Primary Endpoint In Part Research Articles

Afatinib in patients with advanced non-small cell lung cancer harboring HER2 mutations, previously treated with chemotherapy: A phase II trial

BackgroundDespite 1–4 % of NSCLC tumors harboring mutations in the HER2 gene, there are no approved HER2-pathway-targeted treatments available. We report an open-label, single-arm, multicenter phase II study investigating the efficacy and safety of afatinib in Asian patients with HER2-mutation positive (HER2m+) NSCLC. MethodsEligible patients for Part A had confirmed stage IIIb/IV HER2m + NSCLC, had failed one or two prior lines of chemotherapy, and were EGFR/HER2-inhibitor naïve. Patients received oral afatinib 40 mg/day in continuous 28-day cycles, until disease progression or intolerable adverse events (AEs). Patients qualified for Part B if they had > 12 weeks’ clinical benefit and Eastern Cooperative Oncology Group performance status ≤ 2. In Part B, patients were to receive afatinib at the last received dose, plus paclitaxel 80 mg/m2 weekly, until disease progression or intolerable AEs. The primary endpoint in Part A was objective response (OR); secondary endpoints included disease control (DC), progression-free survival (PFS), and overall survival (OS). Further exploratory endpoints were OR, DC, and PFS in Part B. ResultsEighteen patients received afatinib in Part A. No patient achieved an OR; 11 patients (61.1 %) achieved stable disease, and six patients (33.3 %) had progressive disease. DC rate was therefore 61.1 % (95 % confidence interval [CI]: 35.7, 82.7). A decrease in tumor size from baseline of > 0 to < 30 % was observed in eight patients. At the time of analysis, 16 patients (88.9 %) had progressed or died. Median PFS was 2.76 months (95 % CI: 1.87, 4.60) and median OS was 10.02 months (95 % CI: 8.47, 10.08). All patients experienced ≥ 1 AE, most commonly diarrhea (66.7 %) and rash (33.3 %). No patients met the inclusion criteria for Part B, and recruitment was slow; therefore, the study was terminated. ConclusionsThis study found no clinical benefit of afatinib for EGFR TKI-naïve patients with HER2m + NSCLC.

An open-label, phase I trial of BI 754091 alone and in combination with BI 754111 in Asian patients (pts) with advanced solid tumors.

3054 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, may enhance the anti-tumor response versus PD-1 blockade alone. This Phase I trial investigated BI 754091, an anti-PD-1 antibody, as monotherapy and in combination with BI 754111, an anti-LAG-3 antibody, in Asian pts with advanced solid tumors. Methods: This trial comprised 3 parts. Parts 1 and 2 (dose escalation) were in pts with unresectable/metastatic solid tumors. In Part 1, pts received BI 754091 240 mg intravenously (iv), every 3 weeks (q3w); in Part 2, pts received BI 754091 240 mg in combination with BI 754111 (400 mg, 600 mg or 800 mg iv, q3w). Dose escalation was guided by a Bayesian logistic regression model, with overdose control. The primary endpoint in Parts 1 and 2 was maximum tolerated dose (MTD) of BI 754091 alone or in combination with BI 754111, based on dose-limiting toxicities (DLTs) in Cycle 1. In Part 3, BI 754091 240 mg plus BI 754111 600 mg q3w was assessed in 4 expansion cohorts. Cohorts A–C included pts with: A) gastric/esophagogastric junction cancer; B) esophageal cancer; C) hepatocellular cancer; all had received ≥1 line of prior systemic therapy and no prior anti-PD-(L)1 therapy. Cohort D included pts who had received prior anti-PD-(L)1 therapy for the tumor types in Cohorts A–C. The primary endpoint in Part 3 was objective response (confirmed complete response or partial response [PR] per RECIST 1.1). Results: In Part 1, 6 pts received BI 754091 240 mg. In Part 2, 9 pts received BI 754091 240 mg plus BI 754111 (400 mg/600 mg/800 mg; n = 3 per cohort). No DLTs were reported in Parts 1 and 2. In Part 3, 121 pts were treated (97 [80%] male, median age 61 years [range 23–80]); Cohorts A/B/C/D included 33/33/20/35 pts. All-grade adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 96 (79%) and 47 (39%) pts, respectively. The most commonly reported AEs (all/≥G3) were pyrexia (21%/0%), decreased appetite (17%/2%), anemia (11%/6%), and nausea (9%/0%). 36 (30%) pts reported immune-related AEs, most commonly hypothyroidism, in 7 (6%) pts. Confirmed PR was observed in 6 pts (5%; Cohort A/B, n = 4/2) and 35 (29%) pts had stable disease (Cohort A/B/C/D, n = 9/11/10/5). Conclusions: MTD was not reached for BI 754091 monotherapy or for BI 754091 in combination with BI 754111. The recommended dose for the combination was determined as BI 754091 240 mg plus BI 754111 600 mg q3w. Treatment was well tolerated and consistent with that observed in the global trial. Preliminary anti-tumor activity was seen. Clinical trial information: NCT03433898 .

Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with pembrolizumab in patients with advanced/metastatic breast or non-small cell lung cancer (NSCLC): A phase Ib, multicenter, study.

TPS1100 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase II trial in patients (pts) with heavily pretreated, metastatic HER2+ breast cancer (BC), T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic BC after ≥ 2 prior anti-HER2 based regimens. For HER2-low BC and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase I trial of T-DXd in pts with HER2-low BC or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase Ib study of T-DXd in combination with pembrolizumab in pts with locally advanced/metastatic HER2-expressing BC or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). Methods: This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) pts in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with BC (HER2+ [IHC 3+ or IHC 2+/ISH+] with progression on prior T-DM1; and HER2-low [IHC 1+ or IHC2+/ISH-] with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing [IHC ≥ 1+] or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 pts planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics. Clinical trial information: NCT04042701 .

Phase Ib study of BI 836880, a VEGF/Ang2-blocking nanobody, in combination with BI 754091, an anti-PD-1 antibody: Initial results in patients (pts) with advanced non-small cell lung cancer (NSCLC).

9566 Background: Preclinical studies show that combining anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and BI 754091 is an anti-PD-1 antibody. Each has shown manageable safety and preliminary activity as monotherapy. Here, we report initial results from a Phase Ib study assessing BI 836880 in combination with BI 754091. Methods: In Part 1 (dose escalation), pts with locally advanced or metastatic (m) non-squamous NSCLC who progressed during/after completion of ≥2 cycles of platinum-based chemotherapy (CT) ± a checkpoint inhibitor (CPI) were enrolled. Pts received BI 836880 (cohorts of 360, 500 and 720 mg intravenously [iv] 3-weekly [q3w]) plus fixed-dose BI 754091 (240 mg iv q3w). Dose escalation was guided by Bayesian logistic regression models with overdose control. Primary endpoint in Part 1 was maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), based on dose-limiting toxicities (DLTs) in Cycle 1. Initial safety and efficacy results of Part 1 are reported here. Part 2 will assess safety and efficacy in 6 expansion cohorts: mNSCLC after CPI monotherapy; mNSCLC after CT + CPI; mSCLC after CT ± CPI; immunotherapy-resistant m-melanoma; recurrent glioblastoma after 1st-line CT; and hepatocellular carcinoma after prior sorafenib or lenvatinib ± subsequent CPI. Results: 12 pts received BI 836880 plus BI 754091 (8 male; median age 59.5 years; 8 had received prior CPI). 4 pts remain on treatment (including 1 treated for 15 cycles). 1 pt had a DLT during Cycle 1 (360 mg; G3 pulmonary embolism). All pts experienced an adverse event (AE; any-cause; safety data cut-off Nov 2019), most commonly (all%/G3%) hypertension (58/25), vomiting (42/0), nausea (33/0), and asthenia (33/0). Hypertension was transient. No G4 AEs were reported; one G5 AE occurred (general physical health deterioration). 5 pts had immune-related AEs (G2 hypothyroidism in 2 pts; G2 pruritus, G1 papular rash, and G2 vomiting). To date (Jan 2020), 2 pts have achieved partial response; 1 pt (500 mg dose; CPI-naïve) had 58% target lesion reduction, and 1 (720 mg; prior CPI) had 35% target lesion reduction. 8 pts had stable disease. Conclusions: MTD/RP2D was BI 836880 720 mg plus BI 754091 240 mg q3w. The combination had a manageable safety profile, and preliminary anti-tumor activity was observed. Expansion cohorts are ongoing. Equal contribution: JA and BH Clinical trial information: NCT03468426 .

Trial in Progress: A Phase 3 Study of Itacitinib or Placebo in Combination with Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease (GRAVITAS-309)

Background Allogeneic hematopoietic cell transplantation (HCT) is indicated for several hematologic malignancies and nonmalignant disorders. Chronic graft-versus-host disease (cGVHD) develops in 30%-70% of long-term survivors of HCT and is a significant cause of nonrelapse mortality. Corticosteroids (CS) are the recommended first-line treatment for cGVHD; however, up to 60% of patients treated with CS require additional cGVHD therapy within 2 years. Furthermore, long-term exposure to CS is associated with a wide range of toxicities and increased risk of infection. Novel safe and effective therapies are needed to treat cGVHD and reduce CS dependence. Janus kinases (JAKs) mediate the signaling of proinflammatory cytokines involved in the pathogenesis of cGVHD. Itacitinib is a JAK-1 selective inhibitor that improved graft-versus-host disease (GVHD) and survival without affecting engraftment of donor leukocytes in murine models. In a phase 1 clinical study, itacitinib 200 or 300 mg once daily (QD) was well tolerated in patients with steroid-refractory or steroid-naive acute GVHD (aGVHD). Here we describe the trial design of the first clinical study evaluating the safety and efficacy of itacitinib for the treatment of cGVHD. Study Design and Methods GRAVITAS-309 (NCT03584516) is a 2-part phase 3 study of itacitinib or placebo in combination with CS as initial treatment for cGVHD. Patients aged ≥18 years who underwent allogeneic HCT from any donor type and graft source, with evidence of myeloid and platelet engraftment, and who have active, moderate, or severe cGVHD per National Institutes of Health Consensus Criteria are eligible to participate. Patients are excluded if they received &gt;1 prior HCT (except autologous), had &gt;3 days of systemic CS treatment for cGVHD, received any other systemic treatment for cGVHD, have presence of active uncontrolled infection, or had treatment with a JAK inhibitor within 8 weeks of randomization (patients who previously received a JAK inhibitor for aGVHD are eligible only if they achieved a complete or partial response). Part 1 is a randomized, open-label study to determine optimal dosing of itacitinib in combination with CS (~20 patients randomized 1:1 to itacitinib 200 mg QD or 300 mg QD; Figure 1). The primary endpoints for Part 1 are dose-limiting toxicities (DLTs) through Day 28 as well as clinical safety and laboratory assessments. Main secondary endpoints include pharmacokinetic (PK) parameters and efficacy outcomes (Table 1). After 20 patients have completed 28 days of treatment, an external data monitoring committee will review the data and provide a recommendation for an appropriate dose for Part 2 based on emergent adverse events, clinical laboratory parameters, PK data, and DLTs. Part 2 is a randomized, double-blind, placebo-controlled study using the dose selected in Part 1 to assess the efficacy and safety of itacitinib plus CS vs placebo plus CS (~246 patients stratified by cGVHD severity and randomized 1:1; Figure 1). Patients randomized to the placebo group will be permitted to cross over to the itacitinib group after completion of the primary analysis. The primary endpoint is overall response rate (proportion of patients with complete or partial response) at 6 months. Secondary endpoints include changes in symptom scores using health-related quality-of-life measures, additional efficacy outcomes, PK parameters, and clinical safety assessments (Table 1). Exploratory biomarker analyses will evaluate the effects of JAK inhibition on circulating inflammatory cells (ie, T-cell subsets, B cells, natural killer cells, cytokines) and biomarkers of GVHD in peripheral blood after transplant. Patients will remain on study for a total of 37 months, which includes treatment period, safety follow-up, and posttreatment GVHD follow-up, unless confirmed GVHD progression, start of a new GVHD therapy, or relapse/recurrence of underlying hematologic disease occurs earlier. Efficacy analyses will be performed on the intent-to-treat population; safety analyses will be conducted on all randomized patients who receive ≥1 dose of study drug. The PK-evaluable population will include all patients who receive ≥1 dose of study drug and provide ≥1 postdose plasma PK sample. Disclosures Morariu-Zamfir: Incyte Corporation: Employment. Bleam:Incyte Corporation: Employment. Yan:Incyte Corporation: Employment.

1593TiP - Phase Ib dose-escalation/expansion study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumours

BackgroundPreclinical evidence shows that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) promote an immunosuppressive state in the tumour microenvironment, and that the combination of anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell mediated tumour cell killing. BI 836880, a humanised bispecific nanobody that targets VEGF and Ang2, and BI 754091, an anti-PD-1 antibody, have shown safety and preliminary antitumour activity as monotherapies in phase I studies (RP2D, 720mg iv q3w for BI 836880 and 240mg iv q3w for BI 754091). The safety and efficacy of BI 836880 + BI 754091 are being assessed in this phase Ib trial in patients (pts) with advanced solid tumours. Trial designThis open-label, dose-escalation/cohort-expansion trial is being conducted in two parts: Part 1, dose escalation of BI 836880 with BI 754091 in pts with advanced/metastatic, PD-L1 positive, nonsquamous NSCLC; Part 2, exploratory expansion cohorts (A–F) in 6pt populations (A: metastatic [m] NSCLC after checkpoint inhibitor [CPI] monotherapy; B: mNSCLC after chemotherapy [CTX] + CPI; C: mSCLC after CTX with/without CPI; D: immunotherapy-resistant m-melanoma; E: recurrent glioblastoma after 1st line CTX; F: hepatocellular carcinoma after prior sorafenib or lenvatinib with/without subsequent CPI therapy). In Part 1, pts will receive BI 836880 (cohorts of 360, 500 and 720mg iv q3w) + fixed-dose BI 754091 240mg iv q3w, following a Bayesian logistic regression model with overdose control, with oversight from a safety monitoring committee. The primary endpoint in Part 1 is the MTD/RP2D, based on DLTs in Cycle 1. In Part 2, pts will receive BI 836880 at the RP2D + BI 754091 240mg iv q3w. The primary endpoint in Part 2 is objective response; secondary endpoints are disease control, duration of response, PFS and tumour shrinkage. Safety, PK and exploratory biomarkers will be assessed. ∼220 pts will enroll globally: 20–25 pts in Part 1 and ∼200 in Part 2 (40 in Cohorts A/B; 30 in Cohorts C–F). As of May 2019, 6 pts have been treated in Part 1. Part 2 will begin once the RP2D is established in Part 1. Updates will be presented. Clinical trial identificationNCT03468426. Editorial acknowledgementFiona Scott, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc; supported financially by Boehringer Ingelheim. Legal entity responsible for the studyBoehringer Ingelheim. FundingBoehringer Ingelheim GmbH & Co, Ingelheim, Germany. DisclosureN. Girard: Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: BMS; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: Boehringer; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee: MSD; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: Roche; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: AstraZeneca. B. Hackanson: Honoraria (self), Advisory / Consultancy: Boehringer; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche. M. Wermke: Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Glenmark; Honoraria (self): Kite; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Gemoab. F. Barlesi: Honoraria (self), Honoraria (institution): AstraZeneca; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Boehringer–Ingelheim; Honoraria (self), Honoraria (institution): Eli Lilly Oncology; Honoraria (self), Honoraria (institution): F. Hoffmann–La Roche Ltd; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Merck; Honoraria (self), Honoraria (institution): MSD; Honoraria (self), Honoraria (institution): Pierre Fabre; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution): Takeda; Honoraria (institution): AbbVie; Honoraria (institution): ACEA; Honoraria (institution): Amgen; Honoraria (institution): Bayer; Honoraria (institution): Eisai; Honoraria (institution): Genentech; Honoraria (institution): Ipsen; Honoraria (institution): Ignyta; Honoraria (institution): Innate Pharma; Honoraria (institution): Loxo; Honoraria (institution): MedImmune; Honoraria (institution): Sanofi-Aventis. H.T. Landsteiner: Full / Part-time employment: Boehringer Ingelheim . G. Jayadeva: Full / Part-time employment: Boehringer Ingelheim. J. Alt: Advisory / Consultancy, Consulting fee: Boehringer Ingelheim.

Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study

Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

PF515 A PHASE I STUDY OF THE BTK INHIBITOR ABIVERTINIB (AC0010) IN PATIENTS WITH RELAPSED OR REFRACTORY B‐CELL LYMPHOMA

Background:Bruton's tyrosine kinase (BTK) is a clinically validated target for the treatment of B‐cell malignancies, including relapsed/refractory (R/R) mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), and Waldenström's macroglobulinemia (WM). Abivertinib is a highly selective, irreversible, potent inhibitor of BTK activity, which is being investigated in an open‐label phase I study with dose escalation (part 1) and dose expansion (part 2) (NCT03060850).Aims:This ongoing study is designed to determine the recommended Phase 2 dose (RP2D) of abivertinib in patients with pre‐treated R/R B‐cell lymphoma (part 1) and to evaluate the safety and preliminary efficacy in patients with selected disease (part 2).Methods:In part 1, eligible patients aged 18–75 y, with Eastern Cooperative Oncology Group performance status of 0 or 1, and diagnosed with R/R B‐cell lymphoma were enrolled. Patients received abivertinib until progressive disease or unacceptable toxicity. The primary endpoint of part 1 is to determine RP2D based on dose limited toxicity (DLT), adverse event (AE), tolerability, BTK receptor occupancy, pharmacokinetics and preliminary efficacy. Abivertinib was given twice a day (BID) or once a day in 28‐day treatment cycles in ascending/descending dose cohorts, the starting dose was 200 mg BID. Here, we report the preliminary safety and efficacy outcomes in part 1, and part 2 will be initiated upon determinate of RP2D.Results:As of November 15, 2018, 21 patients with R/R B‐cell malignancy were enrolled for treatment in part 1, including CLL (n = 9), SLL (n = 1), MZL (n = 1), MCL (n = 5), follicular lymphoma (n = 1), lymphoplasmacytic lymphoma (n = 3), mucosa‐associated lymphoid tissue (n = 1). Patients received treatment with abivertinib in 3 dose cohorts (300 mg BID, n = 3; 200 mg BID, n = 14; 150 mg BID, n = 4). The median treatment duration was 27 (range 1–85) weeks; 66.9% (14/21) of patients are still on treatment. Three (14.3%) DLT events of platelet count decrease were reported, 1 at 300 mg BID and 2 at 200 mg BID. Overall, treatment emergent AE occurred in 85.7% (18/21) of patients, with 47.6% (10/21) of grade 3/4 AE. The most common grade 3/4 AE regardless of causality (≥10%) was thrombocytopenia (4/21, 19.0%), followed by neutropenia (3/21, 14.3%). Treatment emergent serious adverse event (SAE) occurred in 23.8% (5/21) of patients, only 1 case (4.8%) of drug‐related SAE abdominal infection was reported. No death occurred during the treatment period. The efficacy was analyzed in the 13 response evaluable patients, 61.5% (8/13) of patients achieved partial response (PR) across 3 dose cohorts and 87.5% (7/8) of patients achieved PR at 200 mg BID. Furthermore, &gt;90% BTK occupancy in peripheral blood was achieved at all 3 dose levels.Summary/Conclusion:Abivertinib was safe and tolerable with encouraging clinical efficacy in patients with R/R B‐cell malignancies, which warrants further evaluation in part 2 of the study.

Randomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) ± lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006.

TPS9118 Background: Lenvatinib (multiple-receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptors α, c-kit, and RET) has antitumor activity in combination with pembrolizumab (anti–PD-1 inhibitor) or with chemo in advanced NSCLC. LEAP-006 (NCT03829319) evaluates first-line lenvatinib with pembrolizumab + chemo for metastatic nonsquamous NSCLC. Methods: This randomized, double-blind, 2-part, phase 3 study enrolls pts ≥18 years with histologically/cytologically confirmed metastatic, nonsquamous, treatment-naive NSCLC without sensitizing genetic aberrations. Pts receive lenvatinib 8 mg daily or matching placebo + pembrolizumab 200 mg + pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 Q3W (4 cycles) followed by maintenance pembrolizumab (35 cycles) + lenvatinib/placebo + pemetrexed (no limit). In part 1 (open-label safety run-in), ~12 pts receive lenvatinib + pembrolizumab + chemo (n ≥6 in each chemo arm). If &lt; 3 dose-limiting toxicities (DLTs; select prespecified AEs) occur in 6 pts in each arm in cycle 1, part 2 will begin enrolling. If ≥3 DLTs occur in 6 pts in each arm, enrollment in part 1 may continue with advisement by the study oversight committee. In part 2, pts are randomized 1:1 to lenvatinib or placebo + pembrolizumab + chemo, stratified by PD-L1 tumor proportion score ( &lt; 50%/≥50%), geographic site (East Asian/other), and ECOG PS (0/1). Tumor imaging occurs at baseline and Q6W until wk 18; then Q9W until wk 54; then Q12W until verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. The primary endpoint in part 1 is safety. The primary endpoints in part 2 are PFS (RECIST v1.1 by BICR) and OS, analyzed by Kaplan-Meier method and stratified log-rank test. Secondary endpoints in part 2 are ORR and DOR (RECIST v1.1 by BICR), safety, and quality of life. Enrollment into part 1 will begin in March 2019. For part 2, approximately 714 pts will enroll in 160 sites in 17 countries. Clinical trial information: NCT03829319.

Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus

Aims/hypothesisCardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes.MethodsIn this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of ≥25 kg/m2 to ≤42 kg/m2, and LDL-cholesterol levels ≥1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In ‘Part A’ of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. ‘Part B’ of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration–time curve (AUC0–4h) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated.ResultsMEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, −1.25 [−1.66, −0.84]; MEDI4166 200 mg, −1.97 [−2.26, −1.68]; MEDI4166 400 mg, −1.96 [−2.23, −1.70]; placebo, −0.03 [−0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC0–4h post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, −10.86 [−17.69, −4.02]; MEDI4166 200 mg, −4.23 [−8.73, 0.28]; MEDI4166 400 mg, −2.59 [−7.14, 1.95]; placebo, −4.84 [−9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%.Conclusions/interpretationMEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166.Trial registrationClinicalTrials.gov NCT02524782FundingThis study was funded by MedImmune LLC, Gaithersburg, MD, USA.

Neratinib in Combination With Trastuzumab for the Treatment of Patients With Advanced HER2-positive Breast Cancer: A Phase I/II Study

BackgroundDespite the availability of several human epidermal growth factor receptor 2 (HER2)-directed treatments, many HER2-positive (HER2+) breast cancers eventually progress because of primary or acquired resistance. Patients and MethodsA 2-part, open-label, multicenter phase I/II study was conducted to determine the recommended dose of neratinib when administered with trastuzumab (part I), and to assess the antitumor activity of this combination in women with locally advanced or metastatic HER2+ breast cancer previously treated with at least 1 prior trastuzumab-based regimen (part II). Patients received oral neratinib (160 or 240 mg/d) once daily plus intravenous trastuzumab 4 mg/kg (loading dose) then 2 mg/kg weekly. Diarrhea prophylaxis was not permitted. The primary endpoint in part II was investigator-assessed 16-week progression-free survival (PFS). ResultsForty-five patients received neratinib plus trastuzumab (part I: neratinib 160 mg/d, n = 4; neratinib 240 mg/d, n = 4; part II: neratinib 240 mg/d, n = 37). In part I, there were no dose-limiting toxicities and the recommended neratinib dose was 240 mg/d. In part II, the 16-week PFS rate was 44.8% (90% confidence interval, 28.8%-59.6%), and the median PFS was 15.9 weeks (95% confidence interval, 15.1-31.3 weeks) in 28 evaluable patients. Three patients had durable clinical benefit lasting 9.4 to 9.7 years. Diarrhea was the most common adverse event (grade 3, n = 7 [15.6%]; grade 4, n = 0). No clinically significant cardiac toxicity was seen. ConclusionsNeratinib in combination with trastuzumab was well-tolerated and had encouraging antitumor activity in patients with advanced trastuzumab-pretreated HER2+ breast cancer. Durable responses can be achieved in some patients.

Patients with Asthma Prescribed Once-Daily Fluticasone Furoate/Vilanterol or Twice-Daily Fluticasone Propionate/Salmeterol as Maintenance Treatment: Analysis from a Claims Database.

IntroductionThere is a paucity of data describing prescribing patterns and adherence to therapy of inhaled corticosteroids (ICS) in combination with long-acting β2-agonists (LABA) in the Japanese population in clinical practice.MethodsThis was a non-interventional, retrospective, cohort study of patients who were prescribed medication for asthma, using data from the Japan Medical Data Center Claims Database. Data from patients aged ≥ 15 years with a prescription of asthma drugs between December 2014 and October 2015 (Day 0, the index date when asthma medication was initiated) were analysed in 12-month pre-index and post-index periods. Part 1 focused on baseline characteristics and epidemiological outcomes in the pre- and post-index period in the overall asthma population, whereas comparing medication adherence [number of prescribed days per year and proportion of days covered (PDC)] between ICS/LABA-naïve patients treated with once-daily fluticasone furoate/vilanterol (FF/VI) and twice-daily fluticasone propionate/salmeterol (FP/SAL) was the primary endpoint in Part 2.ResultsOf the available patient data (N = 2,953,652), 28,699 patients were identified as having asthma. ICS/LABA was the main asthma treatment prescribed; 11,167 (38.9%) patients were continuous ICS/LABA users. In ICS/LABA-naïve asthma patients, treatment with once-daily FF/VI was associated with higher medication adherence compared with twice-daily FP/SAL; mean [standard deviation (SD)] number of prescribed days per year was 97.8 (115.9) for FF/VI versus 80.5 (92.7) for FP/SAL (p = 0.04), mean (SD) PDC was 26.7% (31.5) for FF/VI versus 21.9% (24.8) for FP/SAL (p = 0.04). FF/VI was also associated with a lower rate of treatment discontinuation and no difference in use of short-acting beta2-agonists or oral corticosteroids compared with FP/SAL.ConclusionsICS/LABA was the major prescribed asthma treatment in Japan. Medication adherence was greater with FF/VI, which may indicate that patients are more likely to adhere to once-daily FF/VI versus twice-daily FP/SAL.FundingThis study was funded by GSK (study sponsor).Study RegistrationGSK Study No. 207264, GSK Study Register site: https://www.gsk-clinicalstudyregister.com/search/?search_terms=207264.Electronic supplementary materialThe online version of this article (10.1007/s41030-018-0084-4) contains supplementary material, which is available to authorized users.

Safety of trifluridine/tipiracil (TAS-102) in combination with temozolomide for metastatic neuroendocrine tumors.

TPS549 Background: Low and intermediate grade neuroendocrine tumors (NETs) are incurable once they metastasize. Cytoreductive surgery and locoregional therapies play an important role in their management, but ultimately most patients are treated with systemic therapies. In clinical studies, combination of temozolomide (TMZ) and capecitabine (CAP) demonstrated significant response rates (&gt; 50%) in patients with advanced pancreatic NETs. Trifluridine/tipiracil (FTD/TPI), also known as TAS-102, is a new anti-metabolite agent that is non-cross resistant with 5-fluorouracil (5-FU) and CAP and that has a different toxicity profile from CAP. In clinical trials, FTD/TPI has been associated with limited toxicities in patients with chemotherapy refractory (including 5-FU and CAP) metastatic colorectal cancer. Given that CAP has demonstrated activity in metastatic NETs, we hypothesize that FTD/TPI in combination with TMZ will be well tolerated and will be efficacious in metastatic NETs. Methods: This is a two-part investigator-initiated phase IB clinical trial (NCT02943733). Part 1 is a dose escalation portion of the study that will determine maximum tolerated doses of FTD/TPI administered in combination with TMZ in patients with advanced NETs. Patients with low and intermediate grade NETs of any origin are eligible for part 1. This part follows a classical “3+3” design to establish the phase 2 doses. Both drugs are oral agents that are administered on a 28 day cycle. FTD/TPI is taken twice a day on days 1-5 and days 8-12. TMZ is taken daily on days 8-12. This schedule was selected based on the pre-clinical data demonstrating schedule-dependent synergism between 5-FU and TMZ. Because of concern for overlapping bone marrow toxicities between the two agents, TMZ is started at the dose of 100 mg/m2 and escalated to a goal dose of 200mg/m2 daily if no dose limiting toxicities are observed. FTD/TPI is started at a goal dose of 35 mg/m2. Part 2 of the study will enroll estimated 15 patients with metastatic pancreatic NETs. Primary endpoint of part 2 is overall response rate, and secondary endpoints are progression free survival, disease control rate and overall survival. Part 1 of the trial is currently open to enrollment. Clinical trial information: NCT02943733.

Phase 1 study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5038 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, but not in most normal tissues, making it a potential therapeutic target. We are conducting a two-part phase 1 dose escalation/expansion study of EC1169, a PSMA-targeted conjugate of the microtubule inhibitor tubulysin B hydrazide in mCRPC. The utility of the PSMA-targeted companion imaging agent 99mTc-EC0652 is also being evaluated as a patient selection tool. The safety, efficacy, and imaging-based PSMA selection strategy are being investigated in Part A (dose escalation) and Part B (2-stage, 2-cohort expansion). Methods: Part A pts were eligible if they progressed on abiraterone or enzalutamide, and were treated with a taxane. EC1169 was administered as an IV bolus on days 1, 8 every 21 days. Part B pts are enrolled in 1 of 2 cohorts, mCRPC taxane naïve (cohort 1, 45 pts) and taxane exposed (cohort 2, 40 pts). Prior to treatment, pts undergo a 99mTc-EC0652 SPECT scan. The primary endpoint of Part B is median radiographic progression-free survival (rPFS). Other study evaluations are OS, PSA, and CTC-based biomarkers. Results: Part A is now complete: the RP2 dose is 6.5 mg/m2, on the basis of non-DLT transaminitis. 20 Part A/B pts have been treated at the RP2 dose (7 taxane naïve, 13 taxane exposed). Median age is 69 (range: 59-82). Median number of cycles is 2 (range: 1-7). 10 pts (50%) reported at least 1 treatment related AE. Most treatment related AEs are Gr1 and 2; G3 thrombocytopenia, fatigue, and constipation have occurred in 1 pt each. No Grade 4 treatment related AEs have been reported. No DLT or toxicity requiring dose reductions occurred. Four taxane-exposed pts in Part B have reached their first 9 wk radiographic assessment, of which two have soft tissue disease. One of those two patients (50%) has achieved an unconfirmed RECIST PR. Conclusions: The RP2 dose of EC1169 is 6.5 mg/m2. EC1169 has been well tolerated in 20 pts at the RP2 dose. Imaging with 99mTc-EC0652 suggests excellent disease localization supporting a PSMA-targeted therapeutic strategy. There is evidence of anti-tumor activity in both the dose escalation and expansion cohorts. Clinical trial information: NCT02202447.

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial

Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

Non-Inferior Pharmacokinetics with Comparable Safety and Response Rates for Subcutaneous (SC), Compared with Intravenous (IV), Rituximab in Combination with Fludarabine and Cyclophosphamide (FC) in Patients (Pts) with Untreated Chronic Lymphocytic Leukemia (CLL): Part 2 of the Phase Ib SAWYER Study (BO25341)

Non-Inferior Pharmacokinetics with Comparable Safety and Response Rates for Subcutaneous (SC), Compared with Intravenous (IV), Rituximab in Combination with Fludarabine and Cyclophosphamide (FC) in Patients (Pts) with Untreated Chronic Lymphocytic Leukemia (CLL): Part 2 of the Phase Ib SAWYER Study (BO25341)

Neoadjuvant Chemotherapy and Extrapleural Pneumonectomy (Epp) of Malignant Pleural Mesothelioma (Mpm) with or Without Hemithoracic Radiotherapy: Final Results of the Randomized Multicenter Phase Ii Trial Sakk17/04

ABSTRACT Aim: We have previously documented the feasibility of neoadjuvant chemotherapy and EPP in a multicenter trial of MPM (Weder, Ann Oncol 18: 1196, 2007). The objectives of the trimodality trial SAKK17/04 (NCT00334594) were to evaluate the time to loco-regional relapse with or without high dose hemithoracic radiotherapy in a prospective multicenter randomized phase II trial in patients with R0 and R1 resection after neoadjuvant chemotherapy and EPP. Methods: Eligible patients had pathologically confirmed MPM, surgically resectable TNM stage (T1-3 N0-2 M0), PS0-1, ages 18-70 years. Part 1 had a phase II design, and included neoadjuvant chemotherapy with 3 cycles of cisplatin and pemetrexed, followed by restaging and EPP. The primary endpoint of part 1 was complete macroscopic resection (R0-1). Part 2 randomized consenting patients with R0-1 resection into two parallel phase II arms (control arm A and radiotherapy arm B). The primary endpoint for part 2 was loco-regional relapse-free survival (RFS). To detect a 1 year increase with 80% power and 10% alpha, 37 patients were needed for arm B. Secondary endpoints included operability, tolerability of chemotherapy and radiotherapy, survival, and translational research Results: Because accrual of part 2 was slower than planned, the trial was stopped in 2013. Overall, 153 patients entered the trial, of whom 125 underwent surgery and 99 had a complete macroscopic resection (primary endpoint part 1). Of the later patients, 54 could be randomized 1:1 into each arm. Reasons for non-randomization included patient refusal in 24 and ineligibility or protocol deviations in 21. Of the 27 patients randomized to hemithoracic radiotherapy, 25 completed the treatment as planned. For part 1 the median RFS was 8.8 (95%CI: 7.3–10.7) and median OS was 15.0 (95% CI: 12.1–19.3) months. For part 2 the median local RFS for group A was 7.6 (95%CI: 5.5–10.7) and for group B 9.4 (95%CI: 6.5-11.9) months (primary endpoint part 2), while the overall RFS and OS for group A were 5.7 (95%CI: 3.5-8.8) and 16.9 (95%CI: 10.7-23.6) months and for group B 7.6 (95% CI:5.2-10.6) and 14.9 (95%CI: 7.0–17.6) months. Conclusions: This study did not reach the primary endpoint which was defined as one-year increase in loco-regional relapse-free survival and thus does not support the routine use of hemithoracic RT after neoadjuvant chemotherapy and EPP. Disclosure: All authors have declared no conflicts of interest.

A Multicenter, Open-Label Phase II Study of Metformin With Erlotinib in Second-Line Therapy of Stage IV Non–Small-Cell Lung Cancer Patients: Treatment Rationale and Protocol Dynamics of the METAL Trial

We present the rationale and study design of the METAL (METformin in Advanced Lung cancer) trial (EudraCT number: 2014-000349-59), a multicenter, open label phase II study, designed to evaluate the safety and activity of metformin combined with erlotinib as second-line therapy in patients with stage IV non–small-cell lung cancer. This is a 2-part trial, consisting of a safety run-in part followed by a phase II part. The primary end point for the first part is the maximum tolerated dose and the identification of the recommended phase II dose of metformin in combination with erlotinib. Secondary end points are the study of pharmacokinetics and the antitumor activity evaluation of the experimental combination. The primary end point of part II is the time to disease progression with the combination, and antitumor activity as a secondary end point. Based on the statistical design, we plan to enroll approximately 60 patients.

Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM).

2015 Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. BKM120 is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations demonstrated to inhibit PI3K pathway, and potently inhibits the growth of U87 GBM tumors and human glioma tumor spheres in vitro and in vivo. Methods: The Ivy Foundation Early Phase Clinical Trials Consortium is conducting a phase II study of BKM120 in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1st or 2nd relapse, &gt; 18 yrs, KPS &gt; 60, adequate bone marrow and organ function, controlled blood glucose, and no enzyme-inducing antiepileptic drugs. Patients received BKM120 100mg daily. The study consisted of 2 parts conducted concurrently. Part 1 involved up to 15 patients who received BKM120 daily for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic (PK) studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. Part 2 consisted of up to 50 patients with unresectable GBM treated with BKM120. The primary endpoint for Part 2 was 6-month progression-free survival (p0 =15%; p1= 32%). Results: To date 7 patients have been enrolled into Part 1, 33 into part 2. There were 5 women and 35 men. Median age was 54 yrs (29-68). Treatment was fairly well-tolerated. Major grades 3/4 toxicities were asymptomatic lipase elevation (5), fatigue (3), hyperglycemia (3), rash (3) elevated AST (1), and depression (1). Analysis of tumor from Part 1 showed reduction of pAkt by IHC. Genotyping of tumor specimens is ongoing. To date 33 patients had positive pAkt, 21 had PTEN loss by IHC. Of the first 19 patients who underwent whole exome sequencing, 3 had PIK3Ca mutations and 6 had PTEN mutations. Conclusions: BKM120 is generally well tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAkt. Updated PK and efficacy data and correlation of the latter with tumor genotype will be presented. Clinical trial information: NCT01339052.

TOPGEAR: An international randomized phase III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG).

TPS4141 Background: Optimal management of patients with resectable gastric cancer remains unknown. Since the INT0116 and MAGIC trials, there are 2 standards of care for adjuvant therapy: postoperative chemoradiotherapy (CRT) and perioperative ECF chemotherapy. The important question arising from these studies is whether CRT is superior to chemotherapy alone as adjuvant therapy. This randomized phase II/III trial will compare CRT to chemotherapy alone in the preoperative setting. Methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either preoperative chemotherapy alone (ECFx3 as per MAGIC regimen) or preoperative CRT (ECFx2 followed by 45Gy of radiation with concurrent 5-FU). Following surgery, both groups will receive 3 further cycles of ECF. The trial is being conducted in two Parts; Part I (phase II component) will recruit 120 patients with the aim of demonstrating sufficient efficacy and safety of preoperative CRT, as well as trial feasibility. Part II (phase III component) will recruit a further 632 patients to provide a total of 752. The primary endpoint for Part I is pathological complete response rate, and for Part 2 it is overall survival. The trial includes formal quality of life and biological sub-studies. In addition, the trial incorporates a rigorous quality assurance program that includes real time central review of radiotherapy plans and central review of surgical technique. Current status: This study is an international, intergroup trial led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the Trans-Tasman Radiation Oncology Group (TROG), European Organisation for Research and Treatment of Cancer (EORTC) and the NCIC Clinical Trials Group. To date, 36 patients have been recruited from 20 sites in Australia and New Zealand; European and Canadian sites will commence recruitment in 2012.