Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN.
Purpose:As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored.Experimental Design:Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose-escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles.Results:There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m2dose level was not optimal for repeated dosing and 3.0 mg/m2was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed.Conclusions:Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029).Clin Cancer Res; 23(10); 2442-50. ©2016 AACR.
University of Washington, Seattle, Washington. lchow@seattlecca.org.
Laura Q M
LQM
Chow
University of Washington, Seattle, Washington.
Chihiro
C
Morishima
University of Washington, Seattle, Washington.
Keith D
KD
Eaton
University of Washington, Seattle, Washington.
Christina S
CS
Baik
Fred Hutchinson Cancer Research Center, Seattle, Washington.
Bernardo H
BH
Goulart
University of Washington, Seattle, Washington.
Leslie N
LN
Anderson
VentiRx Pharmaceuticals, Seattle, Washington.
Kristi L
KL
Manjarrez
VentiRx Pharmaceuticals, Seattle, Washington.
Gregory N
GN
Dietsch
VentiRx Pharmaceuticals, Seattle, Washington.
James Kyle
JK
Bryan
VentiRx Pharmaceuticals, Seattle, Washington.
Robert M
RM
Hershberg
University of Washington, Seattle, Washington.
Mary L
ML
Disis
University of Washington, Seattle, Washington.
Renato G
RG
Martins
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000068818:Cetuximab / Q000008:administration & dosage; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D051200:Toll-Like Receptor 8 / Q000235:genetics*
D061067:Antibodies, Monoclonal, Humanized; D001552:Benzazepines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C573973:VTX-2337; D000068818:Cetuximab