these studies often involve strict inclusion criteria. Consequently, patients with a high risk profile as characterized by Fong’s Clinical Risk Score (CRS) are often underrepresented in these studies. Conceptually, this group of patients might benefit the most from chemotherapy. The present study evaluates the impact of neo-adjuvant chemotherapy in high-risk patients with primary resectable colorectal liver metastases, without extrahepatic disease. Our hypothesis is that adding neo-adjuvant chemotherapy to surgery will provide an improvement in overall survival (OS) in patients with a high-risk profile. Methods/Design: CHARISMA is a multicenter, randomized, phase III clinical trial. Patients will be randomized to either surgery alone (standard treatment, arm A) or to 6 cycles of neo-adjuvant oxaliplatin-based chemotherapy, followed by surgery (arm B). Patients must be ≥ 18 years of age with liver metastases of histologically confirmed primary colorectal carcinoma. Patients with extrahepatic metastases are excluded. Liver metastases must be deemed primarily resectable. Only patients with a CRS of 3–5 are eligible. The primary study endpoint is OS. Secondary endpoints are progression free survival (PFS), quality of life, morbidity of resection, treatment response on neo-adjuvant chemotherapy, and whether CEA levels can predict treatment response. Discussion: CHARISMA is a multicenter, randomized, phase III clinical trial that will provide an answer to the question if adding neo-adjuvant chemotherapy to surgery will improve OS in a well-defined high-risk patient group with colorectal liver metastases. Trial registration: The CHARISMA is registered at European Union Clinical Trials Register (EudraCT), number: 2013-004952-39, and in the “Netherlands national Trial Register (NTR), number: 4893.

28 EORTC – NCI – AACR Symposium on Molecular Targets and Cancer Therapeutics 29 November 2016 - 02 December 2016

Introduction: Patients with BRAF V600-mutant colorectal cancer (BRAFm CRC) who relapse following first-line therapy have a poor prognosis, with median overall survival of just 5–6 months. Unlike melanoma, BRAF inhibitor monotherapy has shown limited efficacy in BRAFm CRC. This limited efficacy has been attributed to reactivation of epidermal growth factor receptor (EGFR) signaling with BRAF inhibition and uninhibited phosphatidylinositol 3-kinase (PI3K) signaling. This study evaluated the efficacy and safety of the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab with or without the PI3K&agr; inhibitor alpelisib (BYL719) in patients with advanced BRAFm CRC.Methods: This is an ongoing phase 1b/randomized phase 2 study (ClinicalTrials.gov: NCT01719380). The phase 1b portion confirmed the safety and tolerability of the combination of encorafenib and cetuximab or encorafenib and cetuximab with alpelisib, and did not identify a maximum tolerated dose. Based on the general tolerability of the triplet, the phase 2 encorafenib dose was chosen to be the same in both arms: 200 mg orally (PO) once daily (QD). In the phase 2 portion, patients with advanced BRAFm CRC failing ≥1 prior therapy were randomized 1:1 to the doublet (encorafenib and cetuximab per label) or the triplet (encorafenib, cetuximab, and alpelisib 300 mg PO QD). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), disease control rate (DCR), and overall survival (OS).Results: Of 102 study patients, 52 were randomized to receive the triplet and 50 to receive the doublet. Patients in each group received a median of 2 prior therapies. A planned PFS analysis comparing the triplet to the doublet after 73 events showed a hazard ratio (HR; 95% confidence interval [CI]) of 0.69 (0.43–1.11; P = 0.064), with median PFS (95% CI) of 5.4 (4.1–7.2) months and 4.2 (3.4–5.4) months, respectively. Confirmed ORR (95% CI) and DCR (95% CI) were 27% (16%–41%) and 79% (65%–89%), respectively, with the triplet, and 22% (12%–36%) and 78% (64%–89%), respectively, with the doublet. With 35 events, interim OS analysis (triplet vs doublet) showed an HR (95% CI) of 1.21 (0.61–2.39); median OS was 15.2 months with the triplet and was not reached with the doublet. Grade 3/4 adverse events (AEs), regardless of causality, were reported in 79% of patients who received the triplet and in 58% who received the doublet. Grade 3/4 AEs in >10% of patients in either arm (triplet vs doublet) were anemia (17% vs 6%), hyperglycemia (13% vs 2%), and increased lipase (8% vs 18%).Conclusion: In comparison with historical data, the combination of encorafenib and cetuximab with or without alpelisib showed promising clinical activity in patients with advanced BRAFm CRC, including improved PFS and OS. Addition of alpelisib to the doublet showed a trend toward a PFS benefit, albeit with additional toxicity. Introduction: Patients with BRAF V600-mutant colorectal cancer (BRAFm CRC) who relapse following first-line therapy have a poor prognosis, with median overall survival of just 5–6 months. Unlike melanoma, BRAF inhibitor monotherapy has shown limited efficacy in BRAFm CRC. This limited efficacy has been attributed to reactivation of epidermal growth factor receptor (EGFR) signaling with BRAF inhibition and uninhibited phosphatidylinositol 3-kinase (PI3K) signaling. This study evaluated the efficacy and safety of the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab with or without the PI3K&agr; inhibitor alpelisib (BYL719) in patients with advanced BRAFm CRC. Methods: This is an ongoing phase 1b/randomized phase 2 study (ClinicalTrials.gov: NCT01719380). The phase 1b portion confirmed the safety and tolerability of the combination of encorafenib and cetuximab or encorafenib and cetuximab with alpelisib, and did not identify a maximum tolerated dose. Based on the general tolerability of the triplet, the phase 2 encorafenib dose was chosen to be the same in both arms: 200 mg orally (PO) once daily (QD). In the phase 2 portion, patients with advanced BRAFm CRC failing ≥1 prior therapy were randomized 1:1 to the doublet (encorafenib and cetuximab per label) or the triplet (encorafenib, cetuximab, and alpelisib 300 mg PO QD). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Of 102 study patients, 52 were randomized to receive the triplet and 50 to receive the doublet. Patients in each group received a median of 2 prior therapies. A planned PFS analysis comparing the triplet to the doublet after 73 events showed a hazard ratio (HR; 95% confidence interval [CI]) of 0.69 (0.43–1.11; P = 0.064), with median PFS (95% CI) of 5.4 (4.1–7.2) months and 4.2 (3.4–5.4) months, respectively. Confirmed ORR (95% CI) and DCR (95% CI) were 27% (16%–41%) and 79% (65%–89%), respectively, with the triplet, and 22% (12%–36%) and 78% (64%–89%), respectively, with the doublet. With 35 events, interim OS analysis (triplet vs doublet) showed an HR (95% CI) of 1.21 (0.61–2.39); median OS was 15.2 months with the triplet and was not reached with the doublet. Grade 3/4 adverse events (AEs), regardless of causality, were reported in 79% of patients who received the triplet and in 58% who received the doublet. Grade 3/4 AEs in >10% of patients in either arm (triplet vs doublet) were anemia (17% vs 6%), hyperglycemia (13% vs 2%), and increased lipase (8% vs 18%). Conclusion: In comparison with historical data, the combination of encorafenib and cetuximab with or without alpelisib showed promising clinical activity in patients with advanced BRAFm CRC, including improved PFS and OS. Addition of alpelisib to the doublet showed a trend toward a PFS benefit, albeit with additional toxicity.

Current status: Patients with BRAF-mutated colorectal cancer (CRC) have been shown to have a poor prognosis compared with those patients with wild-type BRAF; however, BRAF inhibitors have demonstrated little activity in BRAF-mutated CRC. Preclinical data suggest that this activity may be increased by combining BRAF inhibitor treatment with EGFR and/or PI3K inhibitors. Herein, we describe results of a phase 1b clinical study of combinations of the selective BRAF inhibitor encorafenib with the EGFR monoclonal antibody cetuximab with or without the α-specific PI3K inhibitor alpelisib for the treatment of patients with metastatic BRAF-mutated CRC. Methods: Patients with metastatic BRAF-mutated CRC were treated with either encorafenib + cetuximab or encorafenib + cetuximab + alpelisib. The primary objective of this study was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of encorafenib. Secondary objectives included investigation of safety, assessment of antitumor activity and determination of the pharmacokinetic profile of encorafenib ± alpelisib. Tumor samples were also studied to investigate genetic determinants of response and explore potential mechanisms of resistance. Results: Patients were enrolled in either the dual arm (encorafenib + cetuximab; n = 26) or the triple arm (encorafenib + cetuximab + alpelisib; n = 28) of the dose escalation phase of the study. The MTD was not reached in either arm; the RP2D was established as 200 mg encorafenib qd + 250 mg/m2 cetuximab qw ± 300 mg alpelisib qd. The most common treatment-related grade 3/4 AEs were fatigue and hypophosphatemia (8% each) in the dual arm and hyperglycemia (11%) and increased lipase (7%) in the triple arm. Percentage change in the target lesion from baseline by best response is presented in Figure 1. The best overall response rates, as determined by RECIST v1.1, were 23.1% in the dual arm (1 CR, 4 PR and 1 unconfirmed [u] PR) and 32.1% in the triple arm (4 PR and 5 uPR). Patients in the dual arm had a median PFS of 3.7 months (95% CI: 2.8–10.6) compared with 4.3 months (95% CI: 4.1–5.4) for patients in the triple arm. Exploratory analyses of biomarkers showed that BRAF amplification appeared to correlate with longer PFS. PI3K activation did not appear to correlate with response and there was no clear relationship between MAPK pathway activation and mutations related to WNT signaling and PFS. PK data were not available at the time of this analysis. Conclusion: Results from this study suggest that either a dual combination of encorafenib with cetuximab or a triple combination of encorafenib with cetuximab and alpelisib are well tolerated with promising activity in patients with metastatic BRAF-mutant CRC. Further biomarker analyses may assist with the clarification of the relationship between gene alterations and clinical outcomes. Enrollment in the phase 2 part of this study is currently ongoing. Figure: LBA-08 Best percentage change in target lesion from baseline by best radiological response for the dual and triple combination patient arms.

showed no meaningful change in median dynamic parameters but did have a significant reduction in viable fraction. Analyzable diffusion data were available for 51/61 patients; 16 patients demonstrated a greater than 30% on-treatment increase in ADC. 15 of these patients were dosed at 30mg/kg. Conclusions: Reduction in median dynamic parameters reflective of vessel permeability and perfusion was observed in 62% of patients. On the Q2W schedule, sustained decrease across all time-points was only observed at 30mg/kg. Increase in ADC was primarily observed in patients treated at 30mg/kg. The DCE-MRI and DW-MRI findings of ontreatment decrease in tumor vessel permeability, perfusion and cellular density support the proposed anti-angiogenic mechanism of action of Vanucizumab.

ABSTRACT Aim: Tivo is a selective oral VEGF TKI with a long half-life and activity against all 3 VEGFRs. Preclinical data showed antitumor activity of tivo when added to chemotherapy (chemo). In a phase 1b study of tivo + mFOLFOX6 in mCRC and other GI cancers, partial responses were shown and the combination was well tolerated. Based on these results, a randomized, open-label, phase 2 trial of tivo + mFOLFOX6 (arm A) vs bev + mFOLFOX6 (arm B) in previously untreated mCRC was initiated. Methods: Eligible patients had no prior systemic chemo, no fluorouracil-containing adjuvant therapy in the previous 6 mo, and an ECOG PS ≤1. No prior VEGF therapy, including bev was permitted, nor a history of significant thromboembolic or vascular disorders within 6 mo before study entry. The primary end point was PFS by investigator radiologic assessment. Secondary end points included PFS by IRR, OS, ORR, DOR, TTF, and biomarker subgroup analysis of LDH; VEGF A, C, D; CD68; myeloid-derived gene signature and serum soluble cytokines. Subjects were randomized 2:1 and stratified by LDH, origin of cancer, and number of metastatic sites, and received mFOLFOX6 q2w on days 1 and 15 of each 28-day cycle with either tivo 1.5 mg qd for 21 days followed by 7 days off treatment or bev 5 mg/kg q2w. Results: Between 12/20/11 and 4/28/13, 265 subjects were randomized: 177 to arm A and 88 to arm B. A prespecified interim analysis included 95 PFS events and met prespecified futility criteria. mPFS (arm A vs arm B) was 9.4 mo vs 10.7 mo (P = .706); mORR: 45.2% vs 43.2% (P = .718). The overall safety profile was comparable between arms, but there were more drug-related ≥grade 3 treatment-emergent AEs in arm A (57.1% vs 35.6%), higher ALT or AST elevations >3 × ULN (16.6% vs 5.7%), and increase in grade for platelets (65.9% vs 43.7%). The most common toxicities included diarrhea, nausea, fatigue, neutropenia, and hypertension. Conclusions: The addition of tivo to mFOLFOX6 vs bev + mFOLFOX6 met prespecified futility criteria and resulted in comparable PFS, ORR, TTF, and DOR with an acceptable safety profile. At the interim analysis, there were no significant associations between serum/tumor biomarkers and outcomes. Disclosure: J.A. Bridgewater: • Advisory board: 2013, 1; I. Kiss: • Ad bds: Roche, Merck, Bayer • Speakers’ bureau: Roche, Merck, Amgen, Bayer, Sanofi; J. Chen, C. Sasse, S. Vossen, C. van Sant, H. Ball, A. Keating, A. Krisvoshik: Astellas employee • Stock • Salary; All other authors have declared no conflicts of interest.

Aim: Tivo is a selective oral VEGF TKI with a long half-life and activity against all 3 VEGFRs. Preclinical data showed antitumor activity of tivo when added to chemotherapy (chemo). In a phase 1b study of tivo + mFOLFOX6 in mCRC and other GI cancers, partial responses were shown and the combination was well tolerated. Based on these results, a randomized, open-label, phase 2 trial of tivo + mFOLFOX6 (arm A) vs bev + mFOLFOX6 (arm B) in previously untreated mCRC was initiated.

ABSTRACT Background The MTD of single-agent BKM120 was previously declared as 100 mg/day in a Phase I study in patients (pts) with advanced solid tumors (NCT01068483; Bendell et al. 2011). Here we report on the analysis of pharmacodynamic biomarkers from pts in the dose-escalation and dose-expansion arms of the Phase I study. The inhibitory effects of BKM120 were investigated (i) in the context of glucose metabolism regulation, a known PI3K-dependent process, and (ii) in the context of tumor biology, by surveying the phosphorylation of proteins downstream of PI3K. Methods 83 pts received oral daily BKM120. Tumor samples were analyzed for PIK3CA mutation and PTEN expression. Blood C-peptide (glucose metabolism) was measured at Cmax (2–4 hrs post-dose) on Day 1 in 72 pts. Pathway phosphorylation in surrogate tissue was investigated in 51 paired skin samples by correlating changes in pS6 (baseline to Day 28) with the mean dose of BKM120 administered in each pt. In 8 pts where pre/post treatment biopsies could be obtained, pS6, pAKT, p4EBP1 and Ki67 were quantified within limits of tissue availability. Results Blood C-peptide at Cmax on Day 1 increased as a function of the 1st dose administered, with no change after 12.5 mg and mean increase of 72% (range: 56–84%) after 150 mg. Inhibition of pS6 on Day 28 (range: 20–60%) was observed in tumor tissue from 5 out of 8 pts. 4 of these 5 pts also demonstrated a decrease in either pAKT (range: 30–70%) or p4EBP1 (range: 27–35%) with 1 pt displaying a mean 30% decrease in all 3 markers. A decrease in proliferation as measured by Ki67 was observed in 4 pts (range: 13–60%) suggesting a potential biological impact in response to PI3K pathway inhibition. Inhibition of pS6 in skin increased moderately with the mean administered dose of BKM120 (mean inhibition of –28, –37, and –40%, for 12.5–60 mg, >60–90 mg, and >90 mg dose ranges, respectively) suggesting a relationship between treatment dose and the degree of PI3K pathway inhibition. Conclusion This analysis supports the notion that daily BKM120 not only has the ability to induce inhibition of the immediate effector of PI3K (pAKT) but also to downregulate the pathway further downstream (pS6) at MTD. Disclosure F. Eskens: Membership on an advisory board: Participant of LEAD summit meetings (Novartis). E. Di Tomaso: Employee of Novartis. D.W. Sternberg: Employee of Novartis. L. Wang: Employee of Novartis. C. Sarr: Employee of Novartis. Stock Ownership in Novartis Pharmaceuticals. J. Baselga: Novartis Scientific Ad Board (NVPBKM120); other pan‐PI3K inhibitors: Consulting for Exelixis; XL147; Roche‐Genentech Scientific Ad Board; GDC0941. All consulting relationships have CA's in place which conform to the Partners/Harvard COI Policies. All other authors have declared no conflicts of interest.

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

3043 Background: PI3K pathway is frequently altered in cancer and can have an impact on tumor survival and proliferation. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor without mTOR and Vps34 activity. Methods: Phase I dose-escalation (DE) study followed by an expansion cohort of daily BKM120 in pts with advanced solid tumors. Bayesian logistic regression model with overdose control guided the DE. Pts in the MTD expansion arm were pre-selected for molecular alterations of PI3K and/or PTEN. Results: 77 pts received oral BKM120 once daily thus far; data on 66 pts, median age 55 y (30-77), are reported here. 6 dose levels were explored: 12.5 mg (1 pt); 25 mg (2 pts), 50 mg (5 pts), 80 mg (11 pts), 100 mg (43 pts), 150 mg (4 pts). Most common tumor types: CRC (24 pts), breast cancer (BC) (18 pts), lung (3 pts) and endometrial (3 pts) cancer. Median duration of treatment was 7.5 wks (0.1-69+) with 18 pts treated for >16 wks. Seven dose-limiting toxicities (DLTs) were observed: 2x G4 hyperglycemia (150mg/d), 1x G3 upper abdominal pain, 1x G3 skin rash, 2x G2 and 1x G3 mood alteration. MTD was 100 mg/d. Most frequent AEs of all grades and suspected to be drug-related were decreased appetite (33%), rash, diarrhea, nausea (each 27%), fatigue, hyperglycemia (each 24%), anxiety (20%), depression (18%), and mucositis (17%). Mood alterations were successfully managed using self-rating questionnaires. pS6 suppression was found in skin in 100 and 150 mg cohorts (30 to 80% decreases from baseline). Increase of C-peptide was observed at all doses suggesting potential impairment of glucose transport by BKM120. Partial tumor responses were observed in 2 pts: one TN-BC with KRAS and p53 mutation, and one ER+/HER2 neg mBC harboring PIK3CA mutation. 58% pts (26 of 45 evaluable) had SD as best response. Eighteen pts had SD > 16 wks, including 8 pts who had tumors with an activated PI3K pathway. A trend towards better activity was observed at the higher dose cohorts, also expressed as metabolic FDG-PET response. Conclusions: BKM120 monotherapy was well tolerated and showed biological and antitumor activity. Further exploration of BKM120 in patients with PI3K pathway alteration is ongoing in endometrial and lung cancer pts.

2518 Background: N (ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates D activity across a variety of solid tumor types. This phase I study was performed to determine the maximum tolerated dose (MTD) and to assess the safety and PK profile of N plus D. Methods: Pts with advanced solid tumors, adequate organ function and ECOG performance status ≤1 were eligible. N at 150 and 200 mg was given PO, QD days (d) 1-3 or d1-5 q21 followed by D 75 mg/ m2 IV on d 1 q21. To compare the PK of either agent alone, N was administered on days 3-5 or 3-7 only in course 2. PK samples were collected for N and D in cycles 1 and 2. Adverse events (AE) were graded by NCI CTCAE V3.0. Results: 15 pts (M/F: 8/7; median age 54 yrs (range 30-71) were treated at 3 dose levels of N: 150 mg and 200mg d1-5 and 200 mg d1-3. DLTs were febrile neutropenia and grade (gr) 4 thrombocytopenia at N 200 mg d1-5 and febrile neutropenia at 200 mg d 1-3. The MTD is set at 150 mg N d1-5 with D 75 mg2 on d1 and at this dose 12 additional pts are currently being enrolled. Other gr 3/4 AEs were neutropenia (43%), fatigue (21%) and thrombocytopenia (14%); frequently occurring grade 1/2 AEs were fatigue (57%), nausea (50%), vomiting (43%), anorexia (36%), constipation (29%), diarrhea (29%), and thrombocytopenia (21%). One pt with NSCLC had a confirmed partial response (PR), one pt with breast cancer had an unconfirmed PR. Five pts showed stable disease; duration of this ranged from 5-18 weeks; 3/5 pts had SD up to 12 weeks, 1/5 pts had SD up to 14 weeks, and 1/5 pts had SD for 18 weeks. Based on limited PK data, there was no apparent PK interaction between N and D (Table). Conclusions: Navitoclax 150 mg for d1-5 can be safely administrated with D 75 mg/m2. This combination is tolerable with no apparent PK interactions. Antitumor activity was observed in 7 pts (2 PR, 5 SD). Cmax/dose (ng/mL/mg)* AUC24/dose (ng*hr/mL/mg)* Navitoclax (150-200 mg, N=7) Navitoclax alone 20.9 ± 10.4 293 ± 174 Navitoclax with D 14.7 ± 11.4 222 ± 166 D (75 mg/m2, N=3) Cmax ( µ g/mL)* AUCinf ( µ g*hr/mL)* D alone 2.6 ± 1.2 2.9 ± 1.2 D with navitoclax 2.3 ± 0.7 2.4 ± 0.7 * Mean +/− SD