Download Vantictumab Phase 1 ASCO 2013

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