Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer.
BACKGROUND
CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients.


METHODS
In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity.


RESULTS
Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥ 3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥ 3 AEs. Common grade ≥ 3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-μg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained.


CONCLUSIONS
Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.
University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Room 7308, Ann Arbor, MI, 48109, USA. kpienta@umich.edu
Kenneth J
KJ
Pienta
Jean-Pascal
JP
Machiels
Dirk
D
Schrijvers
Boris
B
Alekseev
Mikhail
M
Shkolnik
Simon J
SJ
Crabb
Susan
S
Li
Shobha
S
Seetharam
Thomas A
TA
Puchalski
Chris
C
Takimoto
Yusri
Y
Elsayed
Fitzroy
F
Dawkins
Johann S
JS
de Bono
D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000080908:Broadly Neutralizing Antibodies; D002452:Cell Count; D018932:Chemokine CCL2 / Q000097:blood / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D000080908:Broadly Neutralizing Antibodies; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C581643:carlumab