We are requesting three years of support to conduct an open-label, dose-escalating, Phase I clinical trial in subjects with recurrent malignant glioma (MG) to determine the Recommended Phase 2 Dose (RP2D), safety and toxicities of a novel modification of a ??134.5 Herpes Simplex Virus (??134.5 HSV) that expresses human interleukin-12 (M032, NSC733972). This oncolytic HSV was developed under a Program Project Grant (CA071933) and has been extensively tested in vitro and preclinically in two animal species, including nonhuman primates. These studies have shown M032 to be as safe as other clinical oncolytic ??134.5 HSV (G207, 1716) used intracerebrally, to have no unexpected toxicities in immunocompromised mice or immunocompetent animals (mice, non-human primates), and to replicate 10-1000 fold better than G207 in a variety of preclinical models of MG. We have conducted three Phase I clinical trials with G207 in a similar patient population (17 of 35 subjects had objective responses) and will apply our unique knowledge and experience to evaluate this novel HSV. The NExT program produced cGMP clinical grade M032 (NSC733972) at >3 x 109 PFU/ml, generating >560 single-dose vials. The FDA has issued IND #14,946, a trial protocol and informed consent were IRB- approved and the first subject has been treated without DLTs (NCT02062827).
In Aim 1, this first-in-human Phase I clinical trial will use a modified Continual Reassessment Method (CRM) to determine dose modifications to obtain both safety and toxicity data as well as secondary biologic correlative information critical to assessing the potential application of this virus to treat malignant brain tumors. Subjects with biopsy-proven recurrent MG will have M032 infused (400?l/hr x 6 hrs) in up to four sites in the enhancing tumor mass via stereotactically placed catheters and will be monitored adverse effects and survival. Dose escalation in each subsequent subject will occur after a 24 day interval and will be defined by the CRM. We will determine the RP2D, will identify any unanticipated toxicities and will determine, secondarily, progression-free and overall survivals.
In Aim 2, we will simultaneously acquire biological specimens from each subject on a designated longitudinal timeline and process these for immediate analyses or for cryopreservation and batch analyses at a later time. We propose to: a) assess M032 shedding in blood, saliva, and conjunctival secretions by virus culture and PCR; b) document serological (antibody titers) and cellular immune responses (profiling, proliferation and function of immune subsets) to M032 infusion; c) define changes from an immune suppressing environment to an immune enhancing environment, including changes in circulating cytokines and peripheral blood mononuclear cells; and d) establish tumor genotype differences that might reveal molecular bases for tumor susceptibility or resistance. Previously archived tumor tissues (when available) and blood DNA will be analyzed to provide an in-depth molecular profile for each subject's tumor. Analyses will be focused to define a RP2D of M032 and will consider all clinical variables and correlative parameters to better inform future trial designs for the best outcomes.
High-grade malignant gliomas are the most prevalent intracranial malignant brain tumor in adults with a dismal prognosis evidenced by a 12-15 month median survival and a 5-year survival <5%, evincing the need for more effective therapies. We created a novel, oncolytic Herpes Simplex Virus (oHSV) termed M032 (NSC 733972) that expresses human Interleukin-12 and the NExT (NCI) program manufactured clinical grade M032 (>560 doses) for which we have been issued an investigational new drug approval (#14,946) by the FDA. We propose to conduct a first-in-human Phase I clinical trial (NCT02062827) to assess the safety and tolerability of M032, to define any unexpected toxicities, to obtain correlative biologic information, and to determine a Recommended Phase 2 Dose.
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