Christiane Querfeld, MD · 5/9/2018 · H u T 1 0 2 a p o to s is p a th w a y a c tiv a tio n C a...
Transcript of Christiane Querfeld, MD · 5/9/2018 · H u T 1 0 2 a p o to s is p a th w a y a c tiv a tio n C a...
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Christiane Querfeld, MD
2015... 2018 T-Cell Lymphomas: we are close to the finalization
Bologna, IT May 9, 2018
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▪ Epigenetic alterations have been implicated in the pathogenesis of lymphomas and leukemias including CTCL
▪ miRNA profiling and RT-PCR discriminate CTCL and non-malignant inflammation with a high accuracy
▪ miR-155 is overexpressed in CTCL skin
▪ JAK/STAT, NFkB and PI3K pathways are activated in CTCL and regulated by miR-155 that lead to uncontrolled clonal cell expansion
Ralfkiaer et al. Blood 2011; Netchiporouk et al. Cell Cycle 2014; Van Kester et al. 2011; Maj et al. Br J Derm 2012;
Kopp et al. APMIS 2013; Kopp et al. Cell Cycle 2013; Moyal et al. Exp Derm 2013; Moyal et al. Br J Derm 2017
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Archived tissue provided by
Madeleine Duvic (MD Anderson)
0 2 4 6 8 1 0 1 2
0
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H u T 1 0 2 a p o to s is p a th w a y a c t iv a tio n
C a s p a s e 3 /7 a c t iv ity
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d t
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ntr
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B e x a ro te n e
M 1 1 6 6 7
U n tre a te dUntreated
Bexarotene
miR-155 Inhibitor (MRG-106)3
n=10 n=13 n=21n=13
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PHASE 1 COBOMARSEN OPEN LABEL STUDY IN CTCLDESIGN AND INTERIM RESULTSSafety and efficacy
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Objectives:▪ Primary: Investigate safety & tolerability of multiple injections
▪ Secondary: Characterize the pharmacokinetic profile
▪ Exploratory:
❑ Pharmacodynamic profile
❑ Gene expression alterations
❑ Histopathology of lesion biopsy
❑ Imaging of tumor morphology
Part AIntra-tumoral delivery of cobomarsen.
75 mg dose
Part BSystemic SC or IV delivery to determine optimal
potential dose. 300, 600 and 900 mg dose
Pretreatment
biopsy
Placebo MRG-106
Pretreatment
biopsy Placebo
biopsy
MRG-106
biopsyBiopsy
Cobomarsen
Sub-cut.
or IV
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6Database Jan 2018
• Balanced across stages
• Patient population failed
many prior therapies
• miR-155 elevated in most
enrolled patient’s lesions
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Early termination
CAILS assessment day
MRG-106 injected lesions
= last injection day
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102-001 102-003 101-001 102-003 102-001 101-001 110-001
Saline MRG-106
Saline MRG-106
BLOQ BLOQ
MR
G-1
06
(mg/g
tis
su
e)
122 transcripts
Up-regulated vs. untreatedDown-regulated vs. untreated
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MRG-106 Treatment
Decreases Key CTCL
Disease Pathways:
• STAT
• PI3K/AKT
• NFkB
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▪ Cobomarsen has been safe and generally well tolerated at all doses tested ▪ Multiple patients receiving more than a year of therapy (up to 39 grams
cumulative dose) with no serious adverse events attributed to cobomarsen
▪ No significant abnormalities found in liver or kidney function, no abnormalities in platelet counts
▪ No acute inflammatory toxicities
▪ No SAEs attributed to MRG-106
▪ Two Dose-Limiting Toxicities:
▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient at 900 mg SC and 300 mg IV infusion
▪ Grade 3 tumor flare (300 mg IV bolus)
▪ Novel oligonucleotide drug class▪ Elimination of “gap” reduces chemical class based toxicity
▪ Short length minimizes heparin mimetic activity
No Serious
Adverse Events
attributed to
cobomarsen
No acute
inflammatory
toxicities
No significant
abnormalities
found in liver,
kidney or blood
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All Related AEs (grade 1-4): 133 (62.2% subjects)
Hematology
27 (34.1%)
Neutropenia
9 (20.5%)
Lymphopenia
6 (13.6%)
Anemia
1 (2.3%)
Thrombocytopenia
5 (9.1%)
Other
4 (9.1%)
Other Non-Hem
80 (50%)
GI
12 (15.9%)
Neurological
5 (9.1%)
Musculoskeletal
5 (4.5%)
Infection
1 (2.3%)
Skin
17 (20.5%)
Cardiac
3 (4.5%)
Renal
10 (11.4%)
Psychiatric
2 (2.3%)
Other/ Investigations
22 (29.5%)
Vascular
3 (4.5%)
Constitutional/Drug Administration
26 (27.3%)
Infusion reaction
16 (15.9%)
Injuries
1 (2.3%)
Constitutional
9 (15.9%)
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All Related AEs in > 10% of subjects (grade 1-4)
Hematology
27 (34.1%)
Neutropenia
9 (20.5%)
Lymphopenia
6 (13.6%)
Other Non-Hem
80 (50%)
GI
12 (15.9%)
Skin
17 (20.5%)
Renal
10 (11.4%)
Other/ Investigations
22 (29.5%)
Constitutional/Drug Administration
26 (27.3%)
Infusion reaction
16 (15.9%)
Constitutional
9 (15.9%)
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Part B
SQ
Part B
(IV, 2 hr infusion)
Part B
(IV Bolus)
System Organ Class 900mg 300mg 600mg 900mg 300mg Total
Preferred Term n=45
Hematology 4 ( 8.9%)
Neutrophil count decreased 1 1 1 3 ( 6.7%)
White blood cell count decreased 1 1 2 ( 4.4%)
Lymphocyte count decreased 1 1 ( 2.2%)
Skin 2 ( 4.4%)
Pruritus 1 1 2 ( 4.4%)
Rash 1 1 ( 2.2%)
Metabolism and nutrition disorders 1 ( 2.2%)
Hyperuricaemia 1 1 ( 2.2%)
Neoplasms 2 ( 4.4%)
Tumour flare 1 1 2 ( 4.4%)
Vascular 1 ( 2.2%)
Hypertension 1 1 ( 2.2%)
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106-
002
101-
003
111-
001
106-
001
105-
002
102-
004
101-
002
105-
003
102-
005
108-
001
112-
003
108-
002
112-
006
101-
009
102-
008
102-
009
112-
001
102-
007
107-
003
112-
004
105-
004
106-
003
103-
001
111-
002
101-
005
104-
001
112-
005
102-
010
101-
004
-100
-75
-50
-25
0
25
Best
Ch
an
ge i
n m
SW
AT
Sc
ore
(%
)
300 mg
600 mg
900 mg
Subcutaneous IV BolusIV Infusion
* Treatment is ongoing
*
**
*
*
***
**
*
*
55 2629 43256 446 57 21 2586663 69# doses rec'd:
baseline mSWAT: 6 18103 43 20 58 178 595172 47 43 180278222 6 132
910
71
21
66
8
462
6 6
54
10
85
6
6
7
11
5
86
3
18
Note: Database January 2018 IV infusions showed the most consistent
response 13
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0 30 60 90 120 150 180 210 240 270 300 330 360 390 420
Study Day
112-006
112-003
101-009
102-009
107-003
102-008
112-001
102-007
Su
bje
ct
ID
Ongoing
Last Dose
Drug Holiday
PD = Progressive Disease
PR = Partial Response
SD = Stable Disease
Bexarotene (24 mo)
Methotrexate (20 mo)
Interferon alfa (31 mo)
none
none
none
Oxsoralen
(19 mo)
none
112-
003
112-
006
101-
009
102-
008
102-
009
112-
001
102-
007
107-
003
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Ch
an
ge i
n m
SW
AT
Sco
re (
%)
300 mg
600 mg
**
* Treatment is ongoing
**
*
2643
180 6
25
27
2944
43 82
8
178
7
11
6
58
# doses rec'd:
Baseline mSWAT:
300mg Dose Selected for Phase 2 in MFResponse and durability observed
independent of concomitant medication
Conmed (months
before Day1)
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Concomitant med N Median time (min, max)
on therapy prior to study day 1
bexarotene 7 16 months (2, 26)
interferon-alfa 2 26 months (17, 34)
methotrexate 1 22 months
vorinostat 1 4 months
other 2 21 months (3, 45)
Database Jan. 25, 2018
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Day 1
CAILS: 13
Day 19
CAILS: 10
Day 27
CAILS: 8
Day 57
CAILS: 5
Day 103
CAILS: 10
Day 131
CAILS: 8
Day 159
CAILS: 7
Day 186
CAILS: 6
Note: Grey shading = drug administration period, White
Shading = pause in drug administration
▪ There is continued improvement that extended beyond
discontinuation of the first 4 weeks of dosing that
eventually dissipated during the drug holiday
▪ Patient responded with re-initiation of therapy
5 4 5 8 5 1 2 5 1 6 5 2 0 5 2 4 5 2 8 5
0
2
4
6
8
1 0
1 2
1 4
1 6
1 8
2 0
2 2
0
2 0
4 0
6 0
8 0
1 0 0
1 0 2 -0 0 5
S tu d y D a y
mS
WA
T S
co
re
mS
WA
T (%
of B
as
elin
e)
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▪ Age: 51; Sex: Male
▪ Date of diagnosis: 2013
▪ CTCL stage at screening: IB
▪ Baseline mSWAT: 180
▪ Concomitant systemic therapy: Methotrexate (started June 2015)
▪ Has skin (mSWAT) PR lasting > 4 months
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Day 1
mSWAT: 180
Day 93
mSWAT: 68
(62% reduction)
Database Dec. 4, 2017
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▪ 13 of 18 subjects show a significant improvement over the first 100 days on study drug
▪ Improvement and stabilization seem durable, in 4 subjects for up to one year and one subject is stable after 400+days on study drug
▪ Subject 112-001 (300 mg IV infusion) worsen Skindex 29 and mSWAT response after switched to monthly dosing on day 285.
Subject switched to
monthly dosing on day 285
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C5Day1 C6Day1
C8Day1 C9Day1
C7Day1
C10Day1
Day 1 Day 27 C1Day1
C3Day1 C4Day1C2Day1
Mean Skindex 29 Total Score
mS
WA
T S
co
re
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▪ Durable partial responses have been achieved at all dose levels
▪ 300-900 mg appear to represent the top of the dose response curve
▪ 300 and 600 mg IV-infusions had similar efficacy and tolerability, offering the most consistent response rate based on skin mSWAT scores
▪ 6 of 8 (75%) patients (initially assigned to 300 or 600 mg dose level) achieved skin PR
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▪ Cobomarsen is generally well-tolerated to date
▪ No SAEs deemed related to study drug
▪ Two Dose-Limiting Toxicities:▪ Grade 3 worsening pruritus, possible tumor flare, occurred twice in one patient
(900 mg SC cohort, 300 mg IV-infusion)
▪ Grade 3 tumor flare in 300 mg iv bolus patient
▪ 6 of 8 (75%) patients treated for > 1 month with 300 or 600 mg systemically had ≥ 50% mSWAT score reduction
▪ Best improvement in mSWAT score appeared to be seen after 1 or more months of dosing
▪ Cobomarsen treatment resulted in durable improved quality of life, as measured by the Skindex 29 Total Score
▪ This improvement parallels improvements in disease, as measured by the mSWAT score, in most subjects, even if the patients achieve less than a defined PR
▪ Study in CTCL is on-going (enrollment closed)
▪ Study has expanded to include patients with CLL, DLBCL, and ATLL, diseases in which miR-155 expression is increased
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Primary endpoint:
▪ Overall Response Rate of four months (ORR4) using
Global Response
Key Secondary endpoints:
▪ Progression-free survival
▪ Patient reported outcomes
▪ Pain, itching
A RANDOMIZED, PARALLEL, OPEN LABEL, ACTIVE CONTROL, GLOBAL TRIAL IN PATIENTS WITH STAGE IB-III MYCOSIS FUNGOIDES
Key inclusion criteria
▪ Stage Ib-III
▪ Must have received at least one prior therapy for CTCL (per NCCN guidelines for generalized skin involvement)
▪ mSWAT score ≥ 10
▪ No concurrent systemic therapy
Stratification factors
▪ Stage (Ib-IIa vs IIb-III)
▪ Prior Therapies (1-2 vs. 3 or more)
Open Label; Randomize to:
cobomarsen IV Infusionvs.
Vorinostat
Randomize
Cobomarsen (300mg IV Infusion)
n=~65 subjects
Vorinostatn=~65 subjects
Follow until progressionor death
Follow until progression or death
Open label extension
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Jennifer DeSimone (Inova)
Herbert Eradat (UCLA)
Francine Foss (Yale)
Joan Guitart (Northwestern)
Ahmad Halwani (Huntsman)
Auris Huen (MD Anderson)
Youn Kim (Stanford)
Theresa Pacheco (University of Colorado)
Lauren Pinter-Brown (UC Irvine)
Pierluigi Porcu (Thomas Jefferson)
Christiane Querfeld (City of Hope)
Basem William (The Ohio State University)
INVESTIGATORS
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