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367 BAY80-6946 is a Potent and Selective PI3K Inhibitor That Induces Apoptosis in Breast Cancers by Blocking AKT and Non-AKT PI3K Effector Pathways
112 Thursday 8 November 2012 in pathophysiology of many tumor types, and synergy between the PI3K inhibitor GDC-0941 and the EGFR inhibitor erlotinib has been demonstrated preclinically. Methods: This is a multi-center, open-label, 3+3 dose escalation study designed to determine the recommended phase 2 dose of GDC-0941 with erlotinib in patients with advanced solid tumors. In cohort 1, GDC-0941 is given for 21 days of each 28-day cycle (21/28). In cohorts 2 and higher, GDC-0941 is given for 5 days with 2 days off (5/7), in every 28-day cycle. Erlotinib is given QD (28/28). Results: Forty-three patients have been treated with GDC-0941 + erlotinib in 7 successive cohorts. In the first 3 cohorts, the erlotinib dose was 150 mg, and in the next 4 cohorts it was reduced to 100 mg QD due to dose limiting toxicities (DLTs). GDC-0941 was given in 2 schedules: in 21/28 in the first cohort and 5/7 in all subsequent cohorts. The highest dose that has cleared the DLT-assessment window is 250 mg GDC-0941 in combination with 100 mg erlotinib. Evaluation of 330 mg GDC-0941 (5/7), the singleagent maximum tolerated dose, in combination with 100 mg erlotinib (QD) is ongoing. Most common adverse events (AEs) related to GDC-0941 in >20% pts across all CTCAE v3 Grades (G) were not dissimilar to singleagent AE profiles. They were diarrhea (51% G1/2; 7% G3), fatigue (47% G1/2), nausea (35% G1/2; 5% G3), rash (26% G1/2; 7% G3), decreased appetite (26% G1/2), dysgeusia (23% G1/2) and vomiting (19% G1/2; 2% G3). DLTs noted were G3 ALT, G3 dyspnea and G4 colitis (GDC-0941 60 mg, 21/28 + 150 mg erlotinib); G3 mucositis, G3 rash, G4 DVT and G3 ALT (GDC-0941 60 mg, 5/7 + erlotinib 150 mg); G3 stomatitis (165 mg, 5/7 + erlotinib 100 mg). Two patients had partial responses per RECIST 1.0 (1 parotid gland cancer, 1 mesothelioma). Twelve patients (29%) achieved stable disease as their best response. Based on the PK profiles of GDC0941 and erlotinib, no drug–drug interactions were apparent. Biomarker analysis is ongoing. Conclusions: GDC-0941 at 250 mg in combination with 100 mg erlotinib is well-tolerated. Based on preclinical anti-tumor activity, an exposure consistent with the combination effect has been achieved at this 250 mg dose. Evaluation of 330 mg GDC-0941 + erlotinib is ongoing. Antitumor activities have been observed. 366 POSTER Phase I Dose-escalation Study of the Oral Dual MTOR/PI3K Inhibitor BEZ235, Solid Dispersion System (SDS) Sachet Formulation, in Patients with Advanced Solid Tumors J. Rodon Ahnert1 , H.A. Burris2 , J.H.M. Schellens3 , M. Schuler4 , O. Goodman5 , C. Britten6 , D. Richards7 , D. Demanse8 , A. Silva9 , J. Baselga10 . 1 Vall d’Hebron University Hospital, Medical Oncology Department, Barcelona, Spain; 2 Sarah Cannon Research Institute, Drug Development Program, Nashville, USA; 3 The Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands; 4 ¨ ¨ Westdeutsches Tumorzentrum Universitatsklinikum Essen Universitat Duisburg-Essen, Department of Medical Oncology, Essen, Germany; 5 UC San Diego Nevada Cancer Institute, Medical Oncology/Hematology, Las Vegas, USA; 6 UCLA Jonsson Cancer Center, Department of Medicine (Hematology/Oncology), Los Angeles, USA; 7 Texas Oncology Tyler, Medical Oncology, Tyler, USA; 8 Novartis Pharma AG, Statistics, Basel, Switzerland; 9 Novartis Pharma AG, Clinical Oncology, Basel, Switzerland; 10 Massachusetts General Hospital, Division of Hematology/Oncology, Boston, USA Background: The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer, and its activation has been implicated in oncogenesis, tumor progression, and resistance to anticancer therapies. BEZ235 is an oral, ATP-competitive inhibitor that targets both mTORC1/2 and class I PI3K. Here, we present the updated analysis of the Ph I study of single-agent BEZ235 SDS sachet in patients (pts) with advanced solid tumors (NCT00620594). Material and Methods: Ph I/IB dose-escalation study with expansion cohort of oral BEZ235 QD in pts with advanced solid tumors. Eligibility criteria included pts with histologically confirmed, advanced unresectable solid tumors who had progressed on, or were unable to tolerate, standard therapy within 3 months of study enrollment, or for whom no standard anticancer therapy existed. The primary objective was to determine the MTD of single-agent BEZ235 given QD based on dose-limiting toxicities (DLTs) using a Bayesian logistic regression model with overdose control. Secondary objectives included safety (CTCAE), preliminary activity (RECIST), and pharmacokinetics (PK). Results: At data cut-off (31 January 2012), 61pts had been treated with BEZ235 SDS sachet at 5 dose levels: 800 mg (6pts); 1000 mg (10pts), 1200 mg (24pts) 1400 mg (14pts), 1600 mg (7pts). Primary sites of cancer included: CRC (19pts), breast (12pts), lung (8pts), and kidney (5pts). At data cut-off, 7pts remained on study. The primary reason for discontinuation was disease progression (59%). 11 DLTs were reported for 10 pts: Gr3 fatigue (3×1400 mg); Gr3 thrombocytopenia
Poster Session – PI3 Kinase (1×1000 mg, 1×1600 mg); Gr3 asthenia (1×1400 mg); Gr3 hyperglycemia (1×1400 mg); Gr3 mucositis (1×1400 mg); Gr2 nausea (1×1200 mg); Gr3 diarrhea (1×1400 mg) and Gr3 vomiting (1×1200 mg). The MTD of BEZ235 SDS sachet was declared at 1200 mg/d, and the RP2D at 1000 mg/d. The most common Gr3 study drug-related AEs (>4%) were: fatigue (5pts), thrombocytopenia (4pts) and GI events (nausea [4pts] and diarrhea [3pts]). 1pt had Gr4 skin rash. No treatment-related deaths have been reported to date. 18/61pts (30%) had stable disease, 22 progressive disease (36%) and 21 had unknown response (34%) as per RECIST. PK data will also be presented. Conclusions: The MTD for single-agent BEZ235 SDS sachet was declared as 1200 mg/d, and the RP2D 1000 mg/d. Ongoing studies are investigating BEZ235 given BID, and in combination with other anticancer agents, such as trastuzumab and paclitaxel in breast cancer. 367 POSTER BAY80-6946 is a Potent and Selective PI3K Inhibitor That Induces Apoptosis in Breast Cancers by Blocking AKT and Non-AKT PI3K Effector Pathways M. Will1 , W. Toy1 , P. Payal1 , V. Rodrik-Outmezguine1 , C. Schneider2 , J. Paul2 , N. Liu2 , N. Rosen1 , S. Chandarlapaty1 . 1 Memorial Sloan-Kettering Cancer Center, New York City, USA; 2 Bayer Pharma AG, Berlin, Germany Background: Hyperactivation of the PI3K-AKT signaling pathway is a common mechanism for transformation in breast tumors. We have previously demonstrated that AKT inhibition is feasible and selectively benefits tumors with PI3K activation. However, we have also found that one of the major consequences of AKT inhibition is the relief of feedback inhibition of RTKs and PI3K. As a result, AKT inhibition profoundly induces PI3K activity. As PI3K activation and PIP3 generation stimulate a number of protein kinases along with AKT, we hypothesized that in selected tumors PI3K inhibition would better target oncogenic signaling and have superior antitumor effects. Materials and Methods: We compared the effects of an ATP-competitive inhibitor of PI3K (BAY80-6946) with an allosteric inhibitor of AKT (MK2206) upon oncogenic signaling. We further evaluated the differential anti-tumor consequences of AKT and PI3K inhibition across a panel of breast cancer models. Results: We found that both AKT and PI3K inhibition potently suppressed AKT signaling. Both inhibitors relieved AKT-dependent feedback suppression of RTK (e.g. HER3) expression to nearly equivalent levels. While the degree of inhibition of AKT substrates (e.g. PRAS40 and GSK3b) was nearly the same, several PI3K dependent signaling intermediates were more effectively inhibited by BAY80-6946. For instance, the mTOR substrates S6K and 4E-BP1 were more effectively downregulated by PI3K inhibition than AKT inhibition. We have established that these differences were not due to off target effects of the PI3K inhibitor upon the related mTOR kinase. The ability of BAY80-6946 to more potently inhibit PI3K signaling was closely correlated with more effective inhibition of growth and induction of apoptosis. The differences in both pathway inhibition and induction of apoptosis were selectively observed in specific intrinsic breast cancer subtypes. Conclusions: BAY80-6946 is a highly selective inhibitor of PI3K that potently inhibits oncogenic PI3K signaling and induces apoptosis. Both AKT dependent and non-AKT dependent effector pathways of PI3K appear to be necessary for tumor cell survival in select breast cancer subtypes. AKT inhibitor induced relief of feedback on RTK-PI3K signaling may attenuate the antitumor efficacy of this class of drugs. 368 POSTER GDC-0068, a Novel and Selective Akt Inhibitor Demonstrates Improvement in Anti-tumor Activity When Combined with Androgen Receptor Pathway Antagonists, MDV3100 and Abiraterone, in Prostate Cancer Models M.A. Nannini1 , A. Arrazate1 , J. Bower1 , L.B. Lee1 , J. Lin1 , B.B. Lee1 , R. Kassees1 , K. Lin1 , D. Sampath1 . 1 Genentech, Translational Oncology, South San Francisco CA, USA Background: Akt, a serine/threonine protein kinase, is a key signaling node in the PI3K/Akt/mTOR pathway and plays an essential role in regulating tumor cell proliferation, migration and survival. Both androgen receptor (AR) and PI3K/Akt signaling are aberrantly up-regulated in prostate cancer. Inhibition of AR signaling in advanced prostate cancer results in decreased tumor burden and improved survival. The PI3K/Akt pathway is activated in up to 100% of metastatic prostate cancers and PTEN loss confers poor prognosis. Non-clinical data suggests that there is cross-talk between the AR and PI3K/Akt pathways. We previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068 that is currently in Phase 1 clinical trials. We hypothesized that the combination of antiandrogens and GDC-0068 would induce anti-tumor activity in prostate cancer models.
Poster Session – PI3 Kinase (1×1000 mg, 1×1600 mg); Gr3 asthenia (1×1400 mg); Gr3 hyperglycemia (1×1400 mg); Gr3 mucositis (1×1400 mg); Gr2 nausea (1×1200 mg); Gr3 diarrhea (1×1400 mg) and Gr3 vomiting (1×1200 mg). The MTD of BEZ235 SDS sachet was declared at 1200 mg/d, and the RP2D at 1000 mg/d. The most common Gr3 study drug-related AEs (>4%) were: fatigue (5pts), thrombocytopenia (4pts) and GI events (nausea [4pts] and diarrhea [3pts]). 1pt had Gr4 skin rash. No treatment-related deaths have been reported to date. 18/61pts (30%) had stable disease, 22 progressive disease (36%) and 21 had unknown response (34%) as per RECIST. PK data will also be presented. Conclusions: The MTD for single-agent BEZ235 SDS sachet was declared as 1200 mg/d, and the RP2D 1000 mg/d. Ongoing studies are investigating BEZ235 given BID, and in combination with other anticancer agents, such as trastuzumab and paclitaxel in breast cancer. 367 POSTER BAY80-6946 is a Potent and Selective PI3K Inhibitor That Induces Apoptosis in Breast Cancers by Blocking AKT and Non-AKT PI3K Effector Pathways M. Will1 , W. Toy1 , P. Payal1 , V. Rodrik-Outmezguine1 , C. Schneider2 , J. Paul2 , N. Liu2 , N. Rosen1 , S. Chandarlapaty1 . 1 Memorial Sloan-Kettering Cancer Center, New York City, USA; 2 Bayer Pharma AG, Berlin, Germany Background: Hyperactivation of the PI3K-AKT signaling pathway is a common mechanism for transformation in breast tumors. We have previously demonstrated that AKT inhibition is feasible and selectively benefits tumors with PI3K activation. However, we have also found that one of the major consequences of AKT inhibition is the relief of feedback inhibition of RTKs and PI3K. As a result, AKT inhibition profoundly induces PI3K activity. As PI3K activation and PIP3 generation stimulate a number of protein kinases along with AKT, we hypothesized that in selected tumors PI3K inhibition would better target oncogenic signaling and have superior antitumor effects. Materials and Methods: We compared the effects of an ATP-competitive inhibitor of PI3K (BAY80-6946) with an allosteric inhibitor of AKT (MK2206) upon oncogenic signaling. We further evaluated the differential anti-tumor consequences of AKT and PI3K inhibition across a panel of breast cancer models. Results: We found that both AKT and PI3K inhibition potently suppressed AKT signaling. Both inhibitors relieved AKT-dependent feedback suppression of RTK (e.g. HER3) expression to nearly equivalent levels. While the degree of inhibition of AKT substrates (e.g. PRAS40 and GSK3b) was nearly the same, several PI3K dependent signaling intermediates were more effectively inhibited by BAY80-6946. For instance, the mTOR substrates S6K and 4E-BP1 were more effectively downregulated by PI3K inhibition than AKT inhibition. We have established that these differences were not due to off target effects of the PI3K inhibitor upon the related mTOR kinase. The ability of BAY80-6946 to more potently inhibit PI3K signaling was closely correlated with more effective inhibition of growth and induction of apoptosis. The differences in both pathway inhibition and induction of apoptosis were selectively observed in specific intrinsic breast cancer subtypes. Conclusions: BAY80-6946 is a highly selective inhibitor of PI3K that potently inhibits oncogenic PI3K signaling and induces apoptosis. Both AKT dependent and non-AKT dependent effector pathways of PI3K appear to be necessary for tumor cell survival in select breast cancer subtypes. AKT inhibitor induced relief of feedback on RTK-PI3K signaling may attenuate the antitumor efficacy of this class of drugs. 368 POSTER GDC-0068, a Novel and Selective Akt Inhibitor Demonstrates Improvement in Anti-tumor Activity When Combined with Androgen Receptor Pathway Antagonists, MDV3100 and Abiraterone, in Prostate Cancer Models M.A. Nannini1 , A. Arrazate1 , J. Bower1 , L.B. Lee1 , J. Lin1 , B.B. Lee1 , R. Kassees1 , K. Lin1 , D. Sampath1 . 1 Genentech, Translational Oncology, South San Francisco CA, USA Background: Akt, a serine/threonine protein kinase, is a key signaling node in the PI3K/Akt/mTOR pathway and plays an essential role in regulating tumor cell proliferation, migration and survival. Both androgen receptor (AR) and PI3K/Akt signaling are aberrantly up-regulated in prostate cancer. Inhibition of AR signaling in advanced prostate cancer results in decreased tumor burden and improved survival. The PI3K/Akt pathway is activated in up to 100% of metastatic prostate cancers and PTEN loss confers poor prognosis. Non-clinical data suggests that there is cross-talk between the AR and PI3K/Akt pathways. We previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068 that is currently in Phase 1 clinical trials. We hypothesized that the combination of antiandrogens and GDC-0068 would induce anti-tumor activity in prostate cancer models.