Phase I Evaluation of an Agonist Anti-CD27 Human Antibody … · 2017-02-22 · 0.1 mg/kg 0.3 mg/kg...
1
0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg Phase I Evaluation of an Agonist Anti-CD27 Human Antibody (Varlilumab [CDX-1127]) in Patients with Advanced Hematologic Malignancies Stephen M. Ansell 1 , Donald W. Northfelt 2 , Ian Flinn 3 , Howard A. Burris 3 , Shira N. Dinner 4 , Victor M. Villalobos 5 , Branimir I. Sikic 5 , Matthew H. Taylor 6 , Lana Pilja 7 , Thomas R. Hawthorne 7 , Michael J. Yellin 7 , Tibor Keler 7 , Thomas A. Davis 7 1. Mayo Clinic, Rochester, MN; 2. Mayo Clinic, Scottsdale, AZ; 3. Sarah Cannon Research Institute, Nashville, TN; 4. Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 5. Stanford Cancer Institute, Stanford, CA; 6. Oregon Health & Science University, Portland, OR; 7. Celldex Therapeutics, Inc., Hampton, NJ 0.10 1.00 10.00 100.00 1000.00 1 8 15 22 29 36 43 50 57 64 71 78 85 Varlilumab (μg/mL) 10 mg/kg 3 mg/kg 1 mg/kg 0.3 mg/kg 0.1 mg/kg Dosing and Toxicity ● No dose-limiting toxicity (DLT) or identification of a Maximum Tolerated Dose (MTD) ● Infrequent treatment-related AEs; nearly all mild to moderate in severity ‒ One patient discontinued treatment due to grade 1 vision changes ● No indication of immune-mediated adverse events (colitis, endocrinopathies, etc.) typically associated with check-point blockade Treatment-Related Adverse Events Conclusions: ● Varlilumab has minimal toxicity in patients with B cell lymphoma, even in the elderly ● PK profile is dose proportional, consistent with human antibodies and similar in patients with solid tumors and hematologic malignancies ‒ Dose accumulation is observed during multi-dose phase ‒ Good drug exposure even at lower dose levels ‒ Clearance is seen at low doses given less frequently than weekly ● No anti-varlilumab antibody responses detected ● No significant depletion in absolute lymphocyte counts, T cells or B cells ● Evidence of increased immunologic activity, consistent with expected mechanism of action: ‒ Increased soluble CD27 ‒ Reduction of circulating Tregs ‒ Induction of pro-inflammatory cytokines ● Anti-lymphoma activity is supported by a Complete Response seen in a patient with heavily pretreated Hodgkin Disease Future Directions ● The combined safety and activity data from the hematologic and solid tumor arms of this phase 1 study strongly support the further development of varlilumab, particularly in combination therapy. ● Optimal dosing regimen to be defined ‒ Preliminary data suggest low dose, intermittent activation may be preferable ‒ Future studies to explore continuous receptor saturation vs. ‘on-off’ signaling ● Next steps: ‒ Await data in T-cell lymphomas ‒ Analyze biologic characteristics of Hodgkin patients to explore potential for biomarkers of sensitivity to varlilumab and optimal dosing ‒ Plan combination development (phase 1/2 studies) with rituximab, pomalidomide and ibrutinib Clinical Activity ● Dose-escalation is complete with 24 patients enrolled. ‒ 2 patients (10 mg/kg) continue on treatment with first response assessment pending ● One patient has experienced a Complete Response (ongoing at 12.9 months; see adjacent panel) ● Three patients have had Stable Disease (durations of 4.5, 5.6 and 14 months). ‒ 67 year old male with Stage III non-Hodgkin lymphoma who received varlilumab (0.3 mg/kg) experienced 36% shrinkage of measurable disease, including complete disappearance of disease in inguinal and iliac regions • PFS of 5.6 months • Nine prior courses of therapy including combination chemotherapy, rituximab, ibritumomab tiuxetan and traditional radiation therapy ‒ 52 year old male with Stage IV follicular lymphoma had a PFS of 14 months while receiving varlilumab (0.3 mg/kg for single dose, then 0.1 mg/kg for 5 treatment cycles) ‒ 58 year old male with Stage IV follicular lymphoma had a PFS of 4.5 months while receiving varlilumab (0.1 mg/kg) • Six prior courses of therapy including combination chemotherapy, rituximab, ibritumomab tiuxetan, and experimental therapy. ● 28 year old female with Stage IV Hodgkin lymphoma with para-aortic involvement ‒ Inadequate response to induction, and progression through or shortly thereafter four subsequent salvage attempts ‒ Most recently, had progressed 4 months after multiple sequential myeloablative chemotherapy with hematopoietic stem cell rescue followed by brentuximab vedotin consolidation ● Complete Response (CR) after three cycles of varlilumab (0.3 mg/kg) ‒ Area of measurable lesions first increased by 9%, then regressed to achievement of CR. ‒ B symptoms (drenching sweats, pruritus and weight loss) completely resolved ‒ Remains in remission at 12.9+ months ● Reed-Sternberg cells lacked detectable CD27 expression ● CD27 expressing lymphocytes present in inflammatory infiltrate ‒ CD27+ T cell infiltrates more pronounced relative to 2 other Hodgkin patients Six additional Hodgkin patients treated: • One (10 mg/kg) has not yet been seen for the first tumor response assessment • One (10 mg/kg) discontinued study due to treatment-related vision changes prior to first response assessment • Three (0.1, 0.3 and 10 mg/kg) had progression of disease by the first response assessment • One (10 mg/kg) died due to disease progression prior to first response assessment Stage IV Hodgkin Lymphoma Patient with Complete Response CD27 Expression in Tumor Biopsies Varlilumab Pharmacokinetics Pharmacokinetics similar for patients with solid tumors and hematologic malignancies. For all pooled patients: • T 1/2 ranged from 6 days at 1.0 mg/kg to 10.6 days at 10 mg/kg in day 1 dosing • Vd range 21-51 mL/kg (1680-4080 mL) serum volume of 3000 mL • Exposure was linear across dose groups from 0.3-10 mg/kg Varlilumab Study Day Immunogenicity • No anti-varlilumab antibody responses detected in patients with hematologic malignancies Limit of quantification (LOQ)* * LOQ (0.188 μg/mL) is displayed for time points where the calculated mean is ≤ LOQ. Varlilumab Serum Levels After a Single Dose and through 1 Cycle of Dosing (All Patients with Hematologic Malignancies) Varlilumab (CDX-1127): A Fully Human Monoclonal Antibody to CD27 ● CD27 is a potent co-stimulatory molecule that drives T cell activation and survival through interaction with CD70. ● Varlilumab is an agonist anti-CD27 IgG1 mAb that induces activation and proliferation of human T cells when combined with T-cell receptor stimulation. ‒ Varlilumab has been shown effective in syngeneic murine tumor models alone, and in combination with chemotherapy or check-point inhibitors. ● CD27 can be expressed at high levels on lymphoma and leukemia cells, presenting a target for direct anti-tumor effects. ‒ Varlilumab has potent anti-tumor effects in xenograft models of human lymphoma cell lines and promotes antibody-dependent cell-mediated cytotoxicity. Phase 1 Clinical Study Design ● Two study arms: Hematologic Malignancies and Solid Tumors (Abstract #3027/Poster Board: #19) ● Hematologic malignancy patient eligibility: ‒ Histologic diagnosis of a B cell hematologic malignancy that may express CD27 ‒ Progressive disease subsequent to previous therapies; no remaining approved therapy options ‒ Washout from prior therapies including: • ≥4 weeks for chemotherapy (or 5 half-lives, if longer), monoclonal based therapies and systemic radiation • ≥2 weeks for all other immunotherapy ● Standard 3+3 dose-escalation (0.1, 0.3, 1, 3 or 10 mg/kg) ‒ Weekly dosing to establish safety with maximum exposure ● Potential for subsequent malignancy-specific expansion cohorts to further characterize activity of varlilumab ● Study recently amended to include evaluation of T-cell malignancies Treatment Schema: Dose-Escalation Phase 28‐day observation Single‐Dose Multi‐Dose Retreatment § * * Day: 29 36 43 50 8‐week rest 4‐week rest 85 1 Varlilumab: 90-minute IV infusion * Diagnostic Imaging/Staging performed every 85 days Up to 4 retreatment cycles (5 cycles total) permitted for patients with Stable Disease § Patient Characteristics/Disease History Dose-Escalation (n=24) Age, years [median (range)] ≥ 65 [n(%)] 61 8 (23-92) (33%) Male [n(%)] 16 (67%) ECOG Performance Status [n (%)] 0 1 8 16 (33%) (67%) Tumor Types [n (%)] Diffuse large B-cell (DLBCL) Follicular Hodgkin Non-Hodgkin B-cell, NOS 10 5 7 2 (42%) (21%) (29%) (8%) Stage at Study Entry [n (%)] II III IV 1 5 18 (4%) (21%) (75%) Duration of Disease, years [median (range)] 4.7 (0.7-26.9) Lines of treatment [median (range)] Anticancer therapy Cytotoxic chemotherapy 5.0 3.0 (1-12) (1-9) Prior treatments received [n (%)] Radiation Autologous Transplant 14 11 (58%) (46%) CD27 expression in tumor cells (IHC) [n (%)] Follicular (n=2) Hodgkin (n=3) DLBCL (n=4) 2 0 0 (100%) (0%) (0%) ● In hematologic malignancies, varlilumab may induce anti- tumor activity by both immune activation and direct effector function: • sCD27 was measured with an ELISA using antibodies that bind to CD27 at non- competing sites with varlilumab. • Increases in sCD27 are dose dependent and increase with time. • Nonclinical models indicate that the increase in sCD27 is largely mediated through stabilization of sCD27 by complexing with the antibody. The anti-VEGF antibody (bevacizumab) similarly stabilizes serum VEGF levels (ref. 1,2). • Increased sCD27 is consistent with an inflammatory effect and has been recently associated with improved response to immunotherapy (ref. 3). Varlilumab Increases the Serum Level of Soluble CD27 0 200 400 600 800 1000 1200 1400 0.1mg/kg 0.3mg/kg 1.0mg/kg 3.0mg/kg 10.0mg/kg Serum level of sCD27, pg/ml 1 6hr 2 8 29 85 Varlilumab Study Day References: 1. Gordon, et al. J Clin Oncol. 2001; 19:843-50. 2. Yang, et al. N Engl J Med. 2003; 349:427-34. 3. Huang, et al. J Immunol 2013 Jun 15;190(12):6250-8. Varlilumab Does Not Significantly Deplete Lymphocyte, B or T Cell Count 0.0 0.5 1.0 1.5 2.0 2.5 1 8 15 22 29 36 43 50 57 64 71 78 85 Mean values shown for all patients across all dose levels Lymphocye count (10^9/L) 0 10 20 30 40 50 1 8 15 22 29 36 43 50 57 64 71 78 85 CD4+ Cells CD8+ cells % of Lymphoctes • Absolute lymphocyte counts are not markedly changed. • Flow cytometry showed similar levels of CD4+ and CD8+ T cells throughout treatment. Varlilumab Study Day Varlilumab Study Day Effect on T Regulatory Cells • Significant reduction in T regulatory cells observed in 50% of varlilumab-treated patients analyzed to date Flow cytometry analysis of regulatory T cells defined as CD4+FoxP3+ cells. Calculated as % of total lymphocytes. Varlilumab Induces Pro-inflammatory Cytokine Secretion • Early induction of MIP-1β and MCP-1 (at 2 hours post dose) and later induction of IL-12 and MIG ‒ Other cytokines with significant early induction include IL-6, IL-8 and MIP-1α (not shown) • No increase in IP-10 noted (increased IP-10 was observed in dose-escalation in patients with solid tumors) 0 100 200 300 Serum MIP-1β (pg/mL) p<0.0001 0 500 1000 1500 Serum MCP-1 (pg/mL) p=0.0003 0 200 400 600 800 Serum IL-12 (pg/mL) p=0.044 0 500 1000 1500 Serum MIG (pg/mL) p=0.040 2hr 1 2 8 50 85 29 57 Varlilumab Study Day Mean values shown for all patients across all dose levels Cytokines measured by Luminex 2hr 1 2 8 50 85 29 57 Varlilumab Study Day 2hr 1 2 8 50 85 29 57 Varlilumab Study Day 2hr 1 2 8 50 85 29 57 Varlilumab Study Day Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster. % Treg Varlilumab 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 1 8 29 51 Study Day CTCAE Grade 1 CTCAE Grade 2 All Grades Any Treatment-Related Event 7 (29) 6 (25) 13 (54) Fatigue 3 (13) 3 (13) 6 (25) Decreased appetite 4 (17) 4 (17) Anemia 2 (8) 1 (4) 3 (13) Nausea 3 (13) 3 (13) Diarrhea 2 (8) 2 (8) Vomiting 2 (8) 2 (8) ALT increased 1 (4) 1 (4) 2 (8) AST increased 1 (4) 1 (4) 2 (8) Headache 1 (4) 1 (4) 2 (8) Blood alkaline phosphatase increased 1 (4) 1 (4) Neutropenia 1 (4) 1 (4) Hypotension 1 (4) 1 (4) Table does not include grade 1 adverse events that occurred in one patient. Patients with multiple occurrences of an event are counted only once at the greatest severity experienced. No grade 3, 4 or 5 treatment-related adverse events have been reported.
Transcript of Phase I Evaluation of an Agonist Anti-CD27 Human Antibody … · 2017-02-22 · 0.1 mg/kg 0.3 mg/kg...
0.1 mg/kg0.3 mg/kg1 mg/kg3 mg/kg10 mg/kg
Phase I Evaluation of an Agonist Anti-CD27 Human Antibody (Varlilumab [CDX-1127]) in Patients with Advanced Hematologic Malignancies
Stephen M. Ansell1, Donald W. Northfelt2, Ian Flinn3, Howard A. Burris3, Shira N. Dinner4, Victor M. Villalobos5, Branimir I. Sikic5, Matthew H. Taylor6, Lana Pilja7, Thomas R. Hawthorne7, Michael J. Yellin7, Tibor Keler7, Thomas A. Davis7
1. Mayo Clinic, Rochester, MN; 2. Mayo Clinic, Scottsdale, AZ; 3. Sarah Cannon Research Institute, Nashville, TN; 4. Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 5. Stanford Cancer Institute, Stanford, CA; 6. Oregon Health & Science University, Portland, OR; 7. Celldex Therapeutics, Inc., Hampton, NJ
0.10
1.00
10.00
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1000.00
1 8 15 22 29 36 43 50 57 64 71 78 85
Varli
lum
ab(µ
g/m
L)
10 mg/kg3 mg/kg1 mg/kg0.3 mg/kg0.1 mg/kg
Dosing and Toxicity● No dose-limiting toxicity (DLT) or identification of a Maximum Tolerated Dose (MTD) ● Infrequent treatment-related AEs; nearly all mild to moderate in severity
‒ One patient discontinued treatment due to grade 1 vision changes● No indication of immune-mediated adverse events (colitis, endocrinopathies, etc.)
typically associated with check-point blockade
Treatment-Related Adverse Events
Conclusions:● Varlilumab has minimal toxicity in patients with B
cell lymphoma, even in the elderly● PK profile is dose proportional, consistent with
human antibodies and similar in patients with solid tumors and hematologic malignancies‒ Dose accumulation is observed during multi-dose
phase‒ Good drug exposure even at lower dose levels‒ Clearance is seen at low doses given less
frequently than weekly● No anti-varlilumab antibody responses detected● No significant depletion in absolute lymphocyte
counts, T cells or B cells● Evidence of increased immunologic activity,
consistent with expected mechanism of action:‒ Increased soluble CD27‒ Reduction of circulating Tregs‒ Induction of pro-inflammatory cytokines
● Anti-lymphoma activity is supported by a Complete Response seen in a patient with heavily pretreated Hodgkin Disease
Future Directions● The combined safety and activity data from the
hematologic and solid tumor arms of this phase 1 study strongly support the further development of varlilumab, particularly in combination therapy.
● Optimal dosing regimen to be defined‒ Preliminary data suggest low dose, intermittent
activation may be preferable ‒ Future studies to explore continuous receptor
saturation vs. ‘on-off’ signaling● Next steps: ‒ Await data in T-cell lymphomas‒ Analyze biologic characteristics of Hodgkin
patients to explore potential for biomarkers of sensitivity to varlilumab and optimal dosing
‒ Plan combination development (phase 1/2 studies) with rituximab, pomalidomide and ibrutinib
Clinical Activity● Dose-escalation is complete with 24 patients enrolled.‒ 2 patients (10 mg/kg) continue on treatment with
first response assessment pending● One patient has experienced a Complete Response
(ongoing at 12.9 months; see adjacent panel) ● Three patients have had Stable Disease (durations of
4.5, 5.6 and 14 months).‒ 67 year old male with Stage III non-Hodgkin
lymphoma who received varlilumab (0.3 mg/kg) experienced 36% shrinkage of measurable disease, including complete disappearance of disease in inguinal and iliac regions • PFS of 5.6 months• Nine prior courses of therapy including
combination chemotherapy, rituximab, ibritumomab tiuxetan and traditional radiation therapy
‒ 52 year old male with Stage IV follicular lymphoma had a PFS of 14 months while receiving varlilumab (0.3 mg/kg for single dose, then 0.1 mg/kg for 5 treatment cycles)
‒ 58 year old male with Stage IV follicular lymphoma had a PFS of 4.5 months while receiving varlilumab (0.1 mg/kg)• Six prior courses of therapy including
combination chemotherapy, rituximab, ibritumomab tiuxetan, and experimental therapy.
● 28 year old female with Stage IV Hodgkin lymphoma with para-aortic involvement‒ Inadequate response to induction, and
progression through or shortly thereafter four subsequent salvage attempts
‒ Most recently, had progressed 4 months after multiple sequential myeloablativechemotherapy with hematopoietic stem cell rescue followed by brentuximab vedotinconsolidation
● Complete Response (CR) after three cycles of varlilumab (0.3 mg/kg)‒ Area of measurable lesions first increased
by 9%, then regressed to achievement of CR.
‒ B symptoms (drenching sweats, pruritus and weight loss) completely resolved
‒ Remains in remission at 12.9+ months ● Reed-Sternberg cells lacked detectable CD27
expression● CD27 expressing lymphocytes present in
inflammatory infiltrate ‒ CD27+ T cell infiltrates more pronounced
relative to 2 other Hodgkin patients
Six additional Hodgkin patients treated: • One (10 mg/kg) has not yet been seen for the first tumor response assessment• One (10 mg/kg) discontinued study due to treatment-related vision changes prior to first response assessment• Three (0.1, 0.3 and 10 mg/kg) had progression of disease by the first response assessment• One (10 mg/kg) died due to disease progression prior to first response assessment
Stage IV Hodgkin Lymphoma Patient with Complete Response
CD27 Expression in Tumor Biopsies
Varlilumab Pharmacokinetics
Pharmacokinetics similar for patients with solid tumors and hematologic malignancies. For all pooled patients: • T1/2 ranged from 6 days at 1.0 mg/kg to 10.6 days at 10 mg/kg in day 1 dosing• Vd range 21-51 mL/kg (1680-4080 mL) serum volume of 3000 mL• Exposure was linear across dose groups from 0.3-10 mg/kg
VarlilumabStudy Day
Immunogenicity• No anti-varlilumab antibody responses detected in patients with hematologic malignancies
Limit of quantification (LOQ)*
* LOQ (0.188 µg/mL) is displayed for time points where the calculated mean is ≤ LOQ.
Varlilumab Serum Levels After a Single Dose and through 1 Cycle of Dosing (All Patients with Hematologic Malignancies)
Varlilumab (CDX-1127): A Fully Human Monoclonal Antibody to CD27● CD27 is a potent co-stimulatory molecule that drives T cell activation and survival
through interaction with CD70.● Varlilumab is an agonist anti-CD27 IgG1 mAb that induces activation and
proliferation of human T cells when combined with T-cell receptor stimulation. ‒ Varlilumab has been shown effective in syngeneic murine tumor models alone,
and in combination with chemotherapy or check-point inhibitors.● CD27 can be expressed at high levels on lymphoma and leukemia cells, presenting
a target for direct anti-tumor effects.‒ Varlilumab has potent anti-tumor effects in xenograft models of human lymphoma
cell lines and promotes antibody-dependent cell-mediated cytotoxicity.
Phase 1 Clinical Study Design● Two study arms: Hematologic Malignancies and Solid Tumors
(Abstract #3027/Poster Board: #19) ● Hematologic malignancy patient eligibility: ‒ Histologic diagnosis of a B cell hematologic malignancy that may express CD27‒ Progressive disease subsequent to previous therapies; no remaining approved
therapy options‒ Washout from prior therapies including:
• ≥4 weeks for chemotherapy (or 5 half-lives, if longer), monoclonal based therapies and systemic radiation
• ≥2 weeks for all other immunotherapy● Standard 3+3 dose-escalation (0.1, 0.3, 1, 3 or 10 mg/kg) ‒ Weekly dosing to establish safety with maximum exposure
● Potential for subsequent malignancy-specific expansion cohorts to further characterize activity of varlilumab
● Study recently amended to include evaluation of T-cell malignancies
Treatment Schema: Dose-Escalation Phase
28‐day observation
Single‐Dose Multi‐Dose Retreatment §
* *Day: 29 36 43 50
8‐week rest
4‐week rest
851
Varlilumab: 90-minute IV infusion
* Diagnostic Imaging/Staging performed every 85 daysUp to 4 retreatment cycles (5 cycles total) permitted for patients with Stable Disease§
Patient Characteristics/Disease HistoryDose-Escalation (n=24)
Age, years [median (range)]≥ 65 [n(%)]
618
(23-92)(33%)
Male [n(%)] 16 (67%)ECOG Performance
Status [n (%)]01
816
(33%)(67%)
Tumor Types [n (%)]
Diffuse large B-cell (DLBCL)FollicularHodgkinNon-Hodgkin B-cell, NOS
10572
(42%)(21%)(29%)(8%)
Stage at Study Entry [n (%)]
IIIIIIV
15
18
(4%)(21%)(75%)
Duration of Disease, years [median (range)] 4.7 (0.7-26.9)Lines of treatment
[median (range)]Anticancer therapy Cytotoxic chemotherapy
5.03.0
(1-12)(1-9)
Prior treatments received [n (%)]
Radiation Autologous Transplant
1411
(58%)(46%)
CD27 expression in tumor cells (IHC) [n (%)]
Follicular (n=2)Hodgkin (n=3)DLBCL (n=4)
200
(100%)(0%)(0%)
● In hematologic malignancies, varlilumab may induce anti-tumor activity by both immune activation and direct effector function:
• sCD27 was measured with an ELISA using antibodies that bind to CD27 at non-competing sites with varlilumab.
• Increases in sCD27 are dose dependent and increase with time.
• Nonclinical models indicate that the increase in sCD27 is largely mediated through stabilization of sCD27 by complexing with the antibody. The anti-VEGF antibody (bevacizumab) similarly stabilizes serum VEGF levels (ref. 1,2).
• Increased sCD27 is consistent with an inflammatory effect and has been recently associated with improved response to immunotherapy (ref. 3).
Varlilumab Increases the Serum Level of Soluble CD27
0
200
400
600
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1000
1200
14000.1mg/kg0.3mg/kg1.0mg/kg3.0mg/kg10.0mg/kg
Seru
m le
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f sC
D27
, pg/
ml
1
6hr 2 8 29 85
Varlilumab Study Day
References: 1. Gordon, et al. J Clin Oncol. 2001; 19:843-50.2. Yang, et al. N Engl J Med. 2003; 349:427-34.3. Huang, et al. J Immunol 2013 Jun 15;190(12):6250-8.
Varlilumab Does Not Significantly Deplete Lymphocyte, B or T Cell Count
0.0
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Mean values shown for all patients across all dose levels
Lym
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10^9
/L)
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1 8 15 22 29 36 43 50 57 64 71 78 85
CD4+ CellsCD8+ cells%
of L
ymph
octe
s
• Absolute lymphocyte counts are not markedly changed.• Flow cytometry showed similar levels of CD4+ and CD8+ T cells throughout treatment.
Varlilumab Study Day Varlilumab Study Day
Effect on T Regulatory Cells
• Significant reduction in T regulatory cells observed in 50% of varlilumab-treated patients analyzed to date
Flow cytometry analysis of regulatory T cells defined as CD4+FoxP3+ cells. Calculated as % of total lymphocytes.
Varlilumab Induces Pro-inflammatory Cytokine Secretion
• Early induction of MIP-1β and MCP-1 (at 2 hours post dose) and later induction of IL-12 and MIG‒ Other cytokines with significant early induction include IL-6, IL-8 and MIP-1α (not
shown)• No increase in IP-10 noted (increased IP-10 was observed in dose-escalation in patients
with solid tumors)
0
100
200
300
Seru
m M
IP-1β
(pg/
mL) p<0.0001
0
500
1000
1500
Seru
m M
CP-
1 (p
g/m
L) p=0.0003
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800
Seru
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-12
(pg/
mL) p=0.044
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1500
Seru
m M
IG (p
g/m
L)
p=0.040
2hr1 2 8 50 8529 57
VarlilumabStudy Day
Mean values shown for all patients across all dose levelsCytokines measured by Luminex
2hr1 2 8 50 8529 57
VarlilumabStudy Day
2hr1 2 8 50 8529 57
VarlilumabStudy Day
2hr1 2 8 50 8529 57
VarlilumabStudy Day
Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster.
% T
reg
Varlilumab
0.0
0.5
1.0
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2.0
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3.0
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1 8 29 51
Study Day
CTCAE Grade 1
CTCAE Grade 2
All Grades
Any Treatment-Related Event 7 (29) 6 (25) 13 (54)Fatigue 3 (13) 3 (13) 6 (25)Decreased appetite 4 (17) 4 (17)Anemia 2 (8) 1 (4) 3 (13)Nausea 3 (13) 3 (13)Diarrhea 2 (8) 2 (8)Vomiting 2 (8) 2 (8)ALT increased 1 (4) 1 (4) 2 (8)AST increased 1 (4) 1 (4) 2 (8)Headache 1 (4) 1 (4) 2 (8)Blood alkaline phosphatase increased 1 (4) 1 (4)Neutropenia 1 (4) 1 (4)Hypotension 1 (4) 1 (4)Table does not include grade 1 adverse events that occurred in one patient. Patients with multiple occurrences of an event are counted only once at the greatest severity experienced. No grade 3, 4 or 5 treatment-related adverse events have been reported.
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