- Email: [email protected]
213 A phase I dose-finding study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in Japanese and Taiwanese patients with advanced or metastatic solid tumors
72
Thursday 20 November 2014
Plenary Session 6
212 ORAL PRESENTATION Novel anti-tumor activity of targeted LSD1 inhibition by GSK2879552 H. Mohammad1 , K. Smitheman1 , G. Van Aller2 , M. Cusan3 , S. Kamat4 , Y. Liu2 , N. Johnson2 , C. Hann4 , S. Armstrong3 , R. Kruger2 . 1 GlaxoSmithKline, Cancer Epigenetics, Collegeville PA, USA; 2 GlaxoSmithKline, Cancer Epigenetics, Collegeville, USA; 3 MSKCC, Pediatrics, New York, USA; 4 Johns Hopkins University, Oncology, Baltimore, USA Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. LSD1 mediated H3K4 demethylation can result in repressive chromatin environment that silences gene expression and has been shown to play a role in development and hematopoietic differentiation. LSD1 is overexpressed in multiple tumor types, including acute myeloid leukemia (AML). Together, these studies suggest LSD1 is an important regulator of the epigenome that modulates gene expression through modification of histones and its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel, potent, irreversible, GSK LSD1 inhibitor (GSK2879552) in AML and small cell lung cancer (SCLC). Screening of over 150 cancer cell lines revealed that SCLC and AML cells have a unique requirement for LSD1. While LSD1 inhibition did not affect the global levels of H3K4me1 or H3K4me2, local changes in these histone marks were observed near transcriptional start sites of putative LSD1 target genes. This increase in the transcriptionally activating histone modification correlates with increased gene expression. Treatment of AML cells with GSK2879552 promotes the expression of cell surface markers associated with a differentiated immunophenotype, including CD11b and CD86. In an MV-4−11 engraftment model, increases in CD86 and CD11b were observed as early as 8 hours post dosing. GSK2879552 treatment resulted in a potent anti-proliferative growth effect in a subset of SCLC cell lines tested and all AML cell lines tested. Potent growth inhibition was also observed on AML blast colony forming ability of bone marrow samples derived from primary AML patient samples. The effects of LSD1 inhibition were further characterized in vivo using a mouse model of AML induced by transduction of mouse hematopoietic progenitor cells with a retrovirus encoding MLL-AF9 and GFP. Primary AML cells were transplanted into secondary recipient mice that were treated with an LSD1 tool molecule inhibitor for 17 days. Control mice succumbed to AML by 45 days post transplant, while treated mice showed prolonged survival. GSK2879552 treatment of mice engrafted with SCLC cell lines resulted in greater than 80% tumor growth inhibition. Studies using patient derived primary SCLC showed similar efficacy demonstrating the growth inhibition of SCLC with an LSD1 inhibitor extended beyond cell lines. Together, these data demonstrate that pharmacological inhibition of LSD1 may provide a promising treatment for AML and SCLC. A Phase I clinical trial using GSK2879552 was initiated in March, 2014. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
Thursday 20 November 2014
13:30–15:35
PLENARY SESSION 6
Proffered Paper Session 213 ORAL PRESENTATION A phase I dose-finding study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in Japanese and Taiwanese patients with advanced or metastatic solid tumors T. Doi1 , C.C. Lin2 , A. Ohtsu3 , J.C.H. Yang2 , K. Shitara3 , L.C. Pronk4 , A. Sarashina5 , A.L. Cheng2 . 1 National Cancer Center Hospital East, Gasrtointestinal Oncology, Chiba, Japan; 2 National Taiwan University Hospital, Department of Oncology, Taipei, Taiwan; 3 National Cancer Center Hospital East, Department of Experimental Therapeutics, ˜ S.A., Clinical Development Chiba, Japan; 4 Boehringer Ingelheim Espana Oncology, Barcelona, Spain; 5 Nippon Boehringer Ingelheim Co. Ltd, Clinical PK/PD department, Kobe, Japan Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that contributes to activation of multiple downstream-signaling pathways involved in tumor cell survival, proliferation, invasion, and metastasis. BI 853520 is a potent and highly selective inhibitor of FAK with an IC50 of 1nM. It has shown efficacy in multiple xenograft models of human cancer.
Material and Methods: This is a phase I, dose-finding study of BI 853520 given as a continuous oral dosing regimen in 28-day cycles in a mixed population of Japanese and Taiwanese patients (pts) with progressive, advanced or metastatic solid tumors. Endpoints include safety, determination of maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and efficacy, determined according to RECIST v1.1 criteria. Results: To date, 18 pts have received doses of 50, 100 and 200 mg qd of which 14 pts are evaluable for dose limiting toxicity (DLT). Male/female ratio was 12/6, median age 65 years (range, 35−77 years), ECOG PS 0/1:10/8. Primary tumor types: 4 gastric cancer, 2 colorectal cancer; 2 oesophageal cancer, and 10 others. Median number of prior systemic treatments: 3. Drug-related adverse events (AEs) in >10% of pts included proteinuria (44.4%), diarrhea (38.9%), nausea (22.2%), vomiting (22.2%), inflammatory fibrous thickening in the palm of the hand (11.1%), maculopapular rash (11.1%) and decreased appetite (11.1%), all of NCI Common Terminology Criteria for AEs (v4.03) grade 1−2 except for one patient who had proteinuria grade 3 that occurred during cycle 2 at the 200 mg dose and was considered DLT. So far, no DLTs have been observed during cycle 1 and no drug-related serious AEs have been reported. The MTD was determined as 200 mg qd and the 200 mg cohort is expanded to a total of 12 patients to confirm the MTD. PK:Preliminary data suggest that plasma exposure increased with increasing doses. Based on the observed accumulation and half-life, a once-daily dosing scheme is supported. Preliminary efficacy: Of 12 evaluable pts, 1 pt with gastric cancer achieved a partial response (100 mg qd), 2 pts presented stable disease: 1 pt with oesophageal cancer and 1 with urachal cancer lasting 7 and 8 cycles, respectively (both 50 mg qd), and 9 pts progressed. Conclusion: The safety profile of BI 853520 is favourable. PK analysis supports the once-daily dosing schedule. Recruitment at the 200 mg dose is ongoing to confirm the MTD. An update will be provided at the meeting.
214 ORAL PRESENTATION Homologous recombination deficiency (HRD) score and niraparib efficacy in high grade ovarian cancer P. Haluska1 , K.M. Timms2 , M. AlHilli1 , Y. Wang3 , A.M. Hartman2 , J. Jones2 , A. Gutin2 , Z. Sangale2 , C. Neff2 , J. Lynchbury2 , L. Rudolph-Owen3 , M.A. Becker1 , S. Agarwal3 , K.M. Wilcoxen3 . 1 Mayo Clinic, Rochester, USA; 2 Myriad Genetics, Salt Lake City, USA; 3 Tesaro Inc., Waltham, USA Purpose: The therapeutic potential of PARP inhibitors is predicted to extend beyond BRCA mutant (BRCAmut ) phenotypes to homologous recombination deficient (HRD) cancers. An HRD assay amenable for clinical testing was applied to treatment na¨ıve, high grade ovarian primary tumor samples. Niraparib treated patient-derived tumorgraft models selected from these primary ovarian tumors were utilized to evaluate the correlation between HRD score, BRCA deficiency, platinum sensitivity and niraparib anti-tumor response. Methods: Utilizing patient-derived ovarian xenografts we previously demonstrated response to niraparibin both BRCAmut and BRCA wild type (BRCAwt ) tumors. BRCAmut status alone was neither necessary nor sufficient to predict response to niraparib. To understand the selectivity observed, samples from a collection of >100 high grade ovarian tumors were subjected to HRD analysis. The HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT2 capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using all three algorithms; Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI) and Large-scale State Transistions (LST). The final HRD score is the sum of the LOH+TAI+LST scores with numerical outputs ranging from 0– 100. RNAseq analysis was also conducted on a subset of the ovarian tumors. Niraparib was then evaluated as a monotherapy in a series of high grade ovarian cancer tumorgrafts with a diverse range of HRD scores. Intraperitoneal tumorgrafts were monitored for tumor growth with twiceweekly transabdominal ultrasound imaging. In-vivo response to niraparib was correlated to the HRD score, BRCA status, patient’s platinum response and RNAseq data. Results: One hundred and six high grade ovarian tumors were evaluated for HRD, BRCA mutation, and RNAseq analysis. Twenty one tumors (20%) had a deleterious somatic or germline BRCAmut . BRCA1 hypermethylation was evaluated in 98 tumors and found in 6, representing approximately 6% of this cohort. Collectively, there was 26% BRCA deficiency in this primary tumor collection. HRD scores ranged from 1−86 with a median score of 32 and an average score of 39. All BRCAmut tumors and 83% (5/6) of the BRCA1 hypermethylated tumors had an HRD score of 31 or greater. The BRCA1 hypermethylated tumor with a low HRD score does not have loss of heterozygosity (LOH) at BRCA1, and likely retains functional BRCA1. Invivo response to niraparib monotherapy was demonstrated in BRCAmut and
Thursday 20 November 2014
Plenary Session 6
212 ORAL PRESENTATION Novel anti-tumor activity of targeted LSD1 inhibition by GSK2879552 H. Mohammad1 , K. Smitheman1 , G. Van Aller2 , M. Cusan3 , S. Kamat4 , Y. Liu2 , N. Johnson2 , C. Hann4 , S. Armstrong3 , R. Kruger2 . 1 GlaxoSmithKline, Cancer Epigenetics, Collegeville PA, USA; 2 GlaxoSmithKline, Cancer Epigenetics, Collegeville, USA; 3 MSKCC, Pediatrics, New York, USA; 4 Johns Hopkins University, Oncology, Baltimore, USA Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. LSD1 mediated H3K4 demethylation can result in repressive chromatin environment that silences gene expression and has been shown to play a role in development and hematopoietic differentiation. LSD1 is overexpressed in multiple tumor types, including acute myeloid leukemia (AML). Together, these studies suggest LSD1 is an important regulator of the epigenome that modulates gene expression through modification of histones and its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel, potent, irreversible, GSK LSD1 inhibitor (GSK2879552) in AML and small cell lung cancer (SCLC). Screening of over 150 cancer cell lines revealed that SCLC and AML cells have a unique requirement for LSD1. While LSD1 inhibition did not affect the global levels of H3K4me1 or H3K4me2, local changes in these histone marks were observed near transcriptional start sites of putative LSD1 target genes. This increase in the transcriptionally activating histone modification correlates with increased gene expression. Treatment of AML cells with GSK2879552 promotes the expression of cell surface markers associated with a differentiated immunophenotype, including CD11b and CD86. In an MV-4−11 engraftment model, increases in CD86 and CD11b were observed as early as 8 hours post dosing. GSK2879552 treatment resulted in a potent anti-proliferative growth effect in a subset of SCLC cell lines tested and all AML cell lines tested. Potent growth inhibition was also observed on AML blast colony forming ability of bone marrow samples derived from primary AML patient samples. The effects of LSD1 inhibition were further characterized in vivo using a mouse model of AML induced by transduction of mouse hematopoietic progenitor cells with a retrovirus encoding MLL-AF9 and GFP. Primary AML cells were transplanted into secondary recipient mice that were treated with an LSD1 tool molecule inhibitor for 17 days. Control mice succumbed to AML by 45 days post transplant, while treated mice showed prolonged survival. GSK2879552 treatment of mice engrafted with SCLC cell lines resulted in greater than 80% tumor growth inhibition. Studies using patient derived primary SCLC showed similar efficacy demonstrating the growth inhibition of SCLC with an LSD1 inhibitor extended beyond cell lines. Together, these data demonstrate that pharmacological inhibition of LSD1 may provide a promising treatment for AML and SCLC. A Phase I clinical trial using GSK2879552 was initiated in March, 2014. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
Thursday 20 November 2014
13:30–15:35
PLENARY SESSION 6
Proffered Paper Session 213 ORAL PRESENTATION A phase I dose-finding study of BI 853520, a potent and selective inhibitor of focal adhesion kinase (FAK), in Japanese and Taiwanese patients with advanced or metastatic solid tumors T. Doi1 , C.C. Lin2 , A. Ohtsu3 , J.C.H. Yang2 , K. Shitara3 , L.C. Pronk4 , A. Sarashina5 , A.L. Cheng2 . 1 National Cancer Center Hospital East, Gasrtointestinal Oncology, Chiba, Japan; 2 National Taiwan University Hospital, Department of Oncology, Taipei, Taiwan; 3 National Cancer Center Hospital East, Department of Experimental Therapeutics, ˜ S.A., Clinical Development Chiba, Japan; 4 Boehringer Ingelheim Espana Oncology, Barcelona, Spain; 5 Nippon Boehringer Ingelheim Co. Ltd, Clinical PK/PD department, Kobe, Japan Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that contributes to activation of multiple downstream-signaling pathways involved in tumor cell survival, proliferation, invasion, and metastasis. BI 853520 is a potent and highly selective inhibitor of FAK with an IC50 of 1nM. It has shown efficacy in multiple xenograft models of human cancer.
Material and Methods: This is a phase I, dose-finding study of BI 853520 given as a continuous oral dosing regimen in 28-day cycles in a mixed population of Japanese and Taiwanese patients (pts) with progressive, advanced or metastatic solid tumors. Endpoints include safety, determination of maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and efficacy, determined according to RECIST v1.1 criteria. Results: To date, 18 pts have received doses of 50, 100 and 200 mg qd of which 14 pts are evaluable for dose limiting toxicity (DLT). Male/female ratio was 12/6, median age 65 years (range, 35−77 years), ECOG PS 0/1:10/8. Primary tumor types: 4 gastric cancer, 2 colorectal cancer; 2 oesophageal cancer, and 10 others. Median number of prior systemic treatments: 3. Drug-related adverse events (AEs) in >10% of pts included proteinuria (44.4%), diarrhea (38.9%), nausea (22.2%), vomiting (22.2%), inflammatory fibrous thickening in the palm of the hand (11.1%), maculopapular rash (11.1%) and decreased appetite (11.1%), all of NCI Common Terminology Criteria for AEs (v4.03) grade 1−2 except for one patient who had proteinuria grade 3 that occurred during cycle 2 at the 200 mg dose and was considered DLT. So far, no DLTs have been observed during cycle 1 and no drug-related serious AEs have been reported. The MTD was determined as 200 mg qd and the 200 mg cohort is expanded to a total of 12 patients to confirm the MTD. PK:Preliminary data suggest that plasma exposure increased with increasing doses. Based on the observed accumulation and half-life, a once-daily dosing scheme is supported. Preliminary efficacy: Of 12 evaluable pts, 1 pt with gastric cancer achieved a partial response (100 mg qd), 2 pts presented stable disease: 1 pt with oesophageal cancer and 1 with urachal cancer lasting 7 and 8 cycles, respectively (both 50 mg qd), and 9 pts progressed. Conclusion: The safety profile of BI 853520 is favourable. PK analysis supports the once-daily dosing schedule. Recruitment at the 200 mg dose is ongoing to confirm the MTD. An update will be provided at the meeting.
214 ORAL PRESENTATION Homologous recombination deficiency (HRD) score and niraparib efficacy in high grade ovarian cancer P. Haluska1 , K.M. Timms2 , M. AlHilli1 , Y. Wang3 , A.M. Hartman2 , J. Jones2 , A. Gutin2 , Z. Sangale2 , C. Neff2 , J. Lynchbury2 , L. Rudolph-Owen3 , M.A. Becker1 , S. Agarwal3 , K.M. Wilcoxen3 . 1 Mayo Clinic, Rochester, USA; 2 Myriad Genetics, Salt Lake City, USA; 3 Tesaro Inc., Waltham, USA Purpose: The therapeutic potential of PARP inhibitors is predicted to extend beyond BRCA mutant (BRCAmut ) phenotypes to homologous recombination deficient (HRD) cancers. An HRD assay amenable for clinical testing was applied to treatment na¨ıve, high grade ovarian primary tumor samples. Niraparib treated patient-derived tumorgraft models selected from these primary ovarian tumors were utilized to evaluate the correlation between HRD score, BRCA deficiency, platinum sensitivity and niraparib anti-tumor response. Methods: Utilizing patient-derived ovarian xenografts we previously demonstrated response to niraparibin both BRCAmut and BRCA wild type (BRCAwt ) tumors. BRCAmut status alone was neither necessary nor sufficient to predict response to niraparib. To understand the selectivity observed, samples from a collection of >100 high grade ovarian tumors were subjected to HRD analysis. The HRD analysis is a DNA-based assay that is capable of detecting homologous recombination deficiency independent of its etiology. Genome-wide SNP data was generated from a custom Agilent SureSelect XT2 capture followed by sequencing on an Illumina HiSeq2500. SNP data was analyzed using all three algorithms; Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI) and Large-scale State Transistions (LST). The final HRD score is the sum of the LOH+TAI+LST scores with numerical outputs ranging from 0– 100. RNAseq analysis was also conducted on a subset of the ovarian tumors. Niraparib was then evaluated as a monotherapy in a series of high grade ovarian cancer tumorgrafts with a diverse range of HRD scores. Intraperitoneal tumorgrafts were monitored for tumor growth with twiceweekly transabdominal ultrasound imaging. In-vivo response to niraparib was correlated to the HRD score, BRCA status, patient’s platinum response and RNAseq data. Results: One hundred and six high grade ovarian tumors were evaluated for HRD, BRCA mutation, and RNAseq analysis. Twenty one tumors (20%) had a deleterious somatic or germline BRCAmut . BRCA1 hypermethylation was evaluated in 98 tumors and found in 6, representing approximately 6% of this cohort. Collectively, there was 26% BRCA deficiency in this primary tumor collection. HRD scores ranged from 1−86 with a median score of 32 and an average score of 39. All BRCAmut tumors and 83% (5/6) of the BRCA1 hypermethylated tumors had an HRD score of 31 or greater. The BRCA1 hypermethylated tumor with a low HRD score does not have loss of heterozygosity (LOH) at BRCA1, and likely retains functional BRCA1. Invivo response to niraparib monotherapy was demonstrated in BRCAmut and