gene therapy for cd19-positive hematologic malignancies (sentry-cd19)

Conditions: B-cell Acute Lymphoblastic Leukemia; Large B-cell Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Diffuse Large B Cell Lymphoma; High-grade B-cell Lymphoma; Burkitt Lymphoma; Primary Mediastinal Large B-cell Lymphoma (PMBCL); Non Hodgkin Lymphoma; Mixed Phenotype Acute Leukemia

Summary: this is a phase 1/2, first-in-human, open-label, dose-escalating trial designed to assess the safety and efficacy of vnx-101 in patients with relapsed or refractory cd19-positive hematologic malignancies.

vnx-101 is an investigational adeno-associated virus (aav) gene therapy developed to express a secreted anti-cd19/anti-cd3 scfv diabody (termed gp101). gp101 binds both cluster of differentiation (cd)19 and cd3, inducing t-cells to kill both benign and malignant b-cells. following a single intravenous (iv) infusion, the vector induces the liver and key tissues to continuously secrete gp101 into the bloodstream, resulting in long-term, consistent serum levels of gp101. potential advantages of vnx-101 over autologous car-t therapy include it is off-the-shelf, provides a gentle onset of action, does not require lymphodepletion chemotherapy, engages all t-cells continuously (including those freshly produced from the bone marrow), and utilizes highly efficient signaling through the native t-cell receptor. in this 2-part study, dose-finding data from part 1 of the study (n=\~12 patients) will be used determine the dose for part 2 in patients. part 1 is a dose-finding pk study in adults ≥18 years old designed to determine the minimal dose that achieves target pk serum levels of gp101 at steady state (8-week timepoint) without dose-limited toxicities, defined as the recommended part 2 dose (rp2d). prior to vnx-101 dosing, subjects may undergo standard of care chemotherapy to meet dosing criteria. part 2 (n=\~20) will be opened following data safety monitoring board review of part 1 data and is designed to determine the safety and pharmacokinetics (pk) of vnx-101 at the rp2d in a broader array of subjects. the age range for part 2 will be expanded to include subjects ≥13 years old. patients will be followed for safety and efficacy up to 5 years post vnx-101 dosing. long-term follow-up assessments for safety will be conducted for 6 to 15 years post vnx-101 dosing.

Eligibility criteria:
inclusion criteria: * age: part 1: 18-90 years of age, part 2: 13-90 years of age * relapsed or refractory cd-19 positive leukemia or lymphoma as defined in the protocol * cd19-positive expression * aav specified capsid total antibody \<1:400 * protocol-specified ranges for renal, liver, cardiac and pulmonary function * protocol-specified ranges for hematology parameters exclusion criteria: * hepatoxicity (ast or alt \> 2x upper limit of normal) * history of thrombotic microangiopathy or cardiomyopathy, or evidence of sensory neuropathy * pregnant or nursing (lactating) women * acute graft versus host disease (gvhd): grade 2-4 or chronic gvhd of any grade * history of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity * chemotherapy given within the protocol-specified discontinuation timelines other inclusion/exclusion criteria to be applied per protocol.

Keywords: cd19-positive leukemia lymphoma