1. No category

A Phase 1 Study of MM-302, a HER2targeted PEGylated liposomal doxorubicin,
in Patients with HER2-positive Metastatic
Breast Cancer (MBC)
P LoRusso1, I Krop2, K Miller3, C Ma4, BA Siegel4, AF Shields5, I Molnár6,
T Wickham6, J Reynolds6, K Campbell6, B Hendriks6, T McClure6,
V Moyo6, P Munster7
1Yale
Cancer Center, New Haven, CT; 2Dana-Farber Cancer Institute, Boston, MA; 3Indiana University
Melvin and Bren Simon Cancer Center, Indianapolis, IN, 4Washington University School of Medicine,
St. Louis, MO; 5Karmanos Cancer Institute, Detroit, MI; 6Merrimack Pharmaceuticals, Cambridge, MA;
7Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
Background
• HER2-positive breast cancer affects ~20% of all breast cancer
and represents a particularly aggressive form of the disease
• Despite recently approved agents like pertuzumab and T-DM1,
HER2-positive MBC remains a high unmet medical need
• Anthracyclines are particularly effective in HER2-positive BC;
however use has declined due to several reasons
• Microtubule targeting agents are heavily used in all lines
2
MM-302: HER2-targeted PEGylated liposomal doxorubicin
anti-HER2 scFv
• Targets liposome to HER2-overexpressing cells
• Promotes internalization
• Binds to a different epitope than trastuzumab
• Does not bind to cardiomyocytes
Liposome
• Extended half-life
• Stably encapsulates doxorubicin
• Passive accumulation in tumors
• Size precludes delivery to cardiac tissue
Lipid
Membrane
PEG
75-110 nm
Doxorubicin Crystals
• Effective cytotoxic agent in breast cancer
• DNA intercalator, TOP2A inhibitor, free
radical generator
3
MM-302 Proposed Mechanism of Action
HER2-positive tumor
capillary
SUM190 cells
(HER2-positive)
Extravasation
via leaky
vasculature
Binding and
internalization
22
2
control
MM-302
PLD
doxorubicin
MM-302
Doxorubicin
2
HER2
Cancer Cell
Death
4
MM-302 Proposed Mechanism of Action
Cardiac tissue
Tight vasculature
X
Does not bind to
cardiomyocytes
2
Human stem cell-derived
H e a r t C e lls
cardiomyocytes
5000
d o x o r u b ic in
( f e m t o g r a m s /c e ll)
X
t o t a l c e ll a s s o c ia t e d d o x o r u b ic in
capillary
PLD
4000
M M -3 0 2
3000
2000
1000
0
0
50
100
150
200
In c u b a tio n t im e (m in )
MM-302
Doxorubicin
2
HER2
Reynolds et al., Toxicol Appl Pharmacol. 2012.
5
Preclinical data supporting MM-302 development
BT474-M3-breast
MM-302 binds to a different epitope
than trastuzumab
MM-302
T u m o r V o lu m e (m m 3 )
3000
2500
2000
1500
1000
500
*** *
0
20
trastuzumab
HER2
T u m o r V o lu m e (m m 3 )
Control
MM-302 3 mg/kg weekly
trastuzumab 3.5 mg/kg q3d
MM-302 & trastuzumab
30
40
50
60
D a y s a fte r in o c u la tio n
NCI-N87-gastric
2000
1500
1000
**
500
0
30
40
50
60
70
80
D a y s a fte r in o c u la tio n
90
6
Use of Cyclophosphamide Pretreatment to Enhance
MM-302 Tumor Deposition (BT474-M3)
Nuclear Doxorubicin
No Cyclo
%
D O X P O S N u c le i
60
+ Cyclo
MM-302
doxorubicin
15
10
5
30
20
10
N o C y c lo
800
p e rc e n t c h a n g e fro m d a y 1 4
% i.d ./g tis s u e
20
40
0
900
Tumor Deposition
50
700
600
+ C y c lo (-4 d )
Tumor Shrinkage
CTL
M M - 3 0 2 a lo n e
M M - 3 0 2 + C y c lo
C y c lo 9 6 h r
500
400
300
200
100
0
20
0
N o C y c lo
+ C y c lo ( - 4 d )
30
40
D ay
50
7
MM-302 Phase 1 Study
Arm 1
8, 16, 30, 40 & 50 mg/m2 MM-302, q4w
Patients with locally
advanced/unresectable
or metastatic
HER2-positive
breast cancer
(N=69)
Arm 2
30 & 40 mg/m2 MM-302, q4w
+ 4 mg/kg trastuzumaba, q2w
Arm 3
30 mg/m2 MM-302, q3w
+ 6 mg/kg trastuzumabb, q3w
+ 64Cu-MM-302
Arm 4
30 mg/m2 MM-302, q3w
+ 6 mg/kg trastuzumabb, q3w
+ 450 mg/m2 cyclophosphamide, q3w
+ 64Cu-MM-302
a:
6 mg/kg trastuzumab loading dose, b: 8 mg/kg trastuzumab loading dose
patients
34
10
12
13
8
Key Study Objectives
• Primary Objective:
– To assess the safety and tolerability of:
• MM-302 alone
• MM-302 plus trastuzumab
• MM-302 plus trastuzumab and cyclophosphamide
– To determine the Phase 2 dose
• Key Secondary Objectives:
–
–
–
–
–
–
Describe dose limiting toxicities
Objective response rate
Clinical benefit rate (CR + PR + SD at 24 weeks)
Duration of response
Median progression free survival
Pharmacokinetics
9
Key Inclusion and Exclusion Criteria
• Inclusion:
– Locally advanced/unresectable or MBC HER2 positive
• HER2+ = HER2 IHC 3+ or HER2 ICH 2+ and FISH/CISH-positive
– Measurable disease (RECIST v1.1)
– ECOG 0 or 1
• Exclusion:
– Received 300 mg/mg2 of anthracycline
– NYHA Class III or IV CHF or LVEF 50%
– History of:
•
•
•
•
•
•
Coronary artery disease
Myocardial infarction within the last 12 months
Severe and/or uncontrolled ventricular arrhythmias
Clinically significant valvular heart disease
Angina pectoris requiring medication
Prolonged QTc interval
10
Demographics
TOTAL
N
Age
Median Years (range)
Race
Asian, n (%)
Black or African American, n (%)
Caucasian, n (%)
69
55.0 (31-75)
1 (1.4)
4 (5.8)
64 (92.8)
Prior Regimens for Metastatic Disease
Median (range)
4 (0-11)
Prior Exposure to, n (%)
Anthracycline
Taxane
Trastuzumab
Ado-trastuzumab emtansine (T-DM1)
Pertuzumab
Lapatinib
Hormonal Therapy
37 (53.6)
64 (92.8)
68 (98.6)
35 (50.7)
17 (24.6)
42 (60.9)
33 (47.8)
11
MM-302 Pharmacokinetics
MM-302 Monotherapy
8 mg/m2
16 mg/m2
30 mg/m2
40 mg/m2
50 mg/m2
MM-302 plus trastuzumab
8 mg/m2
16 mg/m2
30 mg/m2
40 mg/m2
50 mg/m2
t1/2= ~2 days in patients receiving 30 mg/m2 MM-302 +/- trastuzumab
12
AEs occurring in ≥20% of population (any grade)
MM-302
MM-302
+ trastuzumab
MM-302 alone + trastuzumab
+ cyclo
Adverse Event1, n (%)
TOTAL
(N=34)
(N=22)
(N=13)
(N=69)
Fatigue
21 (61.8)
10 (45.5)
3 (23.1)
34 (49.3)
Nausea
19 (55.9)
9 (40.9)
6 (46.2)
34 (49.3)
Constipation
7 (20.6)
9 (40.9)
4 (30.8)
20 (29.0)
Decreased Appetite
13 (38.2)
5 (22.7)
2 (15.4)
20 (29.0)
Vomiting
9 (26.5)
5 (22.7)
4 (30.8)
18 (26.1)
Cough
8 (23.5)
7 (31.8)
2 (15.4)
17 (24.6)
Diarrhea
7 (20.6)
5 (22.7)
4 (30.8)
16 (23.2)
Neutropenia
9 (26.5)
3 (13.6)
3 (23.1)
15 (21.7)
Stomatitis
8 (23.5)
6 (27.3)
1 (7.7)
15 (21.7)
Dyspnea
5 (14.7)
5 (22.7)
4 (30.8)
14 (20.3)
1 MedDRA
preferred terms
13
Grade 3/4 Treatment Emergent1 AEs (TEAEs)
MM-302
MM-302
+ trastuzumab
MM-302 alone + trastuzumab
+ cyclo
(N=34)
TOTAL
(N=22)
(N=13)
(N=69)
9 (26%)
1 (10%)
2 (15%)
12 (17%)
6 (17)
2 (6)
1 (3)
2 (6)
1 (3)
1 (3)
1 (3)
1 (3)
1 (3)
1 (3)
1 (10)
1 (10)
-
1 (7)
1 (7)
-
7 (10.1)
2 (2.9)
2 (2.9)
2 (2.9)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
Patients with related Grade 3/4 TEAE, n (%)
Adverse Events2, n (%)
Neutropenia
Leukopenia
Lymphopenia
Mucosal Inflammation
Anemia
Dyspnea
Febrile Neutropenia
Hematocrit decreased
Neutropenic Infection
PPE
Thrombocytopenia
WBC decreased
1 Events
determined by investigator to be “possibly”, “probably” or “definitely” related to study drug treatment
preferred terms
2 MedDRA
14
Related1 SAEs and AEs Leading to Treatment Discontinuation
# of patients experiencing SAE
Individual SAEs2
Febrile Neutropenia
Anemia
White blood cell count decreased
Neutropenia
Thrombocytopenia
Palmar-plantar erythrodysesthesia
Adverse Events2 Leading to Treatment Discontinuation
Aphasia/face edema
Peripheral neuropathy
Cardiac failure
Neutropenia
Hypoxia
Thrombocytopenia
N=69
3 (4.3)
6 (8.7)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
6 (8.7)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
There were no treatment related deaths on study
1 Events
determined by investigator to be “possibly”, “probably” or “definitely” related to study drug treatment
2 MedDRA preferred terms
15
AEs of Special Interest
Adverse Event1
(N=69)
Neutropenia
15 (21.7)
Stomatitis
15 (21.7)
Mucositis
12 (17.4)
Alopecia
7 (10.1)
Infusion Reaction
6 (8.7)
LVEF changes
6 (8.7)
PPE
3 (4.3)
Cardiac failure
1 (1.4)
Neutropenic fever
1 (1.4)
PPE: palmar-plantar erthrodysesthesia syndrome
There were no severe infusion reactions
1 MedDRA
preferred terms
16
Cardiac Safety
• No cardiac events with MM-302 monotherapy (34 pts)
• Infrequent cardiac events with no SAEs in combination arms
– 6 had protocol defined asymptomatic declines in LVEF
• 4 Pts reversible declines - consistent with trastuzumab-induced changes
• 1 Pt decline to 47% noted at off-study assessment
• 1 Pt noted twice to have a range of 45-50% LVEF (off study – unchanged)
• One patient described above discontinued treatment due to LVEF
changes experienced Grade 1 Heart Failure
• 11 patients have cumulative anthracycline exposure >550 mg/m2
– 7 monotherapy pts, 4 in combination with trastuzumab
17
MM-302 Phase 1 Efficacy
Patients Receiving ≥30 mg/m2 MM-302
ORR: 11% (7/62)
CBR: 21% (13/62)
75
b a s e lin e )
50
25
fro m
0
-25
(%
b e s t c h a n g e in t a r g e t le s io n
100
-50
-75
-100
# prior regimens for metastatic disease
Median
prior exposure to, n (%)
Anthracycline
Trastuzumab
Lapatinib
Taxane
Ado-trastuzumab emtansine (T-DM1)
Pertuzumab
Hormonal therapy
24
(m o n th s )
p r o g r e s s io n
fr e e s u r v iv a l
30
18
12
4
mPFS 7.6 months
(95% CI) (3.6-10.9)
37 (60)
61 (98)
38 (61)
57 (92)
34 (55)
17 (27)
30 (48)
*
*
6
*
0
+ trastuzumab
+ cyclophosphamide
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*: patients still on study, ORR: Overall Response Rate, CBR: Clinical Benefit Rate (CR, PR and Stable Disease (SD) at 24 weeks)
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18
Enhanced Efficacy in Anthracycline Naïve Patients
Patients Receiving ≥30 mg/m2 MM-302
ORR: 11% (7/62)
CBR: 21% (13/62)
75
b a s e lin e )
50
25
fro m
0
-25
(%
b e s t c h a n g e in t a r g e t le s io n
100
-50
-75
-100
mPFS 7.6 months
(95% CI) (3.6-10.9)
Anthracycline naive
*
Anthracycline exposed
24
(m o n th s )
p r o g r e s s io n
fr e e s u r v iv a l
30
18
12
*
*
6
0
+ trastuzumab
+ cyclophosphamide
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*: patients still on study, ORR: Overall Response Rate, CBR: Clinical Benefit Rate (CR, PR and Stable Disease (SD) at 24 weeks)
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19
Enhanced Efficacy in Anthracycline Naïve Patients
Patients Receiving ≥30 mg/m2 MM-302
Anthracycline naive
100
ORR: 24% (6/25)
CBR: 28% (7/25)
75
ORR: 3% (1/37)
CBR: 16% (6/37)
50
25
25
0
0
-2 5
-2 5
-5 0
-5 0
-7 5
-7 5
-1 0 0
-1 0 0
30
30
(%
fro m
b a s e lin e )
50
24
(m o n th s )
p r o g re s s io n fre e s u rv iv a l
b e s t c h a n g e in ta r g e t le s io n
75
Anthracycline exposed
100
*
mPFS: 11.0 months
(95% CI)
(1.8-13.1)
24
18
18
12
12
*
6
20
+ cyclophosphamide
5.7 months
(3.6-8.7)
*
6
0
0
+ trastuzumab
mPFS:
(95% CI)
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*: patients still on study, ORR: Overall Response Rate, CBR: Clinical Benefit Rate (CR, PR and Stable Disease (SD) at 24 weeks)
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20
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20
Enhanced PFS in Anthracycline Naïve Patients
Patients Receiving ≥30 mg/m2 MM-302
100
anthracycline
a n t h r a c y c l i n e naive
n a iv e
anthracycline
a n t h r a c y c l i n e exposed
exposed
Prior Anthracycline: Naïve
n=
25
# of Events, n (%) 16 (64.0)
# Censored, n (%) 9 (36.0)
Exposed
37
19 (51.4)
18 (48.6)
mPFS (months)
11.0
(95% CI) (1.8-13.1)
5.7
(3.6-8.7)
P e rc e n t s u rv iv a l
75
median # of prior
regimens for MBC
2
5
50
25
0
0
6
12
18
24
30
p r o g re s s io n fre e s u rv iv a l
(m o n th s )
21
PET/CT
64Cu-MM-302
Breast & Skin
Localizes to Brain and Bone Metastases
Sternal Mass
24 h
45 h
Bone
22
Liver
Brain
19 h
25 h
Brain
44 h
19 h
22
HERMIONE Study Schema (NCT02213744)
HER2-positive
locally advanced/metastatic BC
(N=250)
MM-302
1
30 mg/m2, Q3W
+ trastuzumab
6 mg/kg*, Q3W
Anthracycline naive
Prior metastatic treatment with
pertuzumab and T-DM1
Prior treatment with
trastuzumab
1
Chemotherapy of Physician’s
Choice
(capecitabine, gemcitabine or vinorelbine)
+ trastuzumab
6mg/kg*, Q3W
* 8 mg/kg trastuzumab loading dose
• 70 participating sites (46 in the US, 4 in Canada and 20 in Europe)
• Study currently open and enrolling patients
• Enrollment expected to be completed late 2017
23
Conclusions
• Manageable safety profile as monotherapy, and in
combination with both T and T + C
• Appears to have activity in heavily pretreated MBC
• RR - 24% and an 11 mo mPFS was observed in
anthracycline-naïve patients
• HERMIONE - enrolling anthracycline-naïve patients
that progressed on pertuzumab and TDM-1
24
Acknowledgements
We would like to thank the patients, their
families, caregivers, investigators, and research
staff for their participation
25