A Phase 1 Study of MGD007, a Humanized gpA33 x CD3 DART ® Protein, in Combination with MGA012, an anti-PD-1 Antibody, in Patients with Relapsed/Refractory Metastatic Colorectal Cancer Richard Kim 1 , David P. Ryan 2 , Stacy Stein 3 , James M. Cleary 4 , Liqin Liu 5 , Ralph Alderson 5 , Francine Chen 5 , Peter Lung 5 , Allan Reduta 5 , Syd Johnson 5 , Jan Baughman 5 , Ezio Bonvini 5 , Paul A. Moore 5 , Joanna Lohr 5 , Jon Wigginton 5 , Jan Davidson-Moncada 5 , John Powderly 6 1 Moffitt Cancer Center, Tampa, FL; 2 Massachusetts General Hospital, Boston, MA; 3 Yale University, New Haven, CT; 4 Dana Farber Cancer Institute, Boston, MA; 5 MacroGenics, Inc., Rockville, MD United States; 6 Carolina BioOncology Institute, Huntersville, NC Presented at the Society for Immunotherapy of Cancer (SITC) 33rd Annual Meeng, November 7–11, 2018, Washington, DC SITC 2018 Poster P304 http://ir.macrogenics.com/events.cfm NCT03531632 Study Design Dose Escalation Phase: 3 + 3 + 3 Design ■ 3 planned dose levels of MGD007 ■ MGA012 at fixed dose ■ Patients may receive up to 12 cycles in the absence of disease progression, DLT, or other criteria for permanent discontinuation Cohort Expansion Phase: ■ 25 patients treated at MTD/MAD ■ 90% of patients will be MSS and 10% MSI-H ■ Paired tumor biopsies will be mandatory in 15/25 patients if lesions are accessible with acceptable risk MGD007 and MGA012 Leverage Complementary T-cell-Mediated Mechanisms of Action 0 5000 10000 15000 20000 Concentration (μg/mL) Luminecence (RLU) PanT + MGD007 Treg + MGD007 PanT + Control DART Treg + Control DART 10 -2 10 -4 10 -6 10 0 10 2 A. B. D. E. F. G. C. CD8/GB CD4/GB CD8/ Perforin CD4/ Perforin 0 5 10 15 20 25 MFI MFI MFI MGD007 (400 ng/mL) MGD007 (80 ng/mL) MGD007 (16 ng/mL) MGD007 (3.2 ng/mL) 0 2000 4000 6000 8000 10000 Concentration (ng/mL) Luminescence (RLU) CD3 + T cells CD4 + T cells CD8 + T cells 10 -3 10 -2 10 -1 10 0 10 1 10 2 10 3 10 4 MGD007 Can Recruit CD8, CD4 and Supressive T Cells for Redirected T-cell Killing MGA012 (anti-PD-1 mAb) Reverses PD-1/PD-L1 T-cell Signal Inhibition 0 500 1000 1500 2000 μg/mL (LOG) μg/mL (LOG) μg/mL (LOG) MGA012 Reference PD-1 mAb Total PD-L1 binding Background 0 10000 20000 30000 40000 50000 RUL Luminescence MGA012 Reference PD-1 mAb 0 2000 4000 6000 MGA012 Reference PD-1 mAb Total PD-L2 binding Background 0 50000 100000 150000 200000 250000 300000 MGA012 mAb (μg/mL) NFAT Activation (Luminecence) CD3 x TAA + MGA012 CD3 x TAA + Isotype Control no CD3 x TAA 10 -3 10 -2 10 -1 10 0 10 1 10 -2 10 -1 10 0 10 1 10 -3 10 -4 10 -2 10 -1 10 0 10 -3 10 -4 10 -2 10 -1 10 0 (A) MGD007-mediated cytotoxicity against gpA33+ Colo205-luc colorectal cancer cell line in presence of human T cells (CD3, CD8, or CD4 as indicated; E:T = 10:1). (B) Dose-dependent up-regulation of granzyme B (GB) and perforin levels following incubation of MGD007 with Colo205 and purified T cells (E:T = 10:1). (C) Tregs expanded in vitro for 15 days support MGD007 mediate cytotoxicity against gpA33+ Colo205. (D–E) MGA012 blockade of soluble PD-L1 or PD-L2 binding to NSO cells engineered to expressed cell surface PD-1. (F) MGA012 mediated enhancement of TCR activation of Jurkat cells under PD-L1/PD-1 mediated inhibition. (G) MGA012 mediated enhancement of CD3 based bispecific DART ® activation of Jurkat cells under PD-L1.PD-1 mediated inhibition. Anti-PD-1 Enhances MGD007-mediated Antitumor Activity in Preclinical Models A. B. C. D. MGD007 Up Regulates PD-L1 MGD007 Up Regulates PD-1 MGD007/anti-PD-1 Combination Antitumor Activity Anti-PD-1 (MGA012) Enhances MGD007-mediated CTL Activity MFI of PD-1 on CD8 T Cells 0 200 400 600 800 Concentration (ng/mL) MGD007 Control CD3 DART 10 -3 10 -2 10 -1 10 0 10 1 10 3 10 2 10 4 MFI of PD-L1 on CD8 T Cells 0 400 800 1200 MGD007 Control CD3 DART Concentration (ng/mL) 10 -3 10 -2 10 -1 10 0 10 1 10 3 10 2 10 4 0 4000 8000 12000 16000 MFI of PD-L1 on Colo205 MGD007 Control CD3 DART Concentration (ng/mL) 10 -3 10 -2 10 -1 10 0 10 1 10 3 10 2 10 4 0 16 80 400 0 10000 20000 30000 40000 Cell Viability LUM (RLU) +20 (ng/mL) +2 (ng/mL) +0.2 (ng/mL) +0.002 (ng/mL) +0.000 (ng/mL) Anti-PD1 MGD007 (ng/mL) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 1000 2000 0 1000 2000 0 1000 2000 0 1000 2000 0 5 10 15 20 25 Study Day 0 500 1000 1500 MGD007 (0.5 mg/kg) 0 5 10 15 20 25 Study Day 0 500 1000 1500 MGD007 (0.05 mg/kg) 0 5 10 15 20 25 30 Study Day MGD007 (0.05 mg/kg) 0 5 10 15 20 25 30 Study Day MGD007 (0.05 mg/kg) + Anti-PD-1 (5 mg/kg) 0 5 10 15 20 25 30 Study Day Anti-PD-1 (5 mg/kg) 0 5 10 15 20 25 Study Day 0 500 1000 1500 Vehicle 0 5 10 15 20 25 30 Study Day Vehicle Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Cells CD8 T Cells CD8 T Cells Monotherapy Combination Cell surface expression of (A) PD-L1 on Colo205 (top), and CD8 T-cells (lower) and (B) PD-1 on CD8 T-cells in presence of MGD007 (E:T = 5:1; 24 hrs). (C) Redirected T-cell killing of Colo205 by MGA012 enhanced by addition of anti-PD1 mAb in presence of T cells (E:T = 3:1; 48 hrs). (D) MC38/hgpA33 colonic adenocarcinoma tumor growth in hCD3KI-Tg mice administered MGD007 alone (upper panels) or MGD007 ± anti-mouse PD-1 (lower panel). MGD007 dosed every 3–4 days; anti-PD-1 dosed on Days 0, 3 and 6. Key Study Objectives Primary: ■ Characterize safety, tolerability, dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD007 in combination with MGA012 Secondary: ■ Characterize pharmacokinetics, pharmacodynamics, and immunogenicity of combination ■ Investigate preliminary anti-tumor activity of combination using both RECIST and immune-related RECIST – Objective response rate, disease control rate, progression-free survival at 16 weeks Exploratory: ■ Investigate immune-regulatory activity of combination in vivo Background gpA33 is Broadly Expressed in Colorectal Cancer (CRC) Expression Across CRC A. Primary Tumor Adenocarcinoma of Colon Metastatic Colon Tumor to Liver Frozen Tissue Type Cases Evaluated Score gpA33 Positive Rate 1+ 2+ 2–3+ 3+ Primary colon cancer 35 0 0 18 17 35/35 Metastatic colon cancer 17 0 0 3 14 17/17 Primary + metastatic colon cancer 52 0 0 21 31 52/52 Expression on Putative Cancer Stem Cells B. CD133 CD133 Control RECA0201 (KRAS mt) RECA0608 (KRAS mt) RECA0624 (KRAS WT) RECA0825 (KRAS WT) gpA33 mAb (RECA47) (A) Immunohistochemical (IHC) analyses performed across 52 CRC patients with anti-gpA33 mAb revealed 100% positivity at 2–3+ level. (B) FACS analyses of freshly isolated CRC biopsy epithelial cells reveal gpA33 expression across all cells including CD133+ subset (top row); (middle and bottom row): IHC analyses across panel of CRC-derived cancer stem-like cells. MGD007 (gpA33 x CD3) Structural Design CD3 gpA33 DART Molecule gpA33 VH CD3 VL gpA33 VL CD3 VH E coil K coil Fc(knob) Chain 1 Chain 2 Chain 3 Fc(hole) ■ Anti-gpA33: humanized monoclonal antibody (mAb) selected from colon cancer stem-like cell immunization ■ Anti-CD3: humanized XR32 mAb ■ Human Fc: IgG1 with mutations to reduce undesired FcγR binding (ala,ala) and enhance heterodimerization (knob/hole); retains FcRN binding to enhance half-life MGA012: Anti-PD-1 Monoclonal Antibody* ■ Humanized proprietary anti-PD-1 mAb – Hinge stabilized humanized IgG4 – Blocks PD-L1 and PD-L2 ligand binding to PD-1 and mediates enhanced T-cell responses ■ Anti-PD-1 becoming mainstay of cancer immunotherapy ■ Basis for combination immunotherapy Technical Profile MGA012 Results Tissue cross-reactivity No unanticipated findings Toxicology in cynomolgus monkeys: IV at 10, 40 or 150 mg/kg; QW x 4 Well tolerated at all doses No unanticipated findings NOAEL = 150 mg/kg Predicted half-life in humans ~18 days *Also known as INCMGA00012; licensed to Incyte 2017. MGD007 Mediates T-cell Lysis of gpA33+ CRC Accompanied with T-cell Expansion CTL Activity Against gpA33+ B. A. T-cell Expansion C. 10 -3 10 -2 10 -1 10 0 10 1 10 2 10 3 10 4 0 10 20 30 40 Concentration (ng/mL) Cytotoxicity (%) JIMT-1 (gpA33 - ) LS174T (gpA33 + ) 10 0 10 1 10 2 10 3 10 4 FL1-H: CFSE 10 0 10 1 10 2 10 3 10 4 FL1-H: CFSE 0 0 20 40 60 80 100 % of Max 20 40 60 80 100 % of Max 64.1 88.4 Day 3 Day 4 10 -3 10 -2 10 -1 10 0 10 1 10 2 10 3 10 4 0 10000 20000 30000 Concentration (ng/mL) Luminescence (RLU) MGD007 Control DART CTL Activity Against CSC Model of CRC (RECA0201-GF) (A) MGD007-mediated cytotoxicity against gpA33 + LS174T colorectal cancer cell in presence of freshly isolated human PBMC (E:T = 30:1; 24h). (B) MGD007 mediated lysis of gpA33 luciferase-transduced RECA020108-GF colorectal Cancer Stem-Like Cells in presence of freshly isolated human T cells (E:T = 10:1; 48 h). (C) Proliferation of T-cells monitored by CFSE dilution in presence of MGD007 (blue) or control DART (red) incubated with gpA33+ LS174T (E:T = 10:1). MGD007 Mediates Antitumor Activity in a CRC PDX Model gpA33 IHC on CRC PDX (BRAF and PIK3 mutated) ■ Immune deficient mice ■ PDX tumor cells implanted on Day 0 ■ Human PBMC engrafted on Day 6 ■ MGD007 (or vehicle) dosing initiated on Day 19 0 500 1000 1500 2000 2500 3000 0 500 1000 1500 2000 2500 3000 0 500 1000 1500 2000 2500 3000 0 500 1000 1500 2000 2500 3000 Vehicle MGD007 (0.1 mg/kg) MGD007 (0.25 mg/kg) MGD007 (0.5 mg/kg) 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Study Day Study Day Study Day Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) Study Day ©2018 MacroGenics, Inc. All rights reserved. Entry Criteria Key Inclusion Criteria ■ Histologically proven, relapsed/refractory metastatic colorectal cancer ■ Eastern Cooperative Oncology Group performance status 0 or 1 ■ Measurable disease per RECIST 1.1 criteria ■ Participants in the Dose Escalation Phase must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. Participants in the Cohort Expansion Phase will be allowed to participate after 1 prior standard regimen. Those who are inappropriate candidates for or have refused treatment with these regimens are also eligible. No more than 5 prior therapies are permitted ■ Availability of sufficient tumor specimens to enable retrospective determination of gpA33, CD3, PD-1, and PD-L1 expression Key Exclusion Criteria ■ Symptomatic central nervous system (CNS) metastases. No concurrent treatment for the CNS disease; no progression of CNS metastases on MRI or CT for at least 14 days after last day of prior therapy for the CNS metastases; no concurrent leptomeningeal disease or cord compression ■ History of known or suspected autoimmune disease with certain exceptions ■ Major surgery, systemic anti-neoplastic therapy, or investigational therapy within 4 weeks ■ Radiation therapy within 2 weeks ■ Systemic corticosteroids (≥10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days ■ History of Grade 3 or greater drug-related diarrhea/colitis during treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, anti PD-L1, or anti-CTLA-4 antibodies ■ Clinically significant cardiovascular disease; gastrointestinal disorders; pulmonary compromise; viral, bacterial, or systemic fungal infections ■ History of positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome ■ History of hepatitis B or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction The Sponsor thanks the patients and their families for participating in this study.
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A Phase 1 Study of MGD007, a Humanized gpA33 x CD3 DART® Protein, in Combination with MGA012, an anti-PD-1 Antibody,
in Patients with Relapsed/Refractory Metastatic Colorectal Cancer Richard Kim1, David P. Ryan2, Stacy Stein3, James M. Cleary4, Liqin Liu5, Ralph Alderson5, Francine Chen5, Peter Lung5, Allan Reduta5, Syd Johnson5, Jan Baughman5, Ezio Bonvini5, Paul A. Moore5, Joanna Lohr5, Jon Wigginton5, Jan Davidson-Moncada5, John Powderly6
1Moffitt Cancer Center, Tampa, FL; 2Massachusetts General Hospital, Boston, MA; 3Yale University, New Haven, CT; 4Dana Farber Cancer Institute, Boston, MA; 5MacroGenics, Inc., Rockville, MD United States; 6Carolina BioOncology Institute, Huntersville, NC
Presented at the Society for Immunotherapy of Cancer (SITC) 33rd Annual Meeting, November 7–11, 2018, Washington, DC
SITC 2018Poster P304
http://ir.macrogenics.com/events.cfmNCT03531632
Study DesignDose Escalation Phase: 3 + 3 + 3 Design■■ 3 planned dose levels of MGD007■■ MGA012 at fixed dose■■ Patients may receive up to 12 cycles in the absence of disease progression, DLT, or other criteria for permanent discontinuation
Cohort Expansion Phase:■■ 25 patients treated at MTD/MAD■■ 90% of patients will be MSS and 10% MSI-H■■ Paired tumor biopsies will be mandatory in 15/25 patients if lesions are accessible with acceptable risk
MGD007 and MGA012 Leverage Complementary T-cell-Mediated Mechanisms of Action
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) PanT + MGD007Treg + MGD007
PanT + Control DARTTreg + Control DART
10-210-410-6 100 102
A. B. D. E.
F. G.C.
CD8/GB CD4/GB CD8/Perforin
CD4/Perforin
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MGD007 Can Recruit CD8, CD4 andSupressive T Cells for Redirected T-cell Killing
MGA012 (anti-PD-1 mAb) Reverses PD-1/PD-L1 T-cell Signal Inhibition
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no CD3 x TAA
10-3 10-2 10-1 100 101 10-2 10-1 100 101
10-310-4 10-2 10-1 10010-310-4 10-2 10-1 100
(A) MGD007-mediated cytotoxicity against gpA33+ Colo205-luc colorectal cancer cell line in presence of human T cells (CD3, CD8, or CD4 as indicated; E:T = 10:1). (B) Dose-dependent up-regulation of granzyme B (GB) and perforin levels following incubation of MGD007 with Colo205 and purified T cells (E:T = 10:1). (C) Tregs expanded in vitro for 15 days support MGD007 mediate cytotoxicity against gpA33+ Colo205. (D–E) MGA012 blockade of soluble PD-L1 or PD-L2 binding to NSO cells engineered to expressed cell surface PD-1. (F) MGA012 mediated enhancement of TCR activation of Jurkat cells under PD-L1/PD-1 mediated inhibition. (G) MGA012 mediated enhancement of CD3 based bispecific DART® activation of Jurkat cells under PD-L1.PD-1 mediated inhibition.
Anti-PD-1 Enhances MGD007-mediated Antitumor Activity in Preclinical ModelsA. B.
C.
D.MGD007 Up Regulates PD-L1 MGD007 Up Regulates PD-1 MGD007/anti-PD-1 Combination Antitumor Activity
Anti-PD-1 (MGA012) EnhancesMGD007-mediated CTL Activity
MFI
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ells
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MGD007Control CD3 DART
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Concentration (ng/mL)10-3 10-2 10-1 100 101 103102 104
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o205 MGD007
Control CD3 DART
Concentration (ng/mL)10-3 10-2 10-1 100 101 103102 104
0 16 80 4000
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Cell
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M (R
LU)
+20 (ng/mL)+2 (ng/mL)+0.2 (ng/mL)+0.002 (ng/mL)+0.000 (ng/mL)
Anti-PD1
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MGD007(0.05 mg/kg)
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MGD007 (0.05 mg/kg) +Anti-PD-1 (5 mg/kg)
0 5 10 15 20 25 30Study Day
Anti-PD-1(5 mg/kg)
0 5 10 15 20 25Study Day
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m3 )
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m3 )
Tumor Cells CD8 T Cells
CD8 T Cells
Monotherapy
Combination
Cell surface expression of (A) PD-L1 on Colo205 (top), and CD8 T-cells (lower) and (B) PD-1 on CD8 T-cells in presence of MGD007 (E:T = 5:1; 24 hrs). (C) Redirected T-cell killing of Colo205 by MGA012 enhanced by addition of anti-PD1 mAb in presence of T cells (E:T = 3:1; 48 hrs). (D) MC38/hgpA33 colonic adenocarcinoma tumor growth in hCD3KI-Tg mice administered MGD007 alone (upper panels) or MGD007 ± anti-mouse PD-1 (lower panel). MGD007 dosed every 3–4 days; anti-PD-1 dosed on Days 0, 3 and 6.
Key Study ObjectivesPrimary: ■■ Characterize safety, tolerability, dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD007 in combination with MGA012
Secondary: ■■ Characterize pharmacokinetics, pharmacodynamics, and immunogenicity of combination■■ Investigate preliminary anti-tumor activity of combination using both RECIST and immune-related RECIST
– Objective response rate, disease control rate, progression-free survival at 16 weeks
Exploratory: ■■ Investigate immune-regulatory activity of combination in vivo
Background
gpA33 is Broadly Expressed in Colorectal Cancer (CRC)Expression Across CRCA.
Primary TumorAdenocarcinoma of Colon
Metastatic ColonTumor to Liver
Frozen Tissue Type Cases Evaluated
Score gpA33Positive
Rate1+ 2+ 2–3+ 3+Primary colon cancer 35 0 0 18 17 35/35Metastatic colon cancer 17 0 0 3 14 17/17Primary + metastatic colon cancer 52 0 0 21 31 52/52
Expression on PutativeCancer Stem Cells
B.
CD13
3
CD13
3
Control
RECA0201(KRAS mt)
RECA0608(KRAS mt)
RECA0624(KRAS WT)
RECA0825(KRAS WT)
gpA33 mAb(RECA47)
(A) Immunohistochemical (IHC) analyses performed across 52 CRC patients with anti-gpA33 mAb revealed 100% positivity at 2–3+ level. (B) FACS analyses of freshly isolated CRC biopsy epithelial cells reveal gpA33 expression across all cells including CD133+ subset (top row); (middle and bottom row): IHC analyses across panel of CRC-derived cancer stem-like cells.
MGD007 (gpA33 x CD3) Structural DesignCD3
gpA33
DART Molecule
gpA33 VHCD3 VL
gpA33 VL CD3 VH E coil
K coil
Fc(knob)Chain 1
Chain 2
Chain 3 Fc(hole)
■■ Anti-gpA33: humanized monoclonal antibody (mAb) selected from colon cancer stem-like cell immunization■■ Anti-CD3: humanized XR32 mAb ■■ Human Fc: IgG1 with mutations to reduce undesired FcγR binding (ala,ala) and enhance heterodimerization (knob/hole); retains FcRN binding to enhance half-life
MGA012: Anti-PD-1 Monoclonal Antibody* ■■ Humanized proprietary anti-PD-1 mAb
– Hinge stabilized humanized IgG4 – Blocks PD-L1 and PD-L2 ligand binding to PD-1 and mediates enhanced T-cell responses
■■ Anti-PD-1 becoming mainstay of cancer immunotherapy■■ Basis for combination immunotherapy
Technical ProfileMGA012 Results
Tissue cross-reactivity No unanticipated findings
Toxicology in cynomolgus monkeys: IV at 10, 40 or 150 mg/kg; QW x 4
Well tolerated at all doses No unanticipated findings
NOAEL = 150 mg/kg
Predicted half-life in humans ~18 days *Also known as INCMGA00012; licensed to Incyte 2017.
MGD007 Mediates T-cell Lysis of gpA33+ CRC Accompanied with T-cell Expansion
CTL ActivityAgainst gpA33+
B.A. T-cell ExpansionC.
10-3 10-2 10-1 100 101 102 103 104
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JIMT-1 (gpA33-)LS174T (gpA33+)
100 101 102 103 104FL1-H: CFSE
100 101 102 103 104FL1-H: CFSE
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88.4
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ines
cenc
e (R
LU)
MGD007 Control DART
CTL Activity AgainstCSC Model of CRC (RECA0201-GF)
(A) MGD007-mediated cytotoxicity against gpA33+ LS174T colorectal cancer cell in presence of freshly isolated human PBMC (E:T = 30:1; 24h). (B) MGD007 mediated lysis of gpA33 luciferase-transduced RECA020108-GF colorectal Cancer Stem-Like Cells in presence of freshly isolated human T cells (E:T = 10:1; 48 h). (C) Proliferation of T-cells monitored by CFSE dilution in presence of MGD007 (blue) or control DART (red) incubated with gpA33+ LS174T (E:T = 10:1).
MGD007 Mediates Antitumor Activity in a CRC PDX ModelgpA33 IHC on CRC PDX
(BRAF and PIK3 mutated)
■■ Immune deficient mice■■ PDX tumor cells implanted on Day 0■■ Human PBMC engrafted on Day 6■■ MGD007 (or vehicle) dosing initiated on Day 19
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0 5 10 15 20 25 30 35 40 45
0 5 10 15 20 25 30 35 40 45
0 5 10 15 20 25 30 35 40 45Study Day Study Day
Study Day
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©2018 MacroGenics, Inc. All rights reserved.
Entry CriteriaKey Inclusion Criteria■■ Histologically proven, relapsed/refractory metastatic colorectal cancer■■ Eastern Cooperative Oncology Group performance status 0 or 1■■ Measurable disease per RECIST 1.1 criteria■■ Participants in the Dose Escalation Phase must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. Participants in the Cohort Expansion Phase will be allowed to participate after 1 prior standard regimen. Those who are inappropriate candidates for or have refused treatment with these regimens are also eligible. No more than 5 prior therapies are permitted■■ Availability of sufficient tumor specimens to enable retrospective determination of gpA33, CD3, PD-1, and PD-L1 expression
Key Exclusion Criteria■■ Symptomatic central nervous system (CNS) metastases. No concurrent treatment for the CNS disease; no progression of CNS metastases on MRI or CT for at least 14 days after last day of prior therapy for the CNS metastases; no concurrent leptomeningeal disease or cord compression
■■ History of known or suspected autoimmune disease with certain exceptions■■ Major surgery, systemic anti-neoplastic therapy, or investigational therapy within 4 weeks■■ Radiation therapy within 2 weeks■■ Systemic corticosteroids (≥10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days■■ History of Grade 3 or greater drug-related diarrhea/colitis during treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, anti PD-L1, or anti-CTLA-4 antibodies■■ Clinically significant cardiovascular disease; gastrointestinal disorders; pulmonary compromise; viral, bacterial, or systemic fungal infections■■ History of positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome■■ History of hepatitis B or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction
The Sponsor thanks the patients and their families for participating in this study.
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