Jun 5, 2018 - Monoclonal antibodies targeting the PD-pathway and other immune- checkpoint inhibitors have shown anticanc
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Preliminary Results of the First-in-Human, Dose-Finding PROCLAIM-CX-072 Trial of the PD-L1 Probody Therapeutic CX-072 as Monotherapy in Patients With Advanced Solid Tumors Karen A. Autio, Hendrik-Tobias Arkenau, Bert O’Neil, Johanna C. Bendell, Anthony El-Khoueiry, James Strauss, Amy Weise, Nataliya Uboha, Naiyer A. Rizvi, Beiyao Zheng, Luc Desnoyers, Mark Stroh, Lori Carman, Rachel Humphrey, Matthias Will, Valentina Boni, Alexander I. Spira, Aung Naing 1
10
10
10
10
10
10
11
Anticancer antibody
Linker
Proteases
12
13
A450
1.5 1.0 0.5 0.0 10–4
10–2
100
102
Antibody or Probody Therapeutic, nM CX-072
CX-072 + MMP14
CX-072 + uPA
Parental antibody
ELISA, enzyme-linked immunosorbent assay; MMP14, matrix metalloproteinase 14; PD-L1, programmed cell death ligand 1; uPA, urokinase-type plasminogen activator. CX-072 (blue) shows reduced binding to recombinant PD-L1 by ELISA, whereas proteolytic activation of CX-072 with uPA or MMP-14 (red, green) restores binding to levels comparable to that of the parental antibody (purple).
M ETHODS phase 1/2a study of CX-072 designed to evaluate the safety and to determine the MTD and/or maximum achieved dose of CX-072 as monotherapy (Part A, dose escalation) • Patients are ≥18 years of age with Eastern Cooperative Oncology Group performance status 0-1 • To be included in Part A, patients (n ≤ 33) are required ── To have any metastatic or advanced unresectable solid tumor or lymphoma (measurable or nonmeasurable disease) ── To be naive to immunotherapy, including to PD-1/PD-L1 and CTLA-4 inhibitor therapy, and to have a tumor type not approved for immune checkpoint inhibitors • CX-072 monotherapy (0.03, 0.1, 0.3, 1, 3, 10, 30 mg/kg) is administered intravenously every 14 days without any premedication
Assessments by RECIST v1.1
• Imaging for tumor response assessment is performed every 8 weeks
for the first 12 months, then every 12 weeks thereafter • After the last dose of study medication, patients will be evaluated every 3 months for disease progression and overall survival until study withdrawal or death • Archival tissue or fresh biopsy samples are provided at baseline. Ontreatment biopsy is optional • Data snapshot for this analysis was taken on April 20, 2018
30 mg/kg
20 mg/kg
LOQ, limit of quantitation. a Gray dashed line represents LOQ for CX-072 assay, and data below the LOQ are assigned a value of LOQ/2. b Cohort A, cycle 1, dose 1. Figure 3B is reprinted by permission from Springer Nature. Herbst RS et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-567. Copyright © 2014.
• Escalation to 30 mg/kg was completed; MTD was not reached • Treatment-emergent AEs (TEAEs) are summarized in Table 3 ── Most treatment-related AEs (TRAEs) were grade 1-2, with grade 3-4 TRAEs occurring in
Othera
7 (31.8)
SAE
1 (50.0)
0
1 (50.0)
1 (33.3)
4 (57.1)
2 (66.7)
0
9 (40.9)
0
0
1 (50.0)
1 (33.3)
4 (57.1)
2 (66.7)
3 (100.0)
11 (50.0)
Grade 3-4
0
0
0
0
1 (14.3)
0
1 (33.3)
2 (9.1)
SAE
0
0
0
0
1 (14.3)
0
0
1 (4.5)
5.6 (4-7)
3.5 (1-6)
1.8 (2-2)
4.4 (4-6)
TRAE
5.9 (2-8)
2.5 (2-4)
