- Email: [email protected]
350 How effective are novel biological therapies? A systematic review of 121 randomized controlled trials (RCTs)
S70 347 POSTER A new role of MTA1 in E2F1-mediated tumour progression and invasion 1 1 D. Goody1 , D. Engelmann1 , S. Mikkat2 , S. Gupta3 , B. Putzer ¨ . University of Rostock, Institute of Experimental Gene Therapy and Cancer 2 Research, Rostock, Germany; University of Rostock, Proteome Center, Rostock, Germany; 3 University of Rostock, Department of Systems Biology and Bioinformatics, Rostock, Germany
Background: Tumour metastasis is considered to be one of the most important problems in cancer research and the identification of mechanisms that drive this multistep process provides urgently needed opportunities for therapeutic interventions. A number of cancer types have been defined by dysfunction of transcriptional coregulators which function through interaction with transcription factors. The transcription factor E2F1 has recently been associated with cancer aggressiveness and poor patient survival prognosis. Although the role of E2F1 in malignant progression is not fully understood, its physical interaction with oncogenic coregulators is clearly linked to the activation of tumor progression-related gene programs which determines occurrence of metastases and clinical outcome. Material and Methods: In order to identify oncogenic E2F1-coregulator complexes, we employed co-immunoprecipitation assays combined with high throughput mass spectrometry in metastatic cancer cells. The identified protein-protein interactions were validated by Western blotting and subcellular colocalization was confirmed by confocal laser scanning microscopy. Co-expression analysis of both proteins was conducted in a large panel of cancer cell lines originating from various tumor entities. We generated stable cell lines depleted for E2F1 or its coregulators and investigated cancer cell motility and invasiveness by matrigel invasion. Genome-wide transcriptome analyses, ChIP and luciferase reporter assays were applied to determine genes regulated by E2F1-coregulator complexes. Finally, we developed a computer-assisted methodology to predict potential drugs out of a virtual library of 2924 drug like molecules disrupting E2F1-cofactor interactions. Results: The mass spectrometry analysis indicated that MTA1 (metastasisassociated protein 1) co-immunoprecipitated with E2F1. This interaction and nuclear colocalization of both proteins were confirmed. Furthermore, we showed that E2F1 directly regulates MTA1 expression in various tumour cells. We also demonstrate that depletion of E2F1 and its coregulator decreases cancer cell motility and invasiveness in vitro. Moreover, knockdown and overexpression experiments showed the MTA1dependent E2F1-regulation of common target genes in highly metastatic cells. Finally, we predicted potential drug molecules that can be used as inhibitors of E2F1 and MTA1 interaction and analysed its inhibitor function in the regulation of target genes. Conclusions: In this study we showed an as yet unrecognized function of MTA1 as an oncogenic E2F1-coregulator. Taken together, our findings delineate the function of the E2F1:MTA1 complex as a decisive factor for cancer cell fate through regulation of gene expression profiles supporting the pursuit of this complex as a target for future cancer therapy. No conflict of interest. 348 POSTER Preclinical evaluation of combinations of hypofractionated tumor gamma-irradiation and checkpoint-blocking or T cell-recruiting antibodies M. Hettich1 , J. Lahoti1 , S. Prasad1 , G. Niedermann1 . 1 University Clinics Freiburg, Dept. of Radiation Oncology, Freiburg, Germany Background: Combinations of local radiotherapy and immunotherapeutics have the potential to enhance local tumor control and to synergize in the induction of systemic antitumor immune responses. However, the optimal dose/fractionation regimens and optimal immunotherapy combinations still have to be defined. Here, we characterized the T cell responses induced by hypofractionated gamma-irradiation in a murine melanoma model and evaluated the extent of synergy of local tumor irradiation and PD-1 checkpoint-blocking or T cell-recruiting antibodies. PD-1 checkpointblocking antibodies enhance antitumor T cell responses; bispecific T cell-recruiting antibodies are capable of redirecting T cells to eradicate malignant cells. As monotherapy, both types of immunotherapeutics have recently shown dramatic efficacy in clinical trials in certain advanced malignancies, but it is not well understood to what extent they synergize with local tumor irradiation. Materials and Methods: We used a subcutaneous flank tumor model by employing B16 melanoma cells expressing the prototypic tumor stem cell marker CD133, which is also a marker for melanoma stem cells. An antagonistic antibody blocking the PD-1 immune checkpoint on T cells or a bispecific (CD133×CD3) antibody recruiting T cells to CD133+ tumor cells was administered after hypofractionated irradiation of either small (200–
Abstracts 250 mm3 ) or large (500–750 mm3 ) flank melanomas. Endpoints included tumor growth, overall survival, and immune infiltrate. Results: Single treatments with either anti-PD-1 checkpoint-blocking or CD133-specific T cell-recruiting antibodies had only very little effect on tumor growth. Hypofractionated tumor irradiation alone delayed tumor growth more strongly, but also only transiently for about 2 weeks. Hypofractionated tumor irradiation induced tumor-specific effector T cells. In accordance with this, the double combination of local radiotherapy and anti-PD-1 antibody caused long-lasting tumor regressions including some complete cures, even in mice with large melanomas. Moreover, the cured mice remained immune to subsequent rechallenge with rather high doses of either CD133+ or CD133− B16 melanoma cells. Noteworthy effects were also observed upon administration of the bispecific T cell-recruiting antibody into mice with irradiated tumors. The underlying mechanisms of these observations will be presented at the meeting. Conclusions: The study suggests that the evaluation of potential synergistic radiotherapy/immunotherapy combinations in immunocompetent mouse tumor models can provide crucial information for clinical trial planning. No conflict of interest. 349 POSTER Impact of the re-definition of dose-limiting toxicities (DLTs) according to recent recommendations on the DLT rate in phase 1 trials of molecularly targeted agents C. Helissey1 , A. Poterie2 , C. Massard1 , A. Hollebecque1 , X. Paoletti2 , E. Lanoy2 , J.C. Soria1 , S. Postel-Vinay1 . 1 Institut Gustave Roussy, Department of Drug Development, Villejuif, France; 2 Institut Gustave Roussy, Epidemiology and Biostatistics, Villejuif, France Background: Aims of Phase I trials are to determine the safety profile of a new drug and recommended dose for later trials. Most phase 1 trials now evaluate molecularly targeted agents (MTA) or immunotherapies, for which late or cumulative toxicities also deserve attention. Recent studies suggest that changes are required to better define DLTs, notably using information from cycles (C) beyond C1, and reductions in dose-intensity (Paoletti 2014, Postel-Vinay 2014). We aimed at assessing the impact on the occurrence of DLTs of using this new “extended” DLT definition (extDLT). Material and Methods: All grade (G) 2 toxicities (CTCAEv3.0 and 4.0) occurring in consecutive patients included in a phase I of MTA at Gustave Roussy between March 2008 and October 2013 were recorded. “Extended DLT” included: protocol-defined DLTs, and the following at any cycle: non-hematological G 3−4 toxicities, non-hematological G2 toxicities lasting >7 days, toxicities preventing the patient from receiving >75% of intended RDI, and toxicities that delayed the beginning of the next treatment cycle of more than half a cycle time. Results: A total of 1167 patients (5945 treatment cycles) were included in 115 eligible trials; 110 trials evaluated MTAs and 5 trials immunotherapeutic agents; 4347 toxicities (3221 G2 and 1126 G3−5) were recorded. 715 patients presented extDLTs at any time on trial; 58% and 42% of extDLTs occurred during and after the first cycle, respectively. Fatigue (325), diarrhea (111) and nausea (91) were the most frequent extDLT types. The observer proportion reached 35% of extDLT, suggesting that the targeted DLT rate of 16−33% was exceeded. When performing this simulation on three trials for which most patient data were available at our institution at the four highest dose levels, the targeted DLT rate was exceeded in two trials, and appropriately reached in one trial. Additional analyses are ongoing and ad hoc updates will be presented at the meeting. Conclusion: Extended DLTs occur regularly after cycle 1 in phase 1 trials of targeted agents. The recent experts recommendations based DLT definition highlights toxicity rates exceeding the targeted rate in most trials. The relevance of keeping a 20% targeted DLT rate at cycle 1 only and the impact of such definition on the recommended dose might deserve further exploration. No conflict of interest. 350 POSTER How effective are novel biological therapies? A systematic review of 121 randomized controlled trials (RCTs) D. Cho1 , F. Roncolato2 , J.J. Man1 , S.J. Lord2 , M. Links1 , J. Simes2 , C.K. Lee2 . 1 St George Hospital, Medical Oncology, Sydney, Australia; 2 The University of Sydney, NHMRC Clinical Trials Centre, Sydney, Australia Background: Novel biological agents have led to major advances in cancer therapeutics. Estimating the size of these gains from RCTs and if prior evidence can be used to predict treatment success (TS) will be valuable to guide future trial design. We assessed the effectiveness of novel agents in advanced breast, lung, prostate or colorectal cancers in phase 3 RCTs to address these questions.
Abstracts Methods: A systematic review of all RCTs published in 1995–2014 evaluating the superiority of novel agents over standard chemotherapy or best supportive care in patients (pts) with advanced cancer, which reported overall survival (OS) and progression-free survival (PFS). TS for a novel agent was defined as (1) a statistically significant (p < 0.05) result favoring the novel agent, and (2) trial investigator conclusions that novel agent was superior to standard treatments. We also calculated pooled hazard ratios (HR) for OS and PFS for novel versus standard treatments. Predictors of TS with novel therapy were identified. Results: We identified 121 eligible trials (134 randomized comparisons) involving 77,303 pts. Trial populations included advanced breast (19%), lung (45%), prostate (11%) and colorectal (25%) cancers. 30 (25%) trials restricted recruitment to pts with specific molecular abnormalities. The primary endpoint was OS in 63 (52%), PFS in 51 (42%), and other endpoints in 7 (6%) trials. Investigators concluded TS in 36% of trials. 17% of 100 available comparisons for OS and 59% of 103 available comparisons for PFS reported statistically significant results in favor of novel therapies; HR 0.93 (95% confidence interval [CI], 0.86–1.00, P = 0.05) and HR 0.80 (CI, 0.74–0.85, P < 0.0001) for OS and PFS respectively. TS for PFS was higher in trials with prior studies of similar treatments with time-toevent outcomes (P = 0.03) and trials in populations enriched with molecular subgroups (P = 0.04). Conclusions: In advanced breast, lung, prostate and colorectal cancers, many novel therapies evaluated in phase 3 RCTs have proven to be less effective than might have been expected from prior evidence. RCTs, albeit with improved designs, will still be needed for most new biological therapies. No conflict of interest. 351 POSTER Sensitive pharmacodynamic assessment of PARP inhibitors for individualized treatment in clinic R. De Haan1 , D. Pluim2 , B. Van Triest1 , M. Verheij1,3 , J.H.M. Schellens2,4,5 , C. Vens1,3 . 1 The Netherlands Cancer Institute, Department of Radiation Oncology, Amsterdam, Netherlands; 2 The Netherlands Cancer Institute, Division of Molecular Pathology, Amsterdam, Netherlands; 3 The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, Netherlands; 4 The Netherlands Cancer Institute, Department of Clinical Pharmacology, Amsterdam, Netherlands; 5 Utrecht University, Department of Pharmaceutical Sciences, Utrecht, Netherlands Background: PARP inhibitors such as olaparib (Lynparza) are currently developed in clinic as anti-cancer drugs, both as monotherapy and in combination with chemotherapy and/or radiotherapy. Sensitive and robus pharmacodynamic (PD) evaluations are needed to monitor individual PARP inhibitor responses. A PD assay is currently available that measures PAR levels (poly ADP-ribose, the direct product of PARP) in peripheral blood mononuclear cells (PBMCs). However, endogenous PAR levels are often too low to reliably quantify reductions from PARP inhibitor treatment. We recently found that the biological effective dose (BED) of olaparib in combination treatment is significantly lower than the BED as single agent (Verhagen et al. Radiother Oncol, 2015), further stressing the need for sensitive assays. The aim of our study was therefore to develop protocols and assays that enable sensitive PD evaluation of PARP inhibitors. Material and Methods: PBMCs were isolated from six healthy volunteers and ex vivo irradiated to induce PAR. Different radiation doses, incubation times and temperatures were tested. Cell lysates were prepared and PAR levels were quantified using a commercially available ELISA based PD assay. To test the quantification capacity of PARP inhibition, we incubated PBMCs ex vivo with increasing doses of the PARP inhibitors olaparib and niraparib. IC50 (half maximal inhibitory concentration) values were calculated from the inhibition curves. Results: We found that PAR levels were strongly induced by ex vivo irradiation and reached a steady state level after 1 hour incubation on ice. Radiation increased PAR levels in a dose dependent and strongly linear manner. As reported previously, endogenous PAR levels are too close to background to accurately quantify PAR reduction in most individuals. Ex vivo PAR induction by radiation, however, enabled quantification of PAR level reductions of >99% (achieved by 10uM olaparib, a dose comparable to monotherapy C-max in plasma). Furthermore, it allowed the determination of IC50 values, that were previously not accurately quantifiable, in all healthy volunteers. IC50 values were robust and reproducible in multiple independent blood draws over a three-month course. Notably, enabled by the increased sensitivity, we showed a differential response in different individuals. We found a significant, almost two-fold, lower IC50 for both PARP inhibitors in one of the six healthy volunteers. Clinical relevance of these data is given by the prominent decline in treatment benefit at two-fold lower dose levels in monotherapy trials. Conclusions: Ex vivo irradiation of PBMCs greatly improved the PD evaluation of PARP inhibitors. The sensitive PD potentials promote the
S71 application to all patients in clinical (combination) trials and identified individual responses that may call for individualized PARP inhibitor treatment. No conflict of interest. 352 POSTER Phase Ia/Ib study of pan-PI3K inhibitor, pictilisib (GDC-0941), in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer (JO28645 study) N. Yanagitani1 , A. Horiike1 , S. Kitazono1 , K. Tamura2 , S. Kondo2 , S. Iwasa2 , Y. Tanabe2 , M. Inatani3 , K. Nakamura3 , N. Kotani4 , N. Yamamoto2 , M. Nishio1 . 1 Cancer Institute Hospital of Japanese Foundation for Cancer Research, Department of Thoracic Medical Oncology, Tokyo, Japan; 2 National Cancer Center, Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, Tokyo, Japan; 3 Chugai Pharmaceutical Co., Ltd., Clinical Development Division, Tokyo, Japan; 4 Chugai Pharmaceutical Co., Ltd., Translational Clinical Research Division, Tokyo, Japan Background: Pictilisib is a selective pan-class I PI3K inhibitor. This study aimed to determine maximum tolerated dose (MTD) or recommended dose (RD) of pictilisib as monotherapy and in combination with carboplatin, paclitaxel, and bevacizumab (CP+Bev) in Japanese patients (pts). Materials and Methods: A 3+3 design was used. In Phase 1a, 12 pts with solid tumors received pictilisib monotherapy (140, 260, and 340 mg), and safety, pharmacokinetics (PK) and pharmacodynamics were evaluated. In Phase 1b, 7 pts with non-squamous non-small cell lung cancer (NSCLC) received pictilisib (260 and 340 mg) in combination with CP+Bev, and safety and PK were evaluated. Results: As of 16 Feb 2015, the study was ongoing. In Phase 1a, 1/6 pts had a dose-limiting toxicity (DLT) (Grade 3 maculopapular rash) in the 340 mg cohort, and RD was determined as 340 mg. Common (3 pts) adverse reactions (ARs) were rash (4), dry skin (4), hyperglycemia (3), diarrhea (3), anorexia (3), pyrexia (3), and dysgeusia (3); Grade 3 ARs were maculopapular rash (2). No partial response (PR) was observed but 1 pt (pancreatic cancer) continued the study treatment for 9 months. Cmax and AUC indicated dose proportionality from 140 to 340 mg with relatively short half-life and high interpatient variability. In Phase 1b, 1/3 pts had a DLT (Grade 3 febrile neutropenia, FN) in the 260 mg cohort, and 2/4 pts had DLTs (1 had Grade 3 FN; 1 had Grade 3 FN and Grade 3 erythema multiforme) in the 340 mg cohort. MTD in combination with CP+Bev remains under investigation. Common ARs were neutropenia (5), nausea (5), anorexia (5), alopecia (5), FN (4), leukopenia (4), sensory peripheral neuropathy (4), rash (3), thrombocytopenia (3), hypertension (3), and constipation (3); Grade 3 ARs were neutropenia (5), FN (4), leucopenia (2), anemia (1), lymphopenia (1), and erythema multiforme (1). Two pts had confirmed PR and have continued the study treatment beyond 6 months. Conclusion: RD of pictilisib monotherapy was defined as 340 mg in Japanese pts. Investigation of MTD in combination with CP+Bev is ongoing. High incidence of FN emerged, and data will be evaluated in the context of global studies in NSCLC pts who received similar treatment. Conflict of interest: Advisory Board: M. Nishio is advisory board member of Chugai and Novartis. Corporate-sponsored Research: A. Horiike has received research funding from Chugai. K. Tamura has received research funding from Chugai and Novartis. Y. Fujiwara has received research funding from AstraZeneca, Eli Lilly and GSK. S. Iwasa has received research funding from Chugai and Novartis. N. Yamamoto has received research funding from Quintiles, Astellas, Chugai, Esai, Taiho, BMS and Daiichi-Sankyo. M. Nishio has received research funding from Chugai and Novartis. Other Substantive Relationships: M. Inatani, K. Nakamura and N. Kotani are employees of Chugai. 353 POSTER HIF-2 alpha targeting with a novel RNAi delivery platform as therapy for renal cell carcinoma S. Wong1 , W. Cheng1 , D. Wakefield2 , A. Almeida2 , A. Blokhin2 , L. Almeida2 , H. Hamilton1 , V. Subbotin3 , J. Hegge1 , S. Bertin1 , T. Milarch4 , R. Schmidt4 , Z. Neal1 , A. Perillo-Nicholas2 , G. Zhang1 , J. Montez1 , A. Andersen1 , D. Rozema1 , D. Lewis5 , S. Kanner1 . 1 Arrowhead Research Corporation, Biology, Madison, USA; 2 Arrowhead Research Corporation, Chemistry, Madison, USA; 3 Arrowhead Research Corporation, Pathology, Madison, USA; 4 Arrowhead Research Corporation, LAR, Madison, USA; 5 Arrowhead Research Corporation, Corporate, Madison, USA Background: Therapies for metastatic clear cell renal cell carcinoma (ccRCC) including agents that target the VEGF/VEGFR or mTor signaling
Background: Tumour metastasis is considered to be one of the most important problems in cancer research and the identification of mechanisms that drive this multistep process provides urgently needed opportunities for therapeutic interventions. A number of cancer types have been defined by dysfunction of transcriptional coregulators which function through interaction with transcription factors. The transcription factor E2F1 has recently been associated with cancer aggressiveness and poor patient survival prognosis. Although the role of E2F1 in malignant progression is not fully understood, its physical interaction with oncogenic coregulators is clearly linked to the activation of tumor progression-related gene programs which determines occurrence of metastases and clinical outcome. Material and Methods: In order to identify oncogenic E2F1-coregulator complexes, we employed co-immunoprecipitation assays combined with high throughput mass spectrometry in metastatic cancer cells. The identified protein-protein interactions were validated by Western blotting and subcellular colocalization was confirmed by confocal laser scanning microscopy. Co-expression analysis of both proteins was conducted in a large panel of cancer cell lines originating from various tumor entities. We generated stable cell lines depleted for E2F1 or its coregulators and investigated cancer cell motility and invasiveness by matrigel invasion. Genome-wide transcriptome analyses, ChIP and luciferase reporter assays were applied to determine genes regulated by E2F1-coregulator complexes. Finally, we developed a computer-assisted methodology to predict potential drugs out of a virtual library of 2924 drug like molecules disrupting E2F1-cofactor interactions. Results: The mass spectrometry analysis indicated that MTA1 (metastasisassociated protein 1) co-immunoprecipitated with E2F1. This interaction and nuclear colocalization of both proteins were confirmed. Furthermore, we showed that E2F1 directly regulates MTA1 expression in various tumour cells. We also demonstrate that depletion of E2F1 and its coregulator decreases cancer cell motility and invasiveness in vitro. Moreover, knockdown and overexpression experiments showed the MTA1dependent E2F1-regulation of common target genes in highly metastatic cells. Finally, we predicted potential drug molecules that can be used as inhibitors of E2F1 and MTA1 interaction and analysed its inhibitor function in the regulation of target genes. Conclusions: In this study we showed an as yet unrecognized function of MTA1 as an oncogenic E2F1-coregulator. Taken together, our findings delineate the function of the E2F1:MTA1 complex as a decisive factor for cancer cell fate through regulation of gene expression profiles supporting the pursuit of this complex as a target for future cancer therapy. No conflict of interest. 348 POSTER Preclinical evaluation of combinations of hypofractionated tumor gamma-irradiation and checkpoint-blocking or T cell-recruiting antibodies M. Hettich1 , J. Lahoti1 , S. Prasad1 , G. Niedermann1 . 1 University Clinics Freiburg, Dept. of Radiation Oncology, Freiburg, Germany Background: Combinations of local radiotherapy and immunotherapeutics have the potential to enhance local tumor control and to synergize in the induction of systemic antitumor immune responses. However, the optimal dose/fractionation regimens and optimal immunotherapy combinations still have to be defined. Here, we characterized the T cell responses induced by hypofractionated gamma-irradiation in a murine melanoma model and evaluated the extent of synergy of local tumor irradiation and PD-1 checkpoint-blocking or T cell-recruiting antibodies. PD-1 checkpointblocking antibodies enhance antitumor T cell responses; bispecific T cell-recruiting antibodies are capable of redirecting T cells to eradicate malignant cells. As monotherapy, both types of immunotherapeutics have recently shown dramatic efficacy in clinical trials in certain advanced malignancies, but it is not well understood to what extent they synergize with local tumor irradiation. Materials and Methods: We used a subcutaneous flank tumor model by employing B16 melanoma cells expressing the prototypic tumor stem cell marker CD133, which is also a marker for melanoma stem cells. An antagonistic antibody blocking the PD-1 immune checkpoint on T cells or a bispecific (CD133×CD3) antibody recruiting T cells to CD133+ tumor cells was administered after hypofractionated irradiation of either small (200–
Abstracts 250 mm3 ) or large (500–750 mm3 ) flank melanomas. Endpoints included tumor growth, overall survival, and immune infiltrate. Results: Single treatments with either anti-PD-1 checkpoint-blocking or CD133-specific T cell-recruiting antibodies had only very little effect on tumor growth. Hypofractionated tumor irradiation alone delayed tumor growth more strongly, but also only transiently for about 2 weeks. Hypofractionated tumor irradiation induced tumor-specific effector T cells. In accordance with this, the double combination of local radiotherapy and anti-PD-1 antibody caused long-lasting tumor regressions including some complete cures, even in mice with large melanomas. Moreover, the cured mice remained immune to subsequent rechallenge with rather high doses of either CD133+ or CD133− B16 melanoma cells. Noteworthy effects were also observed upon administration of the bispecific T cell-recruiting antibody into mice with irradiated tumors. The underlying mechanisms of these observations will be presented at the meeting. Conclusions: The study suggests that the evaluation of potential synergistic radiotherapy/immunotherapy combinations in immunocompetent mouse tumor models can provide crucial information for clinical trial planning. No conflict of interest. 349 POSTER Impact of the re-definition of dose-limiting toxicities (DLTs) according to recent recommendations on the DLT rate in phase 1 trials of molecularly targeted agents C. Helissey1 , A. Poterie2 , C. Massard1 , A. Hollebecque1 , X. Paoletti2 , E. Lanoy2 , J.C. Soria1 , S. Postel-Vinay1 . 1 Institut Gustave Roussy, Department of Drug Development, Villejuif, France; 2 Institut Gustave Roussy, Epidemiology and Biostatistics, Villejuif, France Background: Aims of Phase I trials are to determine the safety profile of a new drug and recommended dose for later trials. Most phase 1 trials now evaluate molecularly targeted agents (MTA) or immunotherapies, for which late or cumulative toxicities also deserve attention. Recent studies suggest that changes are required to better define DLTs, notably using information from cycles (C) beyond C1, and reductions in dose-intensity (Paoletti 2014, Postel-Vinay 2014). We aimed at assessing the impact on the occurrence of DLTs of using this new “extended” DLT definition (extDLT). Material and Methods: All grade (G) 2 toxicities (CTCAEv3.0 and 4.0) occurring in consecutive patients included in a phase I of MTA at Gustave Roussy between March 2008 and October 2013 were recorded. “Extended DLT” included: protocol-defined DLTs, and the following at any cycle: non-hematological G 3−4 toxicities, non-hematological G2 toxicities lasting >7 days, toxicities preventing the patient from receiving >75% of intended RDI, and toxicities that delayed the beginning of the next treatment cycle of more than half a cycle time. Results: A total of 1167 patients (5945 treatment cycles) were included in 115 eligible trials; 110 trials evaluated MTAs and 5 trials immunotherapeutic agents; 4347 toxicities (3221 G2 and 1126 G3−5) were recorded. 715 patients presented extDLTs at any time on trial; 58% and 42% of extDLTs occurred during and after the first cycle, respectively. Fatigue (325), diarrhea (111) and nausea (91) were the most frequent extDLT types. The observer proportion reached 35% of extDLT, suggesting that the targeted DLT rate of 16−33% was exceeded. When performing this simulation on three trials for which most patient data were available at our institution at the four highest dose levels, the targeted DLT rate was exceeded in two trials, and appropriately reached in one trial. Additional analyses are ongoing and ad hoc updates will be presented at the meeting. Conclusion: Extended DLTs occur regularly after cycle 1 in phase 1 trials of targeted agents. The recent experts recommendations based DLT definition highlights toxicity rates exceeding the targeted rate in most trials. The relevance of keeping a 20% targeted DLT rate at cycle 1 only and the impact of such definition on the recommended dose might deserve further exploration. No conflict of interest. 350 POSTER How effective are novel biological therapies? A systematic review of 121 randomized controlled trials (RCTs) D. Cho1 , F. Roncolato2 , J.J. Man1 , S.J. Lord2 , M. Links1 , J. Simes2 , C.K. Lee2 . 1 St George Hospital, Medical Oncology, Sydney, Australia; 2 The University of Sydney, NHMRC Clinical Trials Centre, Sydney, Australia Background: Novel biological agents have led to major advances in cancer therapeutics. Estimating the size of these gains from RCTs and if prior evidence can be used to predict treatment success (TS) will be valuable to guide future trial design. We assessed the effectiveness of novel agents in advanced breast, lung, prostate or colorectal cancers in phase 3 RCTs to address these questions.
Abstracts Methods: A systematic review of all RCTs published in 1995–2014 evaluating the superiority of novel agents over standard chemotherapy or best supportive care in patients (pts) with advanced cancer, which reported overall survival (OS) and progression-free survival (PFS). TS for a novel agent was defined as (1) a statistically significant (p < 0.05) result favoring the novel agent, and (2) trial investigator conclusions that novel agent was superior to standard treatments. We also calculated pooled hazard ratios (HR) for OS and PFS for novel versus standard treatments. Predictors of TS with novel therapy were identified. Results: We identified 121 eligible trials (134 randomized comparisons) involving 77,303 pts. Trial populations included advanced breast (19%), lung (45%), prostate (11%) and colorectal (25%) cancers. 30 (25%) trials restricted recruitment to pts with specific molecular abnormalities. The primary endpoint was OS in 63 (52%), PFS in 51 (42%), and other endpoints in 7 (6%) trials. Investigators concluded TS in 36% of trials. 17% of 100 available comparisons for OS and 59% of 103 available comparisons for PFS reported statistically significant results in favor of novel therapies; HR 0.93 (95% confidence interval [CI], 0.86–1.00, P = 0.05) and HR 0.80 (CI, 0.74–0.85, P < 0.0001) for OS and PFS respectively. TS for PFS was higher in trials with prior studies of similar treatments with time-toevent outcomes (P = 0.03) and trials in populations enriched with molecular subgroups (P = 0.04). Conclusions: In advanced breast, lung, prostate and colorectal cancers, many novel therapies evaluated in phase 3 RCTs have proven to be less effective than might have been expected from prior evidence. RCTs, albeit with improved designs, will still be needed for most new biological therapies. No conflict of interest. 351 POSTER Sensitive pharmacodynamic assessment of PARP inhibitors for individualized treatment in clinic R. De Haan1 , D. Pluim2 , B. Van Triest1 , M. Verheij1,3 , J.H.M. Schellens2,4,5 , C. Vens1,3 . 1 The Netherlands Cancer Institute, Department of Radiation Oncology, Amsterdam, Netherlands; 2 The Netherlands Cancer Institute, Division of Molecular Pathology, Amsterdam, Netherlands; 3 The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, Netherlands; 4 The Netherlands Cancer Institute, Department of Clinical Pharmacology, Amsterdam, Netherlands; 5 Utrecht University, Department of Pharmaceutical Sciences, Utrecht, Netherlands Background: PARP inhibitors such as olaparib (Lynparza) are currently developed in clinic as anti-cancer drugs, both as monotherapy and in combination with chemotherapy and/or radiotherapy. Sensitive and robus pharmacodynamic (PD) evaluations are needed to monitor individual PARP inhibitor responses. A PD assay is currently available that measures PAR levels (poly ADP-ribose, the direct product of PARP) in peripheral blood mononuclear cells (PBMCs). However, endogenous PAR levels are often too low to reliably quantify reductions from PARP inhibitor treatment. We recently found that the biological effective dose (BED) of olaparib in combination treatment is significantly lower than the BED as single agent (Verhagen et al. Radiother Oncol, 2015), further stressing the need for sensitive assays. The aim of our study was therefore to develop protocols and assays that enable sensitive PD evaluation of PARP inhibitors. Material and Methods: PBMCs were isolated from six healthy volunteers and ex vivo irradiated to induce PAR. Different radiation doses, incubation times and temperatures were tested. Cell lysates were prepared and PAR levels were quantified using a commercially available ELISA based PD assay. To test the quantification capacity of PARP inhibition, we incubated PBMCs ex vivo with increasing doses of the PARP inhibitors olaparib and niraparib. IC50 (half maximal inhibitory concentration) values were calculated from the inhibition curves. Results: We found that PAR levels were strongly induced by ex vivo irradiation and reached a steady state level after 1 hour incubation on ice. Radiation increased PAR levels in a dose dependent and strongly linear manner. As reported previously, endogenous PAR levels are too close to background to accurately quantify PAR reduction in most individuals. Ex vivo PAR induction by radiation, however, enabled quantification of PAR level reductions of >99% (achieved by 10uM olaparib, a dose comparable to monotherapy C-max in plasma). Furthermore, it allowed the determination of IC50 values, that were previously not accurately quantifiable, in all healthy volunteers. IC50 values were robust and reproducible in multiple independent blood draws over a three-month course. Notably, enabled by the increased sensitivity, we showed a differential response in different individuals. We found a significant, almost two-fold, lower IC50 for both PARP inhibitors in one of the six healthy volunteers. Clinical relevance of these data is given by the prominent decline in treatment benefit at two-fold lower dose levels in monotherapy trials. Conclusions: Ex vivo irradiation of PBMCs greatly improved the PD evaluation of PARP inhibitors. The sensitive PD potentials promote the
S71 application to all patients in clinical (combination) trials and identified individual responses that may call for individualized PARP inhibitor treatment. No conflict of interest. 352 POSTER Phase Ia/Ib study of pan-PI3K inhibitor, pictilisib (GDC-0941), in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer (JO28645 study) N. Yanagitani1 , A. Horiike1 , S. Kitazono1 , K. Tamura2 , S. Kondo2 , S. Iwasa2 , Y. Tanabe2 , M. Inatani3 , K. Nakamura3 , N. Kotani4 , N. Yamamoto2 , M. Nishio1 . 1 Cancer Institute Hospital of Japanese Foundation for Cancer Research, Department of Thoracic Medical Oncology, Tokyo, Japan; 2 National Cancer Center, Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, Tokyo, Japan; 3 Chugai Pharmaceutical Co., Ltd., Clinical Development Division, Tokyo, Japan; 4 Chugai Pharmaceutical Co., Ltd., Translational Clinical Research Division, Tokyo, Japan Background: Pictilisib is a selective pan-class I PI3K inhibitor. This study aimed to determine maximum tolerated dose (MTD) or recommended dose (RD) of pictilisib as monotherapy and in combination with carboplatin, paclitaxel, and bevacizumab (CP+Bev) in Japanese patients (pts). Materials and Methods: A 3+3 design was used. In Phase 1a, 12 pts with solid tumors received pictilisib monotherapy (140, 260, and 340 mg), and safety, pharmacokinetics (PK) and pharmacodynamics were evaluated. In Phase 1b, 7 pts with non-squamous non-small cell lung cancer (NSCLC) received pictilisib (260 and 340 mg) in combination with CP+Bev, and safety and PK were evaluated. Results: As of 16 Feb 2015, the study was ongoing. In Phase 1a, 1/6 pts had a dose-limiting toxicity (DLT) (Grade 3 maculopapular rash) in the 340 mg cohort, and RD was determined as 340 mg. Common (3 pts) adverse reactions (ARs) were rash (4), dry skin (4), hyperglycemia (3), diarrhea (3), anorexia (3), pyrexia (3), and dysgeusia (3); Grade 3 ARs were maculopapular rash (2). No partial response (PR) was observed but 1 pt (pancreatic cancer) continued the study treatment for 9 months. Cmax and AUC indicated dose proportionality from 140 to 340 mg with relatively short half-life and high interpatient variability. In Phase 1b, 1/3 pts had a DLT (Grade 3 febrile neutropenia, FN) in the 260 mg cohort, and 2/4 pts had DLTs (1 had Grade 3 FN; 1 had Grade 3 FN and Grade 3 erythema multiforme) in the 340 mg cohort. MTD in combination with CP+Bev remains under investigation. Common ARs were neutropenia (5), nausea (5), anorexia (5), alopecia (5), FN (4), leukopenia (4), sensory peripheral neuropathy (4), rash (3), thrombocytopenia (3), hypertension (3), and constipation (3); Grade 3 ARs were neutropenia (5), FN (4), leucopenia (2), anemia (1), lymphopenia (1), and erythema multiforme (1). Two pts had confirmed PR and have continued the study treatment beyond 6 months. Conclusion: RD of pictilisib monotherapy was defined as 340 mg in Japanese pts. Investigation of MTD in combination with CP+Bev is ongoing. High incidence of FN emerged, and data will be evaluated in the context of global studies in NSCLC pts who received similar treatment. Conflict of interest: Advisory Board: M. Nishio is advisory board member of Chugai and Novartis. Corporate-sponsored Research: A. Horiike has received research funding from Chugai. K. Tamura has received research funding from Chugai and Novartis. Y. Fujiwara has received research funding from AstraZeneca, Eli Lilly and GSK. S. Iwasa has received research funding from Chugai and Novartis. N. Yamamoto has received research funding from Quintiles, Astellas, Chugai, Esai, Taiho, BMS and Daiichi-Sankyo. M. Nishio has received research funding from Chugai and Novartis. Other Substantive Relationships: M. Inatani, K. Nakamura and N. Kotani are employees of Chugai. 353 POSTER HIF-2 alpha targeting with a novel RNAi delivery platform as therapy for renal cell carcinoma S. Wong1 , W. Cheng1 , D. Wakefield2 , A. Almeida2 , A. Blokhin2 , L. Almeida2 , H. Hamilton1 , V. Subbotin3 , J. Hegge1 , S. Bertin1 , T. Milarch4 , R. Schmidt4 , Z. Neal1 , A. Perillo-Nicholas2 , G. Zhang1 , J. Montez1 , A. Andersen1 , D. Rozema1 , D. Lewis5 , S. Kanner1 . 1 Arrowhead Research Corporation, Biology, Madison, USA; 2 Arrowhead Research Corporation, Chemistry, Madison, USA; 3 Arrowhead Research Corporation, Pathology, Madison, USA; 4 Arrowhead Research Corporation, LAR, Madison, USA; 5 Arrowhead Research Corporation, Corporate, Madison, USA Background: Therapies for metastatic clear cell renal cell carcinoma (ccRCC) including agents that target the VEGF/VEGFR or mTor signaling