Motolimod (formerly VTX-2337)
This section is intended specifically for health care professionals. Information is provided for educational use only and is based on motolimod preclinical and clinical data. Motolimod is not approved for commercial use and is only available for investigational purposes in approved clinical trials.
Motolimod is a clinical stage small molecule TLR8 agonist. This novel cancer immunotherapy enhances various anticancer agents including chemotherapies and monoclonal antibody therapies.
Evidence of the ability of motolimod to augment the antineoplastic effects of other therapies has been shown in laboratory studies. Preclinical pharmacology experiments in a murine model of ovarian cancer demonstrated a potent enhancement of the response to pegylated liposomal doxorubicin (PLD) in vivo (Monk, et al, ASCO abstract 2013). Additional preclinical data demonstrated an augmentation of the antibody dependent cellular toxicity (ADCC) due to natural killer (NK) cells activation when combined with several monoclonal antibodies (Lu et al. Clin. Cancer Res. 2012, Stephenson et al. Cancer Immunol. Immunother. 2013).
Clinical Safety and Efficacy
In a first-in-man Phase 1 study, 33 patients with advanced cancer were treated over 8 dose-escalating cohorts. Motolimod was given subcutaneously on a weekly basis (a cycle was defined as 3 weekly doses followed by one week off). The mean number of weekly doses given in this protocol was 6. Data from this trial demonstrated dose-dependent pharmacology of the compound with clear biomarker activity consistent with that seen in preclinical non-human primate studies. Motolimod was well tolerated, with the predominant drug-related adverse events (> 20% of patients) being injection site reactions, chills, and influenza-like symptoms. Twenty-five percent of patients showed disease stabilization at 8 weeks by RECIST and went on to receive additional doses at the same dose level until disease progression.
A Phase 1b clinical trial assessing the combination of motolimod with pegylated liposomal doxorubicin (PLD) or paclitaxel chemotherapy was undertaken in collaboration with the GOG/NCI(CTEP) in patients with late-stage, platinum-resistant ovarian cancer. The study results indicate that the combination is well tolerated with no evidence of synergistic toxicities. Adverse events were consistent with those reported in prior Phase 1 studies and previous studies of PLD or paclitaxel. Clinical responses were observed in several patients, supporting further evaluation of the regimen.
A randomized, double-blind, placebo-controlled Phase 2 trial of PLD +/- motolimod in patients with platinum-resistant ovarian cancer has been initiated with the GOG. Overall survival is the primary endpoint of this study.
In collaboration with the Seattle Cancer Care Alliance, VentiRx is conducting an investigator-sponsored Phase 1b trial evaluating the combination of motolimod with cetuximab in patients with advanced squamous cell carcinoma of the head and neck. Data from patients enrolled thus far demonstrate that the combination is safe and well tolerated with no synergistic toxicities.
A randomized, double-blind, placebo-controlled Phase 2 trial of motolimod in combination with platinum-based chemotherapy and cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck has been initiated. Progression-free survival is the primary endpoint of this study.
Clinical Development Program
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of VTX-2337 in Combination with Pegylated Liposomal Doxorubicin (PLD) in Patients with Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
In collaboration with the Gynecologic Oncology Group (GOG), VentiRx has initiated GOG-3003, a Phase 2 trial for patients with platinum-resistant ovarian cancer who have progressed within 12 months of receiving platinum-based chemotherapy. This study evaluates whether motolimod combined with the standard-of-care chemotherapy, pegylated liposomal doxorubicin (PLD), has the potential to improve survival outcomes for these patients. Patients will be randomly selected to receive PLD with motolimod or with placebo.
The trial will enroll more than 200 women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer and is being conducted at sites throughout the US.
A Randomized, Double-Blind, Placebo-Controlled Study of Chemotherapy plus Cetuximab in Combination with VTX-2337 in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Active8 is a Phase 2 trial evaluating the potential of motolimod to improve progression-free survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients will be randomly selected to receive the standard-of-care regimen—platinum chemotherapy (cisplatin or carboplatin), 5-FU, and cetuximab—with motolimod or placebo.
The trial is enrolling patients with recurrent or metastatic SCCHN and is being conducted in the US.