Active8: A randomized, double-blind, placebo-controlled study of chemotherapy plus cetuximab in combination with motolimod immunotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

Background

Patients (pts) with recurrent or metastatic SCCHN have poor outcomes despite therapy with the EXTREME regimen (platinum, 5-FU, cetuximab [CTX]). The Toll-like receptor 8 agonist motolimod (M) stimulates the innate immune system, increasing antigen-specific T cell responses against EGFR. In SCCHN pts, M + CTX enhanced NK cell activity, decreased markers of T cell suppression, and reduced myeloid-derived suppressor cells in tumors, with most pts having a characteristic motolimod injection site reaction (ISR). A randomized phase 2 study tested whether M can improve clinical outcomes in SCCHN when combined with EXTREME.

Methods

Pts were randomized 1:1 to EXTREME + motolimod (M) (N = 100) or EXTREME + placebo (N = 95) and stratified by ECOG 0 vs. 1, prior systemic therapy for SCCHN, and choice of cisplatin or carboplatin. The primary endpoint was progression-free survival (PFS) per independent central review. Key secondary endpoints included overall survival (OS) and safety.

Results

Median age was 58 yrs (range, 23–81), ECOG was 0 (38%) or 1 (62%), and 65% of pts had previously received systemic treatment for SCCHN. The majority of pts (80%) were assigned to receive carboplatin at baseline. In the intent-to-treat (ITT) population, the median PFS for EXTREME + M was 185 vs. 181 days for control (HR 0.99, P = 0.266). Median OS in the ITT population was 412 vs. 343 days for EXTREME + M vs. control, respectively (HR 0.95, P = 0.399). A subgroup analysis examining EXTREME + M pts experiencing an ISR showed significant improvements in PFS (216 vs. 181 days, HR 0.69, P = 0.005) and in OS (570 vs. 382 days, HR 0.56, P = 0.015) vs. controls. Adverse events with increased incidence in the EXTREME + M arm included ISR, pyrexia, chills, anemia, influenza-like illness, and dermatitis acneiform.

Conclusions

Adding M to EXTREME did not improve PFS or OS in the ITT population, though significant benefits were observed in a subgroup with immune-related ISR. EXTREME + M was generally well tolerated, with no unexpected adverse events or serious adverse events, and no evidence of synergistic toxicities.

Clinical trial identification

ClinicalTrials.gov Identifier: NCT01836029. Release date: April 12, 2013.

Legal entity responsible for the study

VentiRx Pharmaceuticals, Inc.

Funding

VentiRx Pharmaceuticals, Inc.

Disclosure

E. Cohen: Stock ownership: HLI Advisory boards: BMS, AZ, Pfizer, Merck, Merck Serono, Aspyrian, GenMab. N.F. Saba: Advisory boards: Merck, Pfizer, BMS. R. Haddad: Advisory boards: BMS, Merck, AstraZeneca, Pfizer, Celgene Research grants: BMS, Merck, AstraZeneca, Celgene Consultant: BMS, Merck, AstraZeneca, Pfizer. J.C. Morris: Speaker bureau: Boehringer-Ingelheim. K.L. Manjarrez, G.N. Dietsch: Employee of VentiRx Pharmaceuticals with equity ownership in the company and patents related to motolimod (VTX-2337). J.K. Bryan: I am an employee of VentiRx Pharmaceuticals and have equity ownership in the company. R.M. Hershberg: Employment: VentiRx Pharmaceuticals, Celgene Corp Stock ownership: VentiRx, Celgene Corp Patent: Motolimod (VTX-2337) Board of Directors: VentiRx, Nanostring, Adaptive Biotechnologies Consultant: Frazier Healthcare. R.L. Ferris: Advisory boards: Merck, Celgene, Bristol Myers Squibb, AZ/Medimmune Research grants: VentiRx, Bristol Myers Squibb, AZ/Medimmune. All other authors have declared no conflicts of interest.