safety and preliminary efficacy results of a first-in...

Waterfall and Spider Plots (n=22 evaluable

and with tumor tissue available)Preferred Term

Pamela Munster (3), S.Gail Eckhardt (5), Amita Patnaik (1), Anthony Shields (2), Anthony W. Tolcher (1), S. Lindsey Davis (5), John V. Heymach (6), Lu Xu (4), Ann M. Kapoun (4), Leonardo Faoro (4), Jakob Dupont (4), Renata Ferrarotto (6)(1) South Texas Accelerated Research Therapeutics (START), San Antonio, TX; (2) Wayne State University, Karmanos Cancer Institute, Detroit, MI; (3) University of California, San Francisco, San Francisco, CA; (4) OncoMed Pharmaceuticals, Inc., Redwood City, CA;

(5) University of Colorado-Denver, Aurora, CO; University of Colorado Cancer Center, Aurora, CO. (6) University of Texas MD Anderson Cancer Center, Houston, TX

Summary

• BRON was generally well tolerated

• The recommended single-agent phase 2 dose is 1.5 mg/kg Q3W

• The main toxicity of BRON is on-target diarrhea. Other less common

events included fatigue, nausea, and vomiting

• Diarrhea is a known on-target effect of Notch inhibition and was

controlled in most cases

• BRON has shown single-agent efficacy, where several pts had stable

disease and two patients had a partial response, particularly in the

biomarker-defined population (NICD high)

• Activity observed in ACC, CRC, and breast cancer

• The dose cohorts at or above 1.5 mg/kg Q3W showed clear target

engagement in blood and the tumor

• The sponsor is planning phase 1b combination studies

Background

Baseline Characteristics (n=48)

Study Schema and Objectives

Treatment Exposure (n=27)OMP-59R5 Dose Level (mg/kg)

AEs Occurring in >10 % of Pts (n=48)

All Grades Regardless of RelationshipPreferred Term

AEs Considered Related to BRON

Occurring in > 10% of Pts (n=48)Preferred Term

Safety and preliminary efficacy results of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody

brontictuzumab (OMP-52M51, anti-Notch1) administered intravenously to patients with certain advanced solid tumors

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Study Procedures

Administration: OMP-52M51 intravenously until PD, tox, withdrawal of consent

Schedule: Every 7 days Safety assessments, including standard laboratories

Tumor Assessments: On Day 70 then every 2 cycles

Selected

Refractory

Solid

Tumors

1 mg/kg

2.5 mg/kg

0.5 mg/kg

0.25 mg/kg

Every 4 weeks Every 3 weeks

2 mg/kg

2.5 mg/kg

1.5 mg/kg

1 mg/kg

Dose Escalation Phase

Expansion

Phase

Notch1 ICD-

high

tumors

• Primary Objective:

• Maximum Tolerated Dose (MTD)

• Secondary Objectives:

• Safety

• Pharmacokinetics (PK)

• Immunogenicity

• Efficacy according to Notch1 ICD status

• Exploratory Objectives:

• Biomarker changes in gene and protein expression following OMP-52M51 treatment

Best Objective Responses

(n=29 Evaluable)Preferred Term

Enrolled subjects 48

Male / female (%) 56% / 43%

Age min/max (mean) 28-74 (54)

ECOG 0/1 (%) 29% / 69%

Diagnosis (n, %)

CRC 15 (31%)

Adenoid cystic carcinoma 12 (25%)

Cholangiocarcinoma 7 (15%)

Breast cancer 6 (13%)

Esophageal cancer 3 (6%)

Pancreatic cancer 2 (4%)

Small cell lung cancer 2 (4%)

Gastric cancer 1 (2%)

Evaluable tumor for Notch1 ICD (n, %) 41 (86%)

Overall (N=48)

Preferred Term Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total

Subjects Reporting at Least One TEAE 1 (2.1%) 10 (20.8%) 27 (56.3%) 2 (4.2%) 7 (14.6%) 47 (97.9%)

Diarrhoea 15 (31.3%) 6 (12.5%) 14 (29.2%) - - 35 (72.9%)

Fatigue 10 (20.8%) 14 (29.2%) 3 (6.3%) - - 27 (56.3%)

Nausea 16 (33.3%) 4 (8.3%) 1 (2.1%) - - 21 (43.8%)

Vomiting 8 (16.7%) 4 (8.3%) 1 (2.1%) - - 13 (27.1%)

Aspartate Aminotransferase Increased 8 (16.7%) 2 (4.2%) 2 (4.2%) - - 12 (25.0%)

Alanine Aminotransferase Increased 4 (8.3%) 2 (4.2%) 3 (6.3%) - - 9 (18.8%)

Constipation 7 (14.6%) 2 (4.2%) - - - 9 (18.8%)

Anaemia 3 (6.3%) 4 (8.3%) - - - 7 (14.6%)

Anxiety 7 (14.6%) - - - - 7 (14.6%)

Decreased Appetite 4 (8.3%) 2 (4.2%) 1 (2.1%) - - 7 (14.6%)

Dehydration 2 (4.2%) 2 (4.2%) 3 (6.3%) - - 7 (14.6%)

Dyspnoea 5 (10.4%) 1 (2.1%) - 1 (2.1%) - 7 (14.6%)

Headache 5 (10.4%) 1 (2.1%) - - - 6 (12.5%)

Abdominal Pain 2 (4.2%) 3 (6.3%) - - - 5 (10.4%)

Blood Alkaline Phosphatase Increased 1 (2.1%) 1 (2.1%) 3 (6.3%) - - 5 (10.4%)

Hypoalbuminaemia 2 (4.2%) 3 (6.3%) - - - 5 (10.4%)

Hyponatraemia 2 (4.2%) - 3 (6.3%) - - 5 (10.4%)

Oedema Peripheral 5 (10.4%) - - - - 5 (10.4%)

Pain 2 (4.2%) 1 (2.1%) 2 (4.2%) - - 5 (10.4%)

Urinary Tract Infection 2 (4.2%) 2 (4.2%) 1 (2.1%) - - 5 (10.4%)

Weight Decreased 3 (6.3%) 2 (4.2%) - - - 5 (10.4%)

Overall (N=48)

Preferred Term Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total

Subjects Reporting at Least One TEAE 11 (22.9%) 10 (20.8%) 20 (41.7%) 1 (2.1%) - 42 (87.5%)

Diarrhoea 13 (27.1%) 6 (12.5%) 14 (29.2%) - - 33 (68.8%)

Fatigue 8 (16.7%) 9 (18.8%) 3 (6.3%) - - 20 (41.7%)

Nausea 15 (31.3%) 3 (6.3%) 1 (2.1%) - - 19 (39.6%)

Vomiting 5 (10.4%) 4 (8.3%) 1 (2.1%) - - 10 (20.8%)

Aspartate Aminotransferase Increased 6 (12.5%) 1 (2.1%) 2 (4.2%) - - 9 (18.8%)

Alanine Aminotransferase Increased 2 (4.2%) 2 (4.2%) 2 (4.2%) - - 6 (12.5%)

Grade 3 or higher AEs Occurring in more

than one Pt Regardless of Relationship

(n=48)Preferred Term

Overall (N=48)

Preferred Term Grade 3 Grade 4 Grade 5 Total

Subjects Reporting at Least One TEAE 27 (56.3%) 2 (4.2%) 7 (14.6%) 36 (75.0%)

Diarrhoea 14 (29.2%) - - 14 (29.2%)

Alanine Aminotransferase Increased 3 (6.3%) - - 3 (6.3%)

Blood Alkaline Phosphatase Increased 3 (6.3%) - - 3 (6.3%)

Dehydration 3 (6.3%) - - 3 (6.3%)

Fatigue 3 (6.3%) - - 3 (6.3%)

Hyponatraemia 3 (6.3%) - - 3 (6.3%)

Aspartate Aminotransferase Increased 2 (4.2%) - - 2 (4.2%)

Colorectal Cancer - - 2 (4.2%) 2 (4.2%)

Hypertension 2 (4.2%) - - 2 (4.2%)

Hypokalaemia 2 (4.2%) - - 2 (4.2%)

Hypophosphataemia 2 (4.2%) - - 2 (4.2%)

Neutrophil Count Decreased 2 (4.2%) - - 2 (4.2%)

Pain 2 (4.2%) - - 2 (4.2%)

Respiratory Failure 1 (2.1%) - 1 (2.1%) 2 (4.2%)

Sepsis 1 (2.1%) 1 (2.1%) - 2 (4.2%)

Dose EscalationDose

Expansion

0.25

mg/kg

Q4W

(N=1)

0.50

mg/kg

Q4W

(N=3)

1.00

mg/kg

Q4W

(N=3)

2.50

mg/kg

Q4W

(N=6)

2.50

mg/kg

Q3W

(N=7)

2.00

mg/kg

Q3W

(N=4)

1.00

mg/kg

Q3W

(N=3)

1.50

mg/kg

Q3W

(N=6)

1.50

mg/kg

Q3W

(N=15)

Overall

(N=48)

Total Number of Infusions

Administered per Subject

n 1 3 3 6 7 4 3 6 15 48

Mean (SD) 3.0 (NA) 5.3 (4.93) 3.0 (2.00) 2.0 (0.63) 2.1 (0.69) 2.3 (0.96) 2.7 (1.15) 2.0 (1.10) 2.9 (2.63) 2.7 (2.07)

Median 3.0 3.0 3.0 2.0 2.0 2.5 2.0 2.0 2.0 2.0

25th, 75th Percentile 3.0, 3.0 2.0, 11.0 1.0, 5.0 2.0, 2.0 2.0, 3.0 1.5, 3.0 2.0, 4.0 1.0, 2.0 1.0, 3.0 2.0, 3.0

Min, Max 3, 3 2, 11 1, 5 1, 3 1, 3 1, 3 2, 4 1, 4 1, 11 1, 11

Swimlanes and Notch1 ICD statusPreferred Term

• The Notch pathway plays a key role in embryonic development, the regulation of stem and progenitor cells, and is implicated in human cancer

• Notch-1 (N1) signaling is activated by various mechanisms including N1 activating mutations in certain solid tumors

• Brontictuzumab (BRON, OMP-52M51) is a humanized IgG2 antibody that inhibits the signaling function of N1. As such, BRON is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects on tumor angiogenesis.

• We present data from a phase I dose escalation and expansion study that was initiated in patients (pts) with certain advanced solid tumors (cholangiocarcinoma, breast (BC), colorectal (CRC), esophageal, gastric, pancreatic, small cell lung cancers (SCLC), and adenoid cystic carcinomas (ACC)) that have rates of N1 activation between 12-50%. BRON was administered intravenously to study safety, pharmacokinetics (PK), pharmacodynamics, preliminary efficacy, and to determine the maximum tolerated dose. The trial has a biomarker (Notch1 intracellular domain (NICD)) selected expansion cohort.

• Clinicaltrials.gov NCT01778439

Biomarkers

HES1

HEY1

0.25mg/

kg

Q4W

0.5mg/

kg

Q4W

1.0mg/

kg

Q4W

2.5mg/

kg

Q4W

2.5mg/k

g

Q3W

2.0mg/k

g Q3W

1.0mg/

kg

Q3W

1.5mg/

kg

Q3W

Expansion

#

subjects

treated

1 3 3 6 7 4 3 6 15

#

subjects

evaluable

for DLT

1 3 2 6 6 4 3 6 N/A

# of DLTs 0 0 01

Gr3

fatigue

1Gr3

Diarrhea

1Gr3

Diarrhea

0 0 N/A

Dose Cohorts and DLTs (n=48)

Partial Response in 2 ACC patients after 1

dose (1.5 mg/kg)Preferred Term

Day 1* Day 40

Pre and post treatment tumor biopsies

BC patient treated with 1 dose at 2 mg/kg

and 1 dose at 1 mg/kg

Control

Genes

Pre and post treatment blood

biomarker analysis of 24 patients

*This partial response occurred after the data cut-off date and is not shown in the tables or waterfall plot

Best Objective Responses in NICD high

According to dose (n=14 Evaluable)Preferred Term

Day 1

Day 35

Inhibition of NICD shown in tumor

showing N1 pathway inhibition

Downregulation of Notch target

genes shown in blood

*

***

** ongoing

N=24 N=24

N=24

N=24N=10

N=10

NICD Low

NICD High

TEAE : treatment emergent Adverse Event