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First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; antiFrizzled) targeting the WNT pathway in a Phase I study for patients with advanced solid tumors David C. Smith,1 Lee Rosen,2 Rashmi Chugh,1 Jonathan Goldman,2 Lu Xu,3 Ann M. Kapoun,3 Rainer K. Brachmann,3 Jakob Dupont,3 Robert Stagg,3 Tony Tolcher,4 Kyriakos Papadopoulos4 1University of Michigan, Ann Arbor, MI, USA; 2University of California, Los Angeles, CA, USA; 3OncoMed Pharmaceuticals, Redwood City, CA, USA; 4START, San Antonio, TX, USA BACKGROUND BASELINE CHARACTERISTICS • Failure to effectively target Cancer Stem Cells (CSCs) may be responsible for the limited success of systemic therapies in the metastatic setting. Number of patients • The activated Wnt pathway is strongly associated with CSCs. Median age, yr (range) 59 (38-77) • Vantictumab is a fully human IgG2 monoclonal antibody that was identified by binding to Frizzled 7. Gender (female) 15 (65%) • Vantictumab binds five Frizzled receptors (1, 2, 5, 7, and 8) and inhibits Wnt signaling. • Vantictumab has broad anti-tumor activity in patient-derived xenograft models, in particular when combined with standard-of-care chemotherapy, such as taxanes. • Vantictumab selectively reduces the frequency of CSCs in these models. • Vantictumab can also promote widespread tumor cell differentiation, as shown for pancreatic cancer models. For more details, see Gurney et al., PNAS 109, 11717 (2012) NONCLINICAL EFFICACY DATA Activity of vantictumab in patient-derived pancreatic cancer xenografts Control mAb Gemcitabine Gem+nab-paclitaxel OMP-18R5+Gem/nab-paclitaxel 1000 800 600 400 200 No Treatment 0 6 (26%) 1 17 (74%) Number of prior systemic therapies, median (range) Vantictumab affects Wnt-related gene expression patterns in hair follicles Dose Pt (mg/kg) Colorectal 8 Neuroendocrine 3 Sarcoma Other 2 2 8 0.5 20 40 3 • Hair follicles of control subjects not treated with vantictumab show no significant changes in the same genes (‘Ctrl;’ in gray) 2 (n=5) 3 (n=3) 4 (n=4) 5 (n=3) 6 (n=3) 7 (n=2) 20 40 60 80 0.5 q1w 1 q1w 0.5 q2w 1 q3w 2.5 q3w 5 q3w 10 q3w 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 Fatigue -/1/- -/1/- 3/-/- -/-/- -/-/- -/1/- 1/-/- 7 Nausea -/-/- -/1/- 2/-/- -/-/- 1/-/- 1/-/- -/-/- 5 100 Dose level Days Post Treatment Grade Established OMP-PN13 tumors (left panel) or OMP-PN17 tumors (right panel) were treated with vantictumab (OMP-18R5) in combination with gemcitabine plus nabpaclitaxel. Vantictumab significantly inhibited tumor growth in both models. Doses used – Gemcitabine: 10 mg/kg weekly, nab-paclitaxel: 30 mg/kg weekly, OMP-18R5: 25 mg/kg every two weeks. STUDY OVERVIEW Patients with advanced solid tumors 3+3 dose escalation • Dose levels 5 6 1 (n=3) Cohort 0 Total (n=23) Vomiting 1/-/- 1/-/1* -/-/- -/-/- 1/-/- -/-/- -/-/- 4 Alkaline phosphatase increased -/-/- 2/-/- -/-/- -/-/- -/-/- 1/-/- -/-/- 3 Symbols represent mean with standard deviation for each cohort. Constipation -/-/- -/-/- 1/-/- 1/-/- -/-/- -/-/- 1/-/- 3 Decreased appetite -/-/- -/1/- -/-/- 1/-/- -/-/- -/1/- -/-/- 3 Lines represent model fit. Hypercalcemia -/-/- -/-/- -/-/- -/-/- 1/-/- -/2/- -/-/- 3 Abdominal pain 1/-/- -/-/- 1/-/- -/-/- -/-/- -/-/- -/-/- 2 • 0.5 and 1 mg/kg every one week Anemia -/-/- -/1/- -/-/- -/1/- -/-/- -/-/- -/-/- 2 • 0.5 mg/kg every two weeks Diarrhea 1/-/- -/-/1* -/-/- -/-/- -/-/- -/-/- -/-/- 2 • 1, 2.5, 5 and 10 mg/kg every three weeks • DLT assessment window: 28 days • Pharmacodynamics: blood RNA, hair follicles, tumor (optional) • Tumor assessments: every 8 weeks 4 q1w Related adverse events observed in >5% of patients 300 Days Post Treatment • 1 7 Control mAb Gem+nab-paclitaxel OMP-18R5+Gem/nab-paclitaxel 600 60 2 • Vantictumab causes decreased expression of Wnt pathway target genes and increased expression of differentiation genes (‘OMP18R5;’ in red) • 10 patient samples analyzed: 9 collected 1 week after infusion; 1 collected 2 weeks after infusion PHARMACOKINETICS 1 q1w SAFETY 900 003 (59 yo female) 010 (69 yo female) 012 (77 yo female) Carcinoid Pancreatic neuroendocrine tumor Carcinoid Diagnosis: Diagnosis: Diagnosis: (e.g. chronic glucocorticoid use, high β C-terminal telopeptide [β -CTX, serum marker of bone turnover], and known insufficiency fracture) 2004: resection (curative intent) 2001: resection (curative intent) 2006: liver mets 2006: liver mets Prophylactic Vitamin D and calcium carbonate Less frequent dosing Zoledronic acid for the following criteria • Doubling of β-CTX, serum marker for bone turnover • T-score decline to <-2.5 as measured by DEXA 1. MEK inhibitor + AKT inhibitor Systemic Therapy: 1. Sandostatin (569 days) 1. Regorafenib (1093 days) 2. HSP90 inhibitor 2. αLOXL2 3. αAng2 Systemic Therapy: • PD confirmed (+26%) Systemic Therapy: 3. αCSFR1 2. Vantictumab (SD) • PD confirmed (+20%) • PD confirmed (+45%) 4. Vantictumab (SD) 4. Vantictumab (SD) Time on study with stable disease Tumor types Breast NEUROENDOCRINE TUMORS Patient 003 experienced Grade 2 compression fracture after minor fall on Day 110. Review of program for bone toxicity resulted in revised safety plan. • More stringent exclusion criteria • • • Control subjects 0 0 • • 3 (0-8) 1200 0 • BONE TURNOVER ECOG score 1500 Tumor Volume, mm3 Tumor Volume, mm3 1200 Chemo+/-mAb 23 PHARMACODYNAMICS At current dose levels: • Apparent clearance (CL) ranges from 0.50 to 1.2 mL/hr/kg. • Dose-dependent CL suggests target-mediated clearance plays a major role. • Terminal T1/2 ranges from 1.5 to 3.7 days. • Anti-drug antibody formation in 5 of 21 patients did not affect PK. Data as of 8 May 2013 q1w = every 1 week; q2w = every 2 weeks; q3w = every 3 weeks * Grade 3 vomiting and diarrhea of patient 004 were the only Grade ≥3 adverse events and were considered dose-limiting toxicities for Cohort 2. 8 0.5 q2w 9 TDay ß-Ctx (pg/ml) score 0 Term 0 28 Term 0 28 56 Term 570 196 308 217 219 825 896 708 -1.8 -2.2 -1.0 0 28 Term 0 28 0 28 Term 0 28 -1.2 0 203 28 195 Term 287 q2w 0.2 -1.3 ND 406 551 0.5 ND -0.1 0 298 Term 401 229 681 370 162 598 144 301 Dose Pt (mg/kg) -1.0 -0.4 TDay ß-Ctx (pg/ml) score 0 28 56 84 112 140 168 10 196 224 252 280 308 336 364 0 11 42 Term 0.9 306 286 304 664 270 288 413 372 377 363 424 505 499 420 308 358 327 -1.4 -1.0 Dose Pt (mg/kg) 1 q3w -0.9 12 -1.0 -0.9 -1.0 -1.2 13 0.9 14 0.9 Active patients 0.7 -1.6 15 Zoledronic acid administered TDay ß-Ctx (pg/ml) score 0 28 56 84 112 140 168 196 224 252 280 308 0 Term 0 28 Term 0 28 56 Term 689 846 707 350 759 526 967 688 1216 1174 1223 1045 618 876 471 760 688 340 469 586 156 -1.4 -1.3 Dose Pt (mg/kg) 2.5 q3w 17 -1.4 -1.8 -1.7 -1.7 18 5 19 q3w -0.9 -1.2 2.4 2.2 -0.7 16 20 21 10 q3w -0.8 ND 22 23 TDay ß-Ctx (pg/ml) score 0 28 Term 0 28 0 28 Term 0 28 Term 0 28 56 386 805 345 232 309 607 555 824 648 811 1336 561 665 1111 -0.9 012 -0.8 -1 010 400 600 800 1000 1200 1400 1600 Days most recent prior therapy -1.0 367 -1.2 697 568 -1.3 1449 200 2nd -0.1 -1.0 0 28 0 28 Most recent prior therapy Vantictumab Data as of 8 May 2013 CONCLUSIONS • Vantictumab is well tolerated. • Further dose escalation is ongoing. • Vantictumab clearance is dose-dependent, consistent with target-mediated disposition. • Vantictumab has pharmacodynamic (PD) effects on hair follicles. • PD effects extend beyond serum exposure. = Neuroendocrine tumor 224 280 336 392 • Vantictumab has PD effects on bone, as evidenced by β-CTX increases. • Increased bone turnover can be safely managed through careful monitoring, prophylactic Vitamin D and calcium carbonate, and administration of zoledronic acid, if indicated. • Prolonged stable disease in 3 patients with neuroendocrine tumors may represent single-agent activity. ACKNOWLEDGEMENTS = Active 168 385+ 110 0 -1.0 0.1 629 -0.13 Vertical lines: tumor assessments Data as of 8 May 2013 112 55 42 • PD effects are consistent with Wnt biology. 023 022 021 020 019 018 017 016 015 014 013 012 011 010 009 008 007 006 005 004 003 002 001 56 168 316+ 336 -0.9 TIME ON STUDY 0 710 003 0 Red bold: Initial β-CTX doubling by Day 28; green bold: β-CTX doubling > Day 28 Blue italics: β-CTX values ≥1.7-fold of baseline Data as of 8 May 2013; ND = not done; Termination visit has to occur ≤30 days after last study drug dosing. Lowest T-score is shown, regardless of location (hip, femur or lumbar spine). -0.7 -0.7 448 We thank all patients who participated in this study and their families. Vantictumab is part of OncoMed’s Wnt pathway collaboration with Bayer HealthCare. Days on study ASCO Annual Meeting, Chicago, 3 June 2013