Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumors Howard Burris1, Jordi Rodon2, Sunil Sharma3, Roy Herbst4, Josep Tabernero2, Jeffrey Infante1, Antonio Silva5, David Demanse5, Wolfgang Hackl5, Jose Baselga2 Cannon Research Institute, Nashville, Tennessee, USA; 2Vall d’Hebron University Hospital, Barcelona, Spain; 3Nevada Cancer Institute, Las Vegas, Nevada, USA; 4The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; 5Novartis Pharma AG, Basel, Switzerland 1Sarah Abstract #3005 Disclosures Howard Burris Jordi Rodon Sunil Sharma Roy Herbst Josep Tabernero Jeffrey Infante Jose Baselga Study investigators Antonio Silva, David Demanse, and Wolfgang Hackl are employees of Novartis Pharma AG Novartis Pharma AG is the study sponsor BEZ235 inhibits the PI3K signaling pathway BEZ235 PI3K PTEN TORC2 PIP3 Akt PDK1 Tuberin BEZ235 Rheb TORC1 S6K S6 4EBP1 BKM120 BEZ235: Orally available potent dual inhibitor of PI3K and mTORC1/2 N • Potent, specific, oral PI3K and mTORC1/2 inhibitor O N N N • Broad antiproliferative effect across different tumor types N • Pro-apoptotic effect in PI3Kpathway activated tumor models • Antiangiogenic Class I PI3K Enzyme IC50 nM/L p110α 4.0 ± 2 P110α-H1047R 4.6 ± 0.8 P110α-E545K 5.7 ± 1.0 p110β 75 ± 45 p110δ 7±6 p110γ 5±4 mTOR Panel of 18 other protein kinases 20.7 >10,000 Maira et al. Mol Cancer Ther 2008;7:1851–63 Serra et al. Cancer Res 2008;68:8022–30 BEZ235 Phase I: Study objectives • Primary – MTD of oral BEZ235 administered on a once-daily continuous schedule • Secondary – Safety and tolerability of BEZ235 • AEs per NCI-CTCAE v3.0, hyperglycemia per ADA guidelines (fasting plasma glucose ≥7.0 mmol/L) – Pharmacokinetic profile • Days 1, 8, and 28 in Cycle 1 – Biomarker and pharmacodynamic assessments • PIK3CA (mutation) and PTEN (mutation and protein expression) status in archival tumor samples • Fasting plasma C-peptide levels • Phospho-S6 and Ki-67 levels from pre- and on-treatment biopsies • 18FDG-PET for metabolic anti-tumor activity – Overall response as per RECIST NCI-CTCAE, NCI-Common Terminology Criteria for Adverse Events ADA, American Diabetes Association BEZ235 Phase I: Study design Single-agent dose-escalation Oral, once-daily BEZ235 28-day cycle (N≥24) Declaration of MTDa Fasted, mg/day Fed, mg/day MTD / safety expansion arm in patients with alterations in PIK3CA/PTEN Oral, once-daily BEZ235 28-day cycle Combination with trastuzumab dose escalation arm in patients with HER2+ mBC with a PIK3CA activating mutation • Special safety assessments: • Key exclusion criteria: − Treatment with corticosteroids ≤2 weeks before starting study drug − Diabetes mellitus or history of gestational diabetes − Prior treatment with a PI3K inhibitor aDefined − Fasting plasma glucose − 2-hour plasma glucose during a 75 g fasting OGTT − Hemoglobin A1C as the drug dosage expected to cause a medically unacceptable DLT in >33% of patients during the first treatment cycle; for declaration of MTD, ≥6 patients will have to be treated at this dose level for one treatment cycle OGTT, oral glucose tolerance test BEZ235 Phase I: Patient characteristics Characteristic Median age, years (range) <65 years (%) N=59 55 (29–81) 47 (80%) Primary tumor type N=59 Colorectal 14 (24%) Breast 13 (22%) Lung 5 (9%) Male / Female 20 (34%) / 39 (66%) Ovarian 4 (7%) WHO PS, 0/1 29 (49%) / 30 (51%) Skin melanoma 4 (7%) Soft tissue sarcoma 3 (5%) Prostate 2 (3%) Endometrial 2 (3%) Esophageal 2 (3%) Pancreatic 2 (3%) Head and neck 2 (3%) Othera 6 (10%) Prior antineoplastic therapy 56 (95%) Median number of regimens (range) 3 (0–18) Patients with >3 prior regimens 30 (51%) aOne patient each (1.7%): kidney, adrenal, pleural, choroid, gallbladder, pararenal Cut-off date March 2, 2009 BEZ235 Phase I: Retrospective analysis of tumor mutation status N=59 n Tumor samplesa 51 (86%) Evaluable for PIK3CA Statusb 48 Wild-type 43 (90%) Mutation 5 (10%) Evaluable for PTEN Statusc 51 Wild-type 39 (76%) Mutated 7 (14%) Protein level low (H-score < 40) 10 (20%) Protein level medium (H-score 40-90) 12 (24%) Protein level high (H-score >90) 26 (51%) Tumors with PI3K pathway activation (any PIK3CA/PTEN alterations) a Population 19 (37%) enrichment was not employed. Samples available for 51/ 59 patients, some analyses incomplete due to sample quantity or quality bSNaPshot genotyping, exons 9 and 20 cGenomic DNA sequencing of PTEN exons 1-9, Semiquantitative IHC BEZ235 Phase I: Dose escalation • No DLTs observed in Cycle 1 • Median duration of treatment was 8 weeks – No relationship observed between treatment duration and dose or administration schedule DLT definition • Hematologic AEs − ≥Grade 3 neutropenia for >7 consecutive days or febrile neutropenia − Grade 3 thrombocytopenia for >7 consecutive days or Grade 4 thrombocytopenia • Non-hematologic AEs − ≥Grade 3 toxicity − Grade 2 hyperglycemia that cannot be resolved to Grade 0 in ≤14 consecutive daysa − ≥Grade 2 pancreatitis Schedule Fasted Fed Exposure (wks) >4 >12 Dose (mg) Patients 10 3 2 0 25 6 6 3 50 4 4 4 100 6 5 1 200 5 4 2 300 6 5 0 400 11 8 5 300 6 5 3 400 3 3 1 700 1100 All 5 4 59 5 2 1 1 48 (81%) 21 (36%) aAs per ADA guidelines. BEZ235 Phase I: AEs in >20% of patients, regardless of causality Fasting, dose in mg Fed, dose in mg 10 n=3 25 n=6 50 n=4 100 n=6 200 n=5 300 n=6 400 n=11 300 n=6 400 n=3 700 n=5 1100 n=4 All n=59 n (%) 3 6 2 6 5 5 11 6 3 5 4 56 (95) Fatigue/ Asthenia 2 1 2 4 3 5 2 3 3 Diarrhea 1 2 3 4 2 4 1 4 2 23 (39) 2 2 2 3 3 1 2 3 1 20 (34) 1 2 1 1 3 2 4 1 17 (29) 1 3 1 12 (20) Total events Nausea 1 Vomiting 1 1 Anemia 2 2 • 1 1 1 25 (42) AE incidence was similar in both schedules – Gastrointestinal disorders: 70% – General disorders: 66% – Hematologic disorders: 18% BEZ235 Phase I: most common AEs suspected to be related to study drug Preferred Term, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Total Total events 16 (27) 21 (36) 4 (7) – 41(70) Fatigue / Asthenia 8 (14) 4 (7) 2 (3) – 14 (24) Diarrhea 13 (22) 1 (2) 1 (2) – 15 (25) Nausea 9 (15) 3 (5) – – 12 (20) Vomiting 6 (10) 4 (7) – – 10 (17) Anemia 1 (2) 3 (5) – – 4 (7) Abdominal pain 2 (3) – – – 2 (3) Anorexia 3 (5) 2 (3) – – 5 (9) • • No drug-related SAEs or treatment-related deaths No treatment-related disturbances of glucose homeostasis, vital signs, or cardiac function BEZ235 Phase I: clinical pharmacokinetics – High intra- and inter-patient variability 10000 BEZ235 exposure (AUC0-24 - ng.h/mL) • Non-proportional increase in systemic exposure and Cmax across all doses • Apparent median Tmax 1–7 hrs • Apparent t½ from 1–14.5 hrs • No significant food effect on systemic exposure • Plasma exposure for most patients treated at ≥400 mg/day BEZ235 was within range of steady state exposures in patients with radiologic response 1000 100 10 1 10 50 100 500 1000 Dose (mg) Individual AUC values Day 1 Day 8 Day 28 Partial response, Max AUC0-24 Partial response, Min AUC0-24 BEZ235 Phase I: Dose-dependent increases in plasma C-peptide with BEZ235 • Dose-dependent increases in plasma C-peptide indicate pharmacodynamic activity at Day 8 that is sustained at Day 28 50–100 mg Number of patients = 8 10–25 mg Number of patients = 9 30 200–400 mg Number of patients = 28 C-peptide (ng/ml) 25 20 15 10 Observations at Day 1 Observations at Day 8 Observations at Day 28 5 0 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 Time (hours post dose) Increase relative to 10-25 mg dose Increase relative to Day 1 50–100 mg 40% increase 200–400 mg 53% increase 52% Day 8 56% Day 28 BEZ235 Phase I: BEZ235 decreases tumor phospho-S6 and Ki-67 levels BEZ235 50 mg/day Cycle 1, Day 28 Baseline Tumor tissue from a patient with esophageal cancer with staining for P-S6 P-S6 (H-score) Ki-67 (% cells+) 240 15 120 2 % Decrease 50% 87% BEZ235 Phase I: Clinical activity • 51 patients were evaluable for response – 2 patients with partial responses • ER+ HER2 normal breast cancer, unknown PI3K pathway status (1100 mg/day, response duration 9+ months) • Lung cancer, Cowden syndrome (700 mg/day, response duration 8 months on BEZ235, 10+ months off BEZ235) – 14 patients (27%) with stable disease for ≥4 months • 4 patients (29%) had breast cancer • 6 patients (43%) had tumors with alterations in the PI3K pathway BEZ235 Phase I: Clinical PR in a patient with ER+ HER2 normal breast cancer C1D28 C2D28 18FDG-PET CT BL BEZ235 1100 mg/day BL, Baseline; C, Cycle; D, Day BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months 720 TTP at last prior therapy TTP on BEZ235 treatment according to local review 660 600 A 540 A A 420 380 300 1 2 3 4 5 6 Patientsa 7 8 aAs Fast 100 mg/d Fast 50 mg/d UNK Fast 50 mg/d Fast 25 mg/d Fed 400 mg/d Fast 400 mg/d 0 Fast 400 mg/d 60 Fast 400 mg/d 120 N A 9 10 Fed 100 mg/d A A 180 N Fed 300 mg/d 240 Fast 400 mg/d Time (Days) 480 11 per data cutoff March 2009 A,Tumor PI3K pathway alteration (PIK3CA / PTEN mutation, low/null PTEN expression); N, No identified PI3K pathway alterations TTP, time to progression; UNK, unknown Best percent change from baseline in SLD (measurable lesions) –10 –20 –30 –40 Colorectal Esophagus Adrenal Breast Lung Melanoma Endometrial Colorectal Lung Melanoma Colorectal Colorectal Colorectal Colorectal Cholangiocarcinoma Nasopharyngeal –50 Synovial sarcoma 30 20 10 40 0 • 18 out of 35 evaluable patients had tumor shrinkage as per central review Breast Lung Melanoma Breast Neuroendocrine Breast Breast Breast Breast Prostate Breast Ovarian Esophageal Breast Mesothelioma Colorectal Colorectal Breast BEZ235 Phase I: reduction in tumor burden as per CT 50 Percent change in sSUVmax Baseline – C1D28 –20 –40 Colorectal Melanoma Colorectal Colorectal Colorectal Breast Colorectal Colorectal Colorectal Ovarian Colorectal Adrenal Breast Lung Endometrial Breast Lung Colorectal Breast 60 40 20 Pancreatic Breast Breast Sarcoma Breast Lung Melanoma Colorectal Breast Renal Esophageal Breast Mesothelioma Colorectal Lung Breast Breast Cholangiocarcinoma BEZ235 Phase I: tumor metabolic response as per 18FDG-PETa 0 –60 • 18 out of 37 patients demonstrated a detectable decrease in tumor 18FDG-uptake as per central review aEnd of Cycle 1 C, Cycle; D, Day BEZ235 Phase I: correlation between single-lesion responses by CT and PET 10–300 mg dose group 10 patients with comparable lesions 1.0 1.0 y=0.1756x - 0.0563 R2=0.0086 0.8 % change in sSUVmax 400–1100 mg dose group 8 patients with comparable lesions 0.6 No correlation 0.4 y=1.3549x + 0.0822 R2=0.4474 0.8 0.6 0.4 Significant correlation 0.2 0.2 0 0 –0.2 –0.2 –0.4 –0.4 –0.6 –0.6 –0.8 –0.8 –1.0 –1.0 –1.0 –1.0 –0.8 –0.6 –0.4 –0.2 -0.5 0 0.5 1.0 0 0.2 0.4 0.6 0.8 1.0 % change in SLD • Correlation between CT and PET responses at ≥400 mg/day BEZ235 suggests clinically active exposure levels have been achieved BEZ235 Phase I: summary • • • • No DLTs were observed: MTD not identified SAEs were not reported with BEZ235 treatment Rapid absorption and highly variable systemic exposure Evidence of single-agent activity in patients with heavily pretreated advanced cancer – 2 PRs, 16 cases of tumor shrinkage, 14 SD of ≥4 months – Activity in patients with and without PI3K pathway alterations • Pharmacologically active exposure levels reached at doses of BEZ235 400–1100 mg/day – Dose-dependent effects on plasma C-peptide – Decrease in tumor phospho-S6 – Correlation between CT and PET response BEZ235 Phase I: conclusions • BEZ235 is a potent inhibitor of the PI3K pathway • BEZ235 has a favorable safety profile • BEZ235 demonstrates clinical activity in patients, including those with alterations in the PI3K pathway • Ongoing studies include: – A new formulation of BEZ235 with improved bioavailability and PK properties – Combination treatment with HER2 or MEK-targeted therapies Acknowledgments • Patients and their families • BEZ235 Clinical Study Team • Sponsor-Novartis Sarah Cannon Research Institute Johanna Bendell Suzanne Jones Nevada Cancer Institute Vall d’Hebron University Hospital Francesco Atzori Gemma Sala Javier Cortes MD Anderson Cancer Center Faye Johnson George Blumenschein Justina Price Virtual Scopics S Mahmood Back-up slides BEZ235 Phase I: Patient disposition Status* N=59 n (%) On treatment 5 (9%) Discontinued due to disease progression 46 (78%) Discontinued due to AE 6 (10%) Discontinued at the discretion of the treating physician 1 (2%) Withdrew consent 1 (2%) *Cut-off date March 2, 2009. BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months 720 660 600 PIK3CA: wild-type (WT), mutant (MUT) PTEN: high, medium, low PTEN: wild-type (WT), mutant (MUT) WT Medium MUT MUT Low WT 540 MUT Medium MUT 420 380 1 2 3 4 5 6 7 8 Patientsa TTP, time to progression; UNK, unknown 9 10 Fed 100 mg/d Fast 100 mg/d UNK Fast 50 mg/d Fast 25 mg/d Fed 400 mg/d 0 Fast 400 mg/d 60 Fast 400 mg/d 120 WT High WT MUT Low WT WT Medium Fast 400 mg/d 180 Medium MUT Fed 300 mg/d WT High MUT 240 WT Fast 50 mg/d WT High WT 300 Fast 400 mg/d Time (Days) 480 11 TTP at last prior therapy TTP on BEZ235 treatment according to local review aAs per data cutoff March 2009