Download IPI-549 Phase 1 Data at AACR 2017

A Phase 1/1b First-In-Human Study of IPI-549, a PI3K-g Inhibitor, in Patients with Advanced Solid Tumors
Poster # CT089 PLS
Anthony Tolcher , David Hong , Ryan Sullivan , Bartosz Chmielowski , Antoni Ribas , Joseph Pearlberg , Les Brail , Suresh Mahabhashyam , Lucy Lee , Claudio Dansky Ullmann , Geoff Shapiro , Michael Postow , Jedd D. Wolchok
1
3
4
5
5
5
5
5
6
7
F 69
69
Ffrom
63
In preclinical models, IPI-549 shifts macrophages in the tumorF microenvironment
69 E *
F 63the Onumber
the M2 protumor phenotype to the M1 antitumor phenotype, and increases
F 70
F 63 O
70 P 1,2
of T cells that attack the tumor and the production of pro-inflammatory Fcytokines
F 83
E
O
P
*
F 63
F 70
Monotherapy
*
E
F 63
O
O IPI-549
70 QDP
40F mg
P
F 83 PD
E
F 69
Combination
IPI-549 30 PD
mg QD
PD
+
nivolumab
PD
PD
PD
Gender Age Disease
Gender Age Disease
Monotherapy
Combination
PD
F 69
*
NSCLC
IPI-549 +
O
nivolumab
PD
E
Gender Age Disease
E*
PD
Gender FAge
Disease
63 O
F
F69
70
PE *
F 83
E
PD
PD
PD
PD
PD
PD
On StudyPD
PD
F F6343 ACCO
PD
On Study
PD Progressive Disease/
PD
PD
On Study
PD
Off Study
M 63 P
PD Progressive Disease/
F 70 P
PD
PD
D
Discontinued
On Study
F 63 CRC
Off
Study
PD
Progressive
Disease/
F 70 P
PD
E
Endometrial Cancer
On Study
PD
F F8350 PME
D
Discontinued
Off Study
PD Progressive Disease/
Monotherapy and
O
Ovarian
Carcinoma
E
Endometrial
Cancer
PD
PD
F 83 E
D
Discontinued
Study
PD Progressive Off
F 76 E
PD
Disease/
Melanoma
PCarcinoma
Pancreatic Carcinoma
ACC
Combination
O
Ovarian
E
Endometrial
Cancer
PD F F4351 CRC
D
Discontinued
Off
PD Study
ACCCarcinoma
Adenoid Cystic Carcinoma
P
Pancreatic
F 43 ACC IPI-549 + PD
O
Ovarian
Carcinoma
Expansion Cohorts:
E
Endometrial Cancer
D PD
PDDiscontinued
F
57
ACC
M
63
P
CRC
Colorectal
Carcinoma
nivolumab
ACC
Adenoid
Cystic
Carcinoma
P
Pancreatic
Carcinoma
O
Ovarian
Carcinoma
E
Endometrial Cancer
• 20-25 patients M 63 P
PD
M 72 NET
PM Carcinoma
Peritoneal Mesothelioma
PD
CRC
Colorectal
ACC
Adenoid
Cystic
Carcinoma
P
Pancreatic
Carcinoma
O
Ovarian Carcinoma
per cohort
F M6381 CRC
NETMesothelioma
Neuroendocrine Tumor
PD
MC
PM
Peritoneal
CRC
Colorectal
Carcinoma
ACC
Adenoid
Cystic
Carcinoma
P
Pancreatic Carcinoma
F
63
CRC
• Mandatory preMC Merkel
Cell
NET
Neuroendocrine
Tumor
PM
Peritoneal
Mesothelioma
O
PD
CRC
Colorectal
Carcinoma
F F5057 PM
ACC Adenoid Cystic Carcinoma
HN
Head and Neck
and on-treatments
SCCHN
MC
Merkel
Cell
PD
NET
Neuroendocrine
Tumor
PM
Peritoneal
Mesothelioma
M
74
HN
CRC Colorectal Carcinoma
F 50 PM
biopsies
* Prior
anti-PD-1/PD-L1 therapy
HN
Neck
IPI-549 +
MC Merkel
Cell Head and
F M7665 HNE* D
PD
PD
NET Mesothelioma
Neuroendocrine
Tumor
PM Peritoneal
PD
HN
Neck
* Prior
anti-PD-1/PD-L1
therapy
MC Merkel
Cell Head and
PD
F 76 E nivolumab
PD
NET Neuroendocrine
Tumor
10 mg
QD
Week
36
4
12
20
28
PD
F
51
CRC
*
Prior
anti-PD-1/PD-L1
therapy
HN
Head
and
Neck
MC
Merkel
Cell
PD
10
mg QD 15 mg QD
PD Combination
Response
Response
Response
Response
Response
PD
F
51
CRC
HN
Head and
Neck
* Prior
anti-PD-1/PD-L1
therapy
Assessment
Assessment
Assessment10 mg
Assessment
Assessment
PD
QD
20
mg
QD
15
mg
QD
PD
Expansion
F 57 ACC
* Prior anti-PD-1/PD-L1
therapy
PD F 57 ACC
10
mg
QD 15 mg QD 20 mg QD 30 mg QD
PD
TBD additional
Cohorts Only:
M 72 NET
PD
1010
mgmg
QD QD 15
QD QD
20
QD QDPD30
QD QD 4040
mgmg
QD QD
15mgmg
20mgmg
30mgmg
indications
• Must have de novo
M 72 NET IPI-549 +
PD
15 mg QD 20 mg QD 30 mg QD 40 mg QD
or aquired resistance
PD
M 81 MC
nivolumab
20 mg QD 30 mg QD 40 mg QD
to prior PD-1/PD-L1
PD Patient Demographics: Monotherapy
M 81 MC
Dose
Escalation
30
F 57 O
PD mg QD 40 mg QD
therapy
F 57 O
40 mg QD
PD
Solid tumors
IPI-549 F 63
M 71 CRC
On Study
F
48
B
Progressive Disease/
Off Study
F 82 B *
D
Discontinued
E
Endometrial Cancer
M 75 P
O
Ovarian Carcinoma
P
Pancreatic Carcinoma
M Cystic
27 Carcinoma
GC*
ACC Adenoid
CRC Colorectal Carcinoma
F Mesothelioma
46 N *
PM Peritoneal
NET Neuroendocrine Tumor
F Cell38 O
MC Merkel
HN Head and Neck
PD
PD
PD
PD
On Study
On Study
PD
PD
PD
D
E
O
P
ACC
CRC
PM
NET
MC
HN
PD
Progressive
Disease/
PD
Off Study
Discontinued
Endometrial Cancer
Ovarian Carcinoma
Pancreatic Carcinoma
Adenoid Cystic Carcinoma
Colorectal Carcinoma
Peritoneal Mesothelioma
Neuroendocrine Tumor
Merkel Cell
Head and Neck
On Study
On Study
PD Progressive Disease/
PDOff Study
Progressive Disease/
B
Bladder
OffCancer
Study
CRCD Colorectal
Carcinoma
Disontinued
P
Pancreas Cancer
ACC
GC Germ Adenoid
Cell TumorCystic Carcinoma
N B NSCLCBladder
(Adeno) Cancer
O
Ovarian Cancer
CRC
Colorectal Carcinoma
MC Merkel Cell
Endometrial
SC E Sebaceous
CarcinomaCancer
HN GC
Head and
Neck
Germ
Cell Tumor
Progressive Disease/
Off Study
D
Discontinued* Prior
HNanti-PD-1/PD-L1
Head and therapy
Neck
MC
E
Endometrial Cancer
IPI-549 Merkel
20 mg QDCell
+
Nivo 240mg
Q2W(Adeno)
N
NSCLC
O
Ovarian Carcinoma
NET
Tumor
IPI-549 Neuroendocrine
30 mg QD +
P 10Pancreatic
Carcinoma
mg QD
Nivo 240mg
Q2W Carcinoma
O
Ovarian
ACC 15Adenoid
CysticPCarcinoma
mg QD
Pancreatic Carcinoma
CRC 20Colorectal
Carcinoma
mg QD
PM Peritoneal Mesothelioma
PM 30Peritoneal
Mesothelioma
SC Sebaceous Carcinoma
mg QD
NET 40Neuroendocrine
Tumor
mg QD
* Prior
anti-PD-1/PD-L1 therapy
MC Merkel Cell
HN Head and Neck
EPD
PD F 43 ACC
E
F 70 P
PDF 43 ACC
F 53 therapy
O
* Prior anti-PD-1/PD-L1
IPI-549
20
mg
QD
IPI-549
F
83
E
PD
M 63 P
• Preclinical models have demonstrated antitumor activity of IPI-549 monotherapy in
10 mg QD
F
43
ACC
M 81 MC
+
nivolumab
30
mg
QD
F 83 E
15
mg
QD
PD
M
63
P
multiple solid tumors, including lung cancer, melanoma, head and neck,F colon,
and
43 ACC
20 mg QD
F 63PDCRC
F 69 SC
M
63
P
30 mg QD
F
43
ACC
1,2
F 63PDCRC
breast cancer
40 mg QD
M 63 P
M 54 HN*
F 50 PM
6+6 design
F
63
CRC
PD
M 63 P
F 50 PM
M 73 HN
F 63 CRC
nivolumab
F
76
E
F 50 PM
IPI-549
M 66 HN
F 63 Models
CRC
IPI-549 in Combination with an Anti-PD-1 Antibody in Preclinical
240
mg
Q2W
F 76 E 20 mg QD
F 50 PM
F 51 CRC
* Prior anti-PD-1/PD-L1 therapy
F
76
E
F
50
PM
Weeks 0
4
12
• IPI-549 in combination with anti-PD-1 checkpoint inhibition showed greater
tumor
PD
F 51 CRC
* Prior anti-PD-1/PD-L1 therapy
Enrollment complete
F 76 E
10Response
mg QD
F 57 ACC
Response
F 51 CRC
Assessment
Assessment
for PD
20 mg and
30 mg
growth inhibition, including more complete tumor regressionsFand
survival
76improved
E
10
mg
QD
15
mg QD
PD
F
57
ACC
F 51 CRC
QD combination
M 72 NET PD
2
15 mg QD
20 mg QD
PD
F
57
ACC
rates, compared to either IPI-549 or the checkpoint inhibitor alone
PD
IPI-549
F 51 CRC
cohorts. Safety data
M
72
NET
IPI-549
20 mg
IPI-549
30 mg
20 mg
QDQD + Nivo 240 mg Q2W
30 mg
QDQD + Nivo 240 mg Q2W
PD
F 57 ACC
PD
M
81
MC
15 mg QD
available only for
M
72
NET
PD
30 mg QD
• IPI-549 overcomes checkpoint inhibitor resistance, which is associated
with
increases
PD
40
mg
QD
F 57 ACC
PD
M 81 MC
20PD
mg combination
M 72 NET
F 57 O PD
40 mg QD
PD
M
81
MC
in M2 macrophages, by reprogramming macrophages from the
M2
protumor
Patient
Demographics:
Combination
Dose
Escalation
(20
mg
QD
only)
cohort
M 72 NET
PD PD
F
57
O
PD 74 HN
M 81 MC
M
phenotype to the M1 antitumor phenotype2
F 57 O PD
PD
M 81 MC
Parameter
DLT
Evaluable
Patients
N=6
Parameter
DLT
Evaluable
Patients
N=15
M
74
HN
M
74
HN
IPI-549
*
F 57 O
PD
M 65 HN D
M
74
HN
M 74 HN
10
mg
QD
F 57 O
*
*
PD
60
(38-82)
Age
(years),
median
(range)
M
65
HN
M
65
HN
63
(42-83)
Age
(years),
median
(range)
D
D
M 74 HN
*
*
Week
36
4
12
20
28
M
65
HN
M
65
HN
D
D
M 74 HN
3
(50)
Female,
n
(%)
*
10
(67)
Female,
n
(%)
Week
Week
36
36
4
12
20
28
4
12
20
28
M 65 HN D
Response
Response
Response
3+3
design
Response
NSCLC
=
non-small
cell
lung
cancer
Response
*
Week
Week
4
12 Assessment
20 Assessment
28 Assessment
36
4
12 36 Assessment
20
28
M 65 HN D
Assessment
SCCHN
=
squamous
cell
carcinoma
of
the
head
and
neck
Response
Response
Response
Response
Response
Response27/67/6
Response
Response
Response
Response
0/100/0
ECOG
Status
0/1/2,
%
• Based on the preclinical data, a Phase 1/1b clinical study examining IPI-549 as Week
ECOG
Status
0/1/2,
%
36 Assessment
4 Enrollment completed
12 Assessment
20
28 Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
TBD
=
to
be
determined
Response
Response
Response
Response
Response
Response
Response
Response
Response
Response
Week
through 40 mg QD.
36 Assessment
4
12Data
20QDAssessment
28 Assessment
monotherapy and in combination with nivolumab was initiated (NCT02637531)
Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
=
once
daily
2 (0-4)
Prior Assessment
Lines of Anticancer Therapy, median (range)
Response
Response
Response
Response
Response
3
(0-10)
Prior
Lines
of
Anticancer
Therapy,
median
(range)
available through
40 mg QD.
Assessment
Assessment
Assessment
Q2W
=
once
every
2
weeks
Assessment
Response
Response
Response
Response Assessment
Response
• Data in this presentation as of 20 March 2017
DLT evaluable patient received ≥ 75% of prescribed cycle 1 combination dosing
DLT evaluable
patient received ≥ 75% of prescribed cycle 1 dosing
Assessment
Assessment
Assessment
Assessment
Assessment
F 83
Clinical Study
Study Endpoints
Safety
• Dose-limiting toxicities (DLT)
• Adverse events (AEs) and safety laboratory values
Efficacy
• ORR, DOR and PFS (per RECIST 1.1 and irRC)
Pharmacokinetics/Pharmacodynamics
• Plasma concentrations of IPI-549
• Phospho-AKT (pAKT) levels in immune cell subsets after ex vivo stimulation of whole
blood (with stimulation factors including, but not limited to, CXCL12 and LPS)
• Biopsied tumor tissue biomarkers (including, but not limited to, phosphatase and tensin
homolog [PTEN], phospho-S6, PI3K-g, and markers of the tumor microenvironment)
DLT Criteria (Monotherapy and Combination)
• ≥ Grade 4 thrombocytopenia
• ≥ Grade 4 neutropenia
(> 7 days or complicated by
infection)
• Any febrile neutropenia
Non-hematologic
• Any ≥ Grade 3 toxicity, except
- Grade 3 fatigue (< 7 days)
- Grade 3 nausea
- Grade 3 emesis
- Grade 3 diarrhea not responding to supportive
treatment within 5 days
DLTs are assessed within the first cycle (28 days)
Key Inclusion/Exclusion Criteria
All Patients
• Histological or cytological evidence of advanced and/or metastatic carcinoma or
melanoma and at least 1 measurable disease lesion (per RECIST 1.1)
• No symptomatic or untreated brain metastases
• No primary CNS malignancy
• No history of interstitial lung disease, radiation pneumonitis requiring steroid
treatment, or any evidence of clinically active interstitial lung disease
Patients with Melanoma, NSCLC or SCCHN
• Failure to respond to standard therapy, or for whom no appropriate therapies
are available
• Most recent treatment prior to study entry included an anti-PD-1 or anti-PD-L1
therapy
• For patients with NSCLC harboring a genetic alteration (including but not
limited to alterations in EGFR, ALK, and ROS) for which there is an approved
therapy specific to that alteration, prior progression or intolerance to that therapy
is required
• Patients with SCCHN: HPV positive or negative SCCHN (oral cavity, pharynx,
hypopharynx, larynx, nasopharyngeal [including undifferentiated nasopharyngeal
carcinoma])
• Patients were extensively pretreated
• 6 patients remained on treatment for at least 24 weeks while 3 patients remained on
treatment longer than 32 weeks
Monotherapy Safety
Combination Therapy Safety
• No DLTs have occurred
Adverse Events in Patients Treated with IPI-549 Monotherapy (N=15)
All AEs Grade 1 or 2, unless otherwise noted
AE Category
n
AE Preferred Term
SAEs related to IPI-549
0
–
AEs leading to dose
reduction or discontinuation
0
–
AEs related to IPI-549
2
headache
1
blepharospasm, diarrhea, dizziness, dysesthesia,
fatigue, rash maculo-papular, nausea,
leukopenia*, AST/ALT elevation*, hypoalbuminemia*,
hyponatremia*, hypercholesterolemia*
Nonlaboratory AEs of
interest (unrelated)
2
diarrhea, pyrexia, nausea
1
rash, vomiting
Laboratory AEs of interest
(unrelated)
2
anemia (Grade 3, n=1)
* Occurring in the same patient
AACR Annual Meeting 2017, Washington, D.C., April 4, 2017
• 4 patients received prior anti-PD1/PDL1 therapy (including 1 patient each with bladder
cancer, germ cell tumor, NSCLC [adenocarcinoma], and head and neck carcinoma)
• Patient with CRC at 20 mg (MSI high) had no prior anti-PD1/PDL1 therapy
1
lymphopenia (Grade 3), ALT/AST elevation, neutropenia
• No DLTs have occured
• No unexpected toxicities have occurred
• No drug-related AEs have led to discontinuation of either treatment
Adverse Events in Patients Treated with IPI-549 in Combination
with Nivolumab (N=6)
Monotherapy
• IPI-549 monotherapy was well tolerated
- No DLTs
- No drug-related SAEs
- No drug-related AEs led to treatment discontinuation or dose reduction
• IPI-549 has favorable pharmacokinetic properties
• IPI-549 achieves near complete and sustained inhibition of PI3K-g at ≥ 20 mg QD
• 6 patients remained on treatment for at least 24 weeks, while 3 patients remained on
treatment longer than 32 weeks
• Evaluation of the optimal dose for monotherapy expansion is ongoing
Combination
• IPI-549 20 mg QD in combination with nivolumab was well tolerated
- No DLTs
- No drug-related SAEs
- No drug-related AEs led to treatment discontinuation
• Preliminary data suggest nivolumab does not affect the pharmacokinetics of IPI-549
• Two combination dose escalation cohorts have been fully enrolled (20 mg and 30 mg QD)
• Evaluation of the optimal dose for combination expansion is ongoing
Pharmacokinetics and Pharmacodynamics of IPI-549
PK Concentration-Time Profiles by Dose - Monotherapy 10-40 mg QD
Cycle 1 Day 1
Cycle 2 Day 1
IPI-549 PK Concentration (ng/mL)
E*
Age Disease
E
Time on Treatment by Patient
Inhibition of PI3k-g Activity as Measured by pAKT (T-308) in Circulating Monocytes
% Change from Baseline, pAKT in Monocyte
PI3K-g, T308)
F 69
F 69
Expansion
Time on Treatment by Patient
PK Concentration-Time Profiles by Dose - IPI-549 20mg QD + Nivolumab 240mg Q2W
All AEs Grade 1 or 2, unless otherwise noted
AE Category
n
AE Preferred Term
SAEs related to either therapy
0
–
AEs leading to dose
reduction or discontinuation
1
rash maculo-papular* (reduction of IPI-549; Grade 3)
AEs related to IPI-549
1
rash maculo-papular* (Grade 3), nausea, anemia,
Nonlaboratory AEs of interest
(unrelated)
2
diarrhea
1
vomiting
Laboratory AEs of interest
(unrelated)
1
anemia
IPI-549 PK Concentration (ng/mL)
Gender Age Disease
Gender Age Disease
Dose Escalation
Age Disease
Ongoing
*
Conclusions
Combination Therapy Dose Escalation
IPI-549 PK Concentration (ng/mL)
• PI3K-g is highly expressed in TAMs and blockade of PI3K-g signaling by IPI-549, a
potent, selective oral PI3K-g inhibitor, results in transcriptional and phenotypic Gender
Gender Age Disease
reprogramming of macrophages1,2
F
Gender
Monotherapy Dose Escalation
% Change from Baseline, pAKT in Monocyte
PI3K-g, T308)
Study Design
IPI-549 Targets PI3K-gamma in Tumor Associated Macrophages (TAMs)
Hematologic
7
South Texas Accelerated Research Therapeutics, San Antonio, Texas, USA; 2MD Anderson Cancer Center, Houston, Texas, USA; 3Massachusetts General Hospital, Boston, Massachusetts, USA; 4Department of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA;
5
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; 6Dana-Farber Cancer Institute, Boston, Massachusetts, USA; 7Memorial Sloan Kettering Cancer Center, New York, New York, USA
Background
•
4
IPI-549 PK Concentration (ng/mL)
1
2
Time (hr)
Time (hr)
• IPI-549 demonstrated linear pharmacokinetics with minimal accumulation over time
• IPI-549 achieves near complete and sustained inhibition of PI3K-g at ≥ 20 mg QD
References
1) Kaneda et al. Nature 2016
2) DeHenau et al. Nature 2016