A Phase I Safety and Window-of-Opportunity Study of Preoperative Intra-tumoral Injection of OX40-Ligand Expressing Oncolytic Adenovirus (DNX-2440) in Patients with Resectable Liver Metastasis
A Phase I safety and window-of-opportunity study of preoperative intra-tumoral injection of OX40-ligand expressing oncolytic adenovirus (DNX-2440) in patients with resectable liver metastasis
the primary objective is to establish safety of DNX-2440 preoperative sequential intratumoral injection and to determine the maximum tolerated dose in patients with liver metastasis (secondary liver cancer).
Secondary objectives will include:
To determine efficacy of DNX-2440 in achieving tumor cell killing of injected and bystander tumors
To determine viral replication ability in injected tumor
To measure immunotherapeutic responses following intratumoral injection of DNX-2440 in liver metastasis prior to surgical resection of the tumors (liver resection)
Male or female aged 18 years or older at time of consent
Dose escalation cohort: Diagnosis of liver metastases from colorectal, breast, gastric, periampullary, melanoma, renal cell cancer, sarcoma, squamous cell carcinoma or gastrointestinal stromal tumor
Expansion cohort: Diagnosis of colorectal liver metastases
Diagnosis of liver metastases confirmed by clinical presentation as judged by the treating physician (including cross-sectional imaging study – i.e., CT and/or MRI and/or PET)
Multiple (more than or equal to 2) liver tumors
Target liver lesion (to be injected with DNX-2440) must be 10-40 mm (1-4 cm) in longest diameter
Target lesion (to be injected with DNX-2440) must not impinge on vital structures such as common bile duct, portal or hepatic vein, hepatic artery
Size of bystander (non-target) liver lesion/s must be > 5 mm (0.5 cm) in longest diameter.
Candidate for curative-intent surgery (resection of the liver) (a) Eligible patients will be approached upon confirmation of surgical candidacy for liver resection and treatment plan established as such- i.e., surgery scheduled (b) Patient may have extrahepatic disease, as long as deemed appropriate candidate for curative-intent surgery as described above
Provision of signed and dated informed consent form
Stated willingness to comply with all study procedures and availability for the duration of the study.
Candidates eligible for targeted therapy, as per standard of care guidelines (and based on mutational status as indicated), must have completed therapy
Preoperative chemotherapy is allowed (a) Dose escalation cohort: Eligible candidates include those having completed preoperative chemotherapy and those scheduled for upfront surgery (no preoperative chemotherapy) (b) Expansion cohort: Eligible patients will include only those receiving preoperative chemotherapy (≤ 12 cycles) as part of the perioperative treatment for the CRLM.
Diagnosis of neuroendocrine tumor liver metastasis (e.g. neuroendocrine origin of liver metastasis)
Previously treated liver metastasis by any of the following therapies: ablation of tumor, transarterial chemotherapy, hepatic artery infusion, transarterial radiation therapy (radioembolization), external radiation therapies (including EBRT, SBRT, proton therapy), or any other liver-directed therapies.
Liver metastasis treated with > 12 cycles of systemic chemotherapy
Prior anti-cancer monoclonal antibody (e.g. Avastin) within 14 days of planned DNX-2440 injection
Live vaccines of any kind within 42 days of DNX-2440 administration and while participating in the study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
Immunocompromised subjects, active hepatitis (HBV, HCV), known history of active TB (Mycobacterium tuberculosis), or human immunodeficiency virus (HIV) seropositivity
Females of any age who are pregnant, nursing or would like to get pregnant in the immediate future. Similarly, patients in the process of egg/sperm banking or donating activities.
Patients who do not agree to withhold from donating blood and resected tissue during the study period.
History or current diagnosis of any medical or psychological condition that in the Investigator's opinion, might interfere with the subject’s ability to participate in the study or the inability to obtain informed consent because of psychiatric or complicating medical problems.
White blood cell (WBC) 1.8 x control.
Grade 4 hematological toxicity
Serum creatinine > 1.5 mg/dL
Liver transaminases (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]) or total bilirubin > 5x the upper limits of normal.
Males or females who refuse to use a double-barrier form of birth control during the study and for up to 6 months after injection with DNX-2440.
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