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Human Tumor Explants are Better Predictors of Clinical Trial Outcome than Solid Tumor Cell Line Xenografts for the KSP Inhibitor ARRY-520
Michael J. Humphries, Richard Woessner, Cheryl Napier, Christine Lemieux, Duncan Walker and Shannon L. Winski
Abstract # 1782
Array BioPharma Inc., Boulder, CO
Available at www.arraybiopharma.com
ARRY-520 in vivo activity: Solid tumor cell line xenografts and patient-derived explants
Tumor Type
Colon
Solid tumor cell line xenograft
Pancreas
Ovarian
Colon
Patient-derived explant model
Biliary
ARRY-520 in vitro potency
1.6 nM median (mean 2.8 ± 4.4)
Solid Tumor Cell EC50s
•
•
In vitro viability: Cancer cell lines in log phase growth were treated with ARRY-520 for 72-96 hours. Cell
viability was assessed using an Alamar Blue metabolic reagent. EC50 values are shown representing three or
more independent experiments.
Model Type
Model Name
ANBL-6
H929
JJN3
RPMI8226
KAS-6
Increasing the confidence of clinical success
Multiple myeloma cell line xenograft
Cell line xenograft models have limitations
Cell Line
•
•
•
•
CRC2598
CRC2598
Retain heterogeneity
Retain microenvironment
Retain architecture
Genetic alterations reflect
primary tumor
• Reflect prior treatment
All in vivo studies were performed in accordance with IACUC guidelines and in harmony with
the Guide for Laboratory Animal Care and Use.
-30
-40
-50
-60
-70
-80
-90
-100
KAS-6
Primary tumor
-20
RPMI-8226
Primary tumor explants are closer to the patient
-10
JJN3
Colo205
0
H929
Colo205
• Selected for growth in
artificial environment
• Lack complex
microenvironment
• Lack heterogeneity
• Excessive genetic
alterations
multiple myeloma cell line xenografts
Other*
3
5
4
5
3
3
11
• 2 patients experienced prolonged
SD at 2.5 mg/m2
0
1) Malignant melanoma pt.
• SD for 9.3 months
• 5 prior therapies
mg/m2/day,
2.5
Day 1 q 3 wks
3.3 mg/m2/day, Day 1 q 3 wks
1.25 mg/m2/day, Day 1, 2 q 2 wks
1.6 mg/m2/day, Day 1, 2 q 2 wks
1.6 mg/m2/day+ G-CSF Day 1, 2 q 2 wks
-20
Not active
2) Ovarian cancer pt.
• SD for 4.0 months
• 10 prior therapies
-40
0
2
4
6
8
10
•
Goncalves et al. 2010. ASCO Abst. #2570
Time On Study (Months)
-60
A2780
N87
HCT116
LoVo
HT-29
Colo205
CRC13B2
BxPC3
LOX
-100
PR
•
32 patients were evaluable for
response
•
Median of 6 prior therapies
•
19% response rate (>MR)
• 4 PR
• 2 MR
• 1 unconfirmed PR:
(progressed with skeletal lesions)
PR
MR
PR
MR
PR
In vivo efficacy: All studies were performed in
female SCID-Beige mice bearing growthstaged tumors. ARRY-520 was administered as
an intraperitoneal bolus using the indicated
dose and schedule. All regimens were welltolerated. Best anti-tumor responses are
displayed as maximal tumor regression.
Models exhibiting tumor regression were
considered active.
unconfirmed PR
•
Lonial, S. et al. 2011. ASH Abst. #2935
1.5 mg/m2/day+ G-CSF, D1, 2 q2wks
On Study
0.0
GEJ / Esophagus
20
schedule
Days 1, 2
Days 1, 2
Days 1, 2
Days 1, 2
Days 1, 2
Phase 2 study of ARRY-520 in patients with
relapsed and refractory multiple myeloma: An
open label, single arm, multicenter study was
conducted to assess the safety and efficacy of
ARRY-520. 32 evaluable patients were
administered 1.5 mg/m2 ARRY-520 as an IV
infusion on days 1, 2, q2w. Prophylactic G-CSF
was administered starting D3 or 4 for 5-7 days.
PANC
Active
ARRY-520 Phase 2:
Relapsed and refractory multiple myeloma
Dose (mg/kg)
12.5
12.5
12.5
12.5
12.5
CRC
• 30 patients were evaluable for
response by modified RECIST
criteria
Broad and potent activity of ARRY-520 in solid tumor cell line xenografts was not reflected in clinical trials
Modest activity in solid tumor explants closely reflected the clinical activity of this drug
ARRY-520 in vivo activity:
Multiple myeloma cell line xenografts
MEL
7 / 11 cell line xenografts displayed activity
1 / 8 patient-derived explants displayed activity
40
Hematologic Tumor Cell EC50s 1 .6 nM median (mean 1.8 ± 1.6)
No evidence of enriched ARRY-520
sensitivity within specific tumor cell types
NSCLC
* Cholangiocarcinoma, ACUP, Mesothelioma, Ovarian, Thyroid, Sarcoma, mixed NSCLC/SCLC, Breast
-80
In vivo efficacy: All studies were performed in female nude or SCID-Beige mice bearing growth-staged
tumors. ARRY-520 was administered as an intraperitoneal bolus using the indicated dose and schedule. All
regimens were well-tolerated. Best anti-tumor responses, either end of study tumor growth inhibition or
maximal tumor regression, are displayed. Models exhibiting tumor regression were considered active.
Head and Neck
# of patients
60
U87
Cell Line
RPMI8226
JJN3
H929
MV4-11
HL-60
K562
KU812
KG1
Molt3
Molt4
K562 ADR
patient-derived explants
solid tumor cell line xenografts
CRC25B2
Tumor Type
Multiple myeloma
Multiple myeloma
Multiple myeloma
Leukemia
Leukemia
Leukemia
Leukemia
Leukemia
Leukemia
Leukemia
Leukemia
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Days 1, 2
Days 1, 2
Days 1, 2
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
Q4D x 3 cycles
CRC2598
Cell Viability EC50, nM
2.5
1.4
1.6
1.2
1.6
1.4
1.1
2.1
1.1
2.1
4.2
20
27
20
20
20
15
27
20
20
25
20
20
20
20
20
20
20
20
20
Disease
AMP38B9
Cell Viability EC50, nM
0.8
0.4
2
3.7
0.9
2.2
0.8
0.8
0.7
3.1
0.6
2.1
0.7
2
14
0.9
2.3
1.6
14
HT-29
HCT116
HCT-15
LoVo
Colo205
BXPC3
A2780
R182
N87
U87
LOX
CRC13B2
CRC18B2
CRC2598
CRC25B2
CRC25B3
CHL38B11
AMP38B9
PAN38B4
ARRY-520 Phase 1: Advanced solid malignancies
80
R182
Tumor Type
Colon
Colon
Colon
Colon
Pancreas
Pancreas
Pancreas
Breast
Breast
Breast
Breast
Prostate
Prostate
Ovarian
Ovarian
Cervical
Epidermoid
Melanoma
Glioblastoma
schedule
CHL38B11
Cell Line
HT-29
HCT-116
CRC13B2-AP2
HCT-15
PANC-1
BxPC3
MiaPaCa
SKBR3
MDA-MB-468
MDA-MB-231
MCF7
DU145
PC-3
A2780
NCI/ADR-RES
HeLa
A431
LOX-IMVI
U87-MG
Pancreas
Dose (mg/kg)
CRC25B3
To probe the disparity between preclinical and clinical activity in solid tumors, we
have retrospectively evaluated the ability of preclinical models to inform clinical
success by comparing ARRY-520 clinical activity in solid tumors, to preclinical
activity in cell line xenograft and patient-derived explants.
Gastric
Brain
Melanoma
ANBL-6
•
ARRY-520 is a novel kinesin spindle protein inhibitor that has demonstrated
significant preclinical activity in solid tumor and hematologic cell line models. In
clinical studies, while ARRY-520 has demonstrated significant single-agent activity
in multiple myeloma, activity in solid tumors has been modest.
Tumor size in response to treatment
•
Model Name
PAN38B4
Patient-derived explant models have significant potential to inform clinical direction
by better reflecting the primary cancer in patients. These models have been treated
with current standards of care, they have not undergone genetic drift or selection for
growth in culture, and they retain the infrastructure of the tumor microenvironment.
Model Type
HCT-15
•
Human tumor cell line xenografts have served as standard models for selecting and
optimizing anticancer drugs. Despite wide use, cell line models are poor predictors
of clinical activity of drugs, particularly cytotoxic agents.
CRC18B2
•
Tumor size in response to treatment
Introduction
2.0
4.0
6.0
8.0
Off Study
10.0
Time on Study (Months)
• Multiple myeloma xenografts are the most sensitive cell line models to ARRY-520
• Mirrors the clinical activity of this drug in heavily pretreated relapsed and refractory multiple myeloma patients
Phase 1 study of ARRY-520 in patients with advanced solid malignancies: An open label, multi-arm,
multicenter, dose escalation study was conducted to assess the safety, pharmacokinetics, and
pharmacodynamics of ARRY-520. 34 patients were administered ARRY-520 as an IV infusion using the
indicated doses and schedules.
Summary
• Preclinical activity in solid tumor cell lines and xenografts rarely
correlates with clinical activity (Johnson et al. 2001. BJC. 84: 1424)
• ARRY-520 has been investigated in preclinical and clinical settings,
enabling an analysis of correlations between clinical and preclinical
activity
• Patient-derived solid tumor explants accurately predicted clinical
outcome while solid tumor cell line xenografts did not
• Multiple myeloma cell line xenografts reflected the potential
clinical activity of ARRY-520
• Patient-derived explants better represent the primary cancer in
patients and thus may allow for improved predictions of clinical
activity.
• Further work is required to understand the differences in solid
tumor and hematological cell line models for predicting clinical
outcome
• Patient-derived solid tumor explants have potential to improve
clinical decision making
• Identify preferred indications/settings for clinical development
• Model system to identify markers for patient response/resistance
Thanks to the patients and their families