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A Phase Ia Study in Patients with Advanced Solid Tumors for the Human Monoclonal Antibody Vantictumab (OMP-18R5; Anti-Frizzled)

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A Phase Ia Study in Patients with Advanced Solid Tumors for the Human Monoclonal Antibody Vantictumab (OMP-18R5; Anti-Frizzled) A Phase Ia study in patients with advanced solid tumors for the human 890 monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway Kyriakos Papadopoulos,1 Lee Rosen,2 Rashmi Chugh,3 Jonathan Goldman,2 Wan-Ching Yen,4 Pete Yeung,4 Lu Xu,4 Ann M. Kapoun,4 Rainer K. Brachmann,4 Robert Stagg,4 Tony Tolcher,1 David Smith3 1START, San Antonio, TX, USA; 2Univervisity of California, Los Angeles, CA, USA; 3University of Michigan, Ann Arbor, MI, USA; 4OncoMed Pharmaceuticals, Redwood City, CA, USA BACKGROUND STUDY OVERVIEW SAFETY PHARMACODYNAMICS TIME ON STUDY • Failure to effectively target Cancer Stem Cells (CSCs) may • Patients with advanced solid tumors Vantictumab affects Wnt-related gene expression 029 Vertical lines: tumor assessments Related adverse events observed in >5% of patients 028 be responsible for the limited success of systemic therapies patterns in hair follicles 027 Unrelated serious adverse event • 3+3 dose escalation 026 in the metastatic setting. 025 Unrelated serious adverse event • Dose levels 1 2 3 4 5 6 7 8 Total 024 Cohort • The activated Wnt pathway is strongly associated with (n=3) (n=5) (n=3) (n=4) (n=3) (n=3) (n=3) (n=1) (n=25) 023 • 0.5 and 1 mg/kg every one week 022 CSCs. 0.5 1 0.5 1 2.5 5 10 15 021 Dose level • 0.5 mg/kg every two weeks q1wk q1wk q2wk q3wk q3wk q3wk q3wk q3wk 020 Investigator decision (lack of clinical benefit) • Vantictumab is a fully human IgG monoclonal antibody that 019 Investigator decision (changes in patient’s condition, further treatment unacceptable) 2 018 Grade 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 1/2/3 was identified by binding to Frizzled 7. • 1, 2.5, 5, 10 and 15 mg/kg every three weeks Control 017 subjects 016 • DLT assessment window: 28 days Fatigue 015 • Vantictumab binds five Frizzled receptors (1, 2, 5, 7, and 8) -/1/- -/1/- 3/-/- -/-/- -/-/- -/1/- 1/-/- -/-/- 7 (28%) 014 and inhibits Wnt signaling. 013 • Pharmacodynamics: blood RNA, hair follicles, tumor Nausea -/-/- -/1/- 2/-/- -/-/- 1/-/- 1/-/- -/-/- -/-/- 5 (20%) 012 • Vantictumab has broad anti-tumor activity in patient-derived (optional) 011 Decreased 010 xenograft models, in particular when combined with -/-/- -/1/- -/-/- 1/-/- -/-/- -/1/- 1/-/- -/-/- 4 (16%) 009 • Tumor assessments: every 8 weeks appetite 008 standard-of-care chemotherapy, such as taxanes. 007 = Active Hypercalcemia -/-/- -/-/- -/-/- -/-/- 1/-/- -/2/- 1/-/- -/-/- 4 (16%) 006 • Vantictumab selectively reduces the frequency of CSCs in 005 004 Dose-limiting toxicity = Neuroendocrine tumor these models. Vomiting 1/-/- 1/-/1* -/-/- -/-/- 1/-/- -/-/- -/-/- -/-/- 4 (16%) 003 BASELINE CHARACTERISTICS 002 001 • Vantictumab can also promote widespread tumor cell Constipation -/-/- -/-/- 1/-/- 1/-/- -/-/- -/-/- 1/-/- -/-/- 3 (12%) differentiation, as shown for pancreatic cancer models. 0 56 112 168 224 280 336 392 448 504 Abdominal pain 1/-/- -/-/- 1/-/- -/-/- -/-/- -/-/- -/-/- -/-/- 2 (8%) Days on study For more details, see Gurney et al., PNAS 109, 11717 (2012). Number of patients 25 Alkaline phos- -/-/- 2/-/- -/-/- -/-/- -/-/- -/-/- -/-/- -/-/- 2 (8%) Data as of 10 September 2013; patients discontinued vantictumab for progressive Median age, yr (range) 59 (38-77) phatase increased disease unless another reason is shown. Gender (female) 15 (64%) Anemia -/-/- -/1/- -/-/- -/1/- -/-/- -/-/- -/-/- -/-/- 2 (8%) • Vantictumab causes decreased expression of Wnt pathway NONCLINICAL EFFICACY DATA target genes and increased expression of differentiation ECOG score Diarrhea 1/-/- -/-/1* -/-/- -/-/- -/-/- -/-/- -/-/- -/-/- 2 (8%) Three neuroendocrine tumor patients genes (‘OMP18R5;’ in red). with prolonged stable disease Dose-ranging experiment 0 6 (24%) • Hair follicles of control subjects not treated with Data as of 2 August 2013 in patient-derived breast cancer xenograft 1 19 (76%) vantictumab show no significant changes in the same 003 (59 yo female) 010 (69 yo female) 012 (77 yo female) q1wk = every 1 week; q2wk = every 2 weeks; q3wk = every 3 weeks genes (‘Ctrl;’ in gray). Carcinoid Pancreatic neuroendocrine Carcinoid 1500 tumor Number of prior systemic * Grade 3 vomiting and diarrhea of patient 004 were the only Grade ≥3 adverse Diagnosis: Diagnosis: 3 paclitaxel 3 (1-8) • 10 patient samples analyzed: 9 collected 1 week after Diagnosis: 1200 therapies, median (range) events and were considered dose-limiting toxicities for Cohort 2. 2004: resection (curative 2006: liver mets vantictumab (5 mg/kg) + paclitaxel infusion; 1 collected 2 weeks after infusion vantictumab (10 mg/kg) + paclitaxel intent) 2001: resection (curative 900 Systemic Therapy: vantictumab (25 mg/kg) + paclitaxel Tumor types intent) Systemic Therapy: 1. Sandostatin (569 vantictumab (45 mg/kg) + paclitaxel 2006: liver mets 600 1. MEK inhibitor + AKT days) Colon 8 Systemic Therapy: 300 BONE TURNOVER inhibitor (55 days) 2. HSP90 inhibitor (710 Tumor Volume, mm Neuroendocrine 4 • PD confirmed 1. Regorafenib (1093 days) 0 days) 0 20 40 60 80 (+26%) 3. αAng2 (336 days) Days Post Treatment vantictumab: q3wk Breast 2 2. Vantictumab (110 days) 2. αLOXL2 (168 days) paclitaxel: 10 mg/kg, q1wk • Patient 003 experienced Grade 2 compression fracture after minor • PD confirmed fall on Day 110. 3. αCSFR1 (42 days) (+20%) Sarcoma 2 • PD confirmed (+45%) Established UM-PE13 tumors (triple-negative breast) were treated • Review of program for bone toxicity resulted in revised safety plan. 4. Vantictumab (SD; with various doses of vantictumab (OMP-18R5) in combination with Other 9 4. Vantictumab (448 days) 441+ days) paclitaxel. 5 mg/kg every 3 weeks (q3wk) of vantictumab resulted in • More stringent exclusion criteria Data as of 2 August 2013 a reduction relative to paclitaxel alone and established the minimum (e.g. chronic glucocorticoid use, high β C-terminal telopeptide efficacious dose. Treatment at 25 mg/kg q3wk resulted in tumor [β -CTX, serum marker of bone turnover], and known regression and corresponds to the maximum efficacious dose. insufficiency fracture) CONCLUSIONS PHARMACOKINETICS • Prophylactic Vitamin D and calcium supplements Dose-partitioning experiment in patient-derived breast • Less frequent dosing • Vantictumab is well tolerated. cancer xenograft to determine PK driver of efficacy • Zoledronic acid for the following criteria • Further dose escalation is ongoing. • Doubling of β-CTX, serum marker for bone turnover • Vantictumab clearance is dose-dependent, • T-score decline to <-2.5 as measured by DEXA scan consistent with target-mediated disposition. T- T- T- T- • A statistically significant correlation was • Vantictumab has pharmacodynamic (PD) effects Ranking of PK parameters Dose Pt Day ß-Ctx Dose Pt Day ß-Ctx Dose Pt Day ß-Ctx Dose Pt Day ß-Ctx at Steady State: (mg/kg) (pg/ml) score (mg/kg) (pg/ml) score (mg/kg) (pg/ml) score (mg/kg) (pg/ml) score observed between β-CTX increases and the on hair follicles. 1 0 570 -1.8 0 689 -1.4 0 386 -0.7 Term -2.2 0 927 -0.7 fraction of time that the serum concentration ¾ AUC: 1x q1w = 2x q2w = 3x q3w = 4x q4w 25 0.5 0 196 -1.0 1 28 846 2.5 16 28 805 15 28 ND • PD effects are consistent with Wnt biology. ¾ Cmax: 4x q4w > 3x q3w > 2x q2w > 1x q1w 2 28 308 of vantictumab was above a threshold of 2 q1w Term 217 ND q3w 56 707 -1.3 q3w Term 345 -0.8 q3w 0 596 -1.3 ¾ Cmin: 1x q1w > 2x q2w > 3x q3w > 4x q4w 0 219 -0.1 84 350 0 232 -1 26 28 1171 µg/mL. 28 825 17 • PD effects extend beyond serum exposure. 3 56 896 112 759 -1.4 28 309 56 1278 -1.5 Term 708 0.2 140 526 0 607 -0.9 0 492 -1.9 •Cmax or AUC did not correlate with β-CTX • Target efficacious dose was reached at dose level 4 0 298 -1.3 27 Term 401 ND 168 967 -1.8 18 28 555 28 ND increases. 1400 1 0 229 -1.2 196 688 Term 824 -1.0 0 385 +0.6 of 10 mg/kg every three weeks. 5 28 681 12 28 ) Control q1w 224 1216 -1.7 3 1200 Term 370 -1.0 0 648 0.1 28 667 • These findings suggest: paclitaxel 6 0 162 -0.4 252 1174 5 19 28 811 •Cmax is PK driver of efficacy in nonclinical 1000 28 598 29 0 964 NID •C may be the driver for β-CTX vantictumab (10mg/kg q1wk) + paclitaxel 0 144 0.9 280 1223 -1.7 q3w Term 1336 -0.1 min 800 vantictumab (20mg/kg q2wk) + paclitaxel 7 28 301 308 1045 efficacy models. Term 0.7 0 561 -1.0 increases. 600 vantictumab (30mg/kg q3wk) + paclitaxel 0 406 -1.6 336 890 -1.9 Active patients 8 20 28 665 vantictumab (40mg/kg q4wk) + paclitaxel 28 551 364 1380* • High intermittent dosing that allows drug • Vantictumab has PD effects on bone, as 400 0 203 -0.7 56 1111 -1.0 9 28 195 392 1332 NID Zoledronic acid Term 287 -0.9 washout below a threshold may evidenced by β-CTX increases. tumor volume (mm volume tumor 200 0.5 21 0 629 -0.13 administered 0 306 -1.4 420 218 0 q2w 28 286 ameliorate bone toxicity. 0 618 -0.9 0 367 -1.2 Red bold: •C (or time above a certain threshold) 0 10 20 30 40 50 60 56 304 -1.0 13 22 min 84 664 Term 876 -1.2 10 28 697 β-CTX doubling by Day 28 Days Post Treatment 112 270 -0.9 0 471 2.4 appears to be the PK driver of toxicity. 140 288 q3w 0 568 -1.3 14 28 760 168 413 -1.0 23 28 1449 Green bold: At current dose levels: 196 372 Term 688 2.2 • Increased bone turnover can be safely managed The top graph shows the PK parameters associated with the various 224 377 -0.9 Term 199 -1.6 β-CTX doubling > Day 28 10 252 363 0 340 -0.7 doses and schedules of vanticumab.
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