Phase 1 Study of CART-BCMA With or Without huCART19 as Consolidation of Standard First or Second-Line Therapy for High-Risk Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Multiple Myeloma
- Sponsor
- University of Pennsylvania
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Adverse event reporting
- Status
- Active, not recruiting
- Last Updated
- 10 months ago
Overview
Brief Summary
This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA, with or without huCART19, in patients responding to first- or second-line therapy for high-risk multiple myeloma. The regimen evaluated in this study is based on established safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in combination with huCART19, and (4) as a single rather than split-dose infusion.
Detailed Description
Phase A: Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have relapsed/refractory myeloma after two prior regimens but who are responding to their current therapy. Phase A Expansion: To occur once safety is demonstrated in Phase A. - Phase B: Randomization Phase in which patients responding to first or second-line therapy will receive either CART-BCMA alone (Cohort 1) or CART-BCMA + huCART19 (Cohort 2) as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. Phase C: Single-dose infusion phase to test the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19 (Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients responding to first- or second-line therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106 with any of the following high-risk features. Subjects in the Phase A Expansion are not required to have any high-risk features.
- •Beta-2-microglobulin ≥ 5.5 mg/L and LDH greater than upper limit of normal. Note: subjects in whom LDH and/or Beta-2-microglobulin were not measured prior to initiation of systemic therapy may qualify based on measurements obtained after initiation of systemic therapy.
- •High-risk FISH features: at least one of the following \[deletion 17p, t(14;16), t(14;20), t(4;14)\] in conjunction with Beta-2-microglobulin ≥ 5.5 mg/L (i.e., revised ISS stage 3). Note: subjects in whom Beta-2-microglobulin was not measured prior to initiation of systemic therapy may qualify based on measurements obtained after initiation of systemic therapy.
- •Metaphase karyotype with \>3 structural abnormalities except hyperdiploidy
- •Plasma cell leukemia (\>20% plasma cells in peripheral blood) at any time prior to physician-investigator confirmation of eligibility.
- •Failure to achieve partial response or better (by IMWG 2016 criteria1) to initial therapy with an "imid/PI" combination (thalidomide, lenalidomide, or pomalidomide in combination with bortezomib, ixazomib, or carfilzomib).
- •Early progression on first-line therapy, defined as progression (according to IMWG 2016 criteria1)
- •i. Within one year of starting first-line therapy with an "imid/PI"combination ii. Within six months of completing first line therapy with an "imid/PI"combination (i.e. a patient who receives an "imid/PI" combination, transitions to observation or maintenance therapy, and progresses within six months of this transition) iii. Within one year of a high-dose melphalan and autologous stem cell transplantation (Phase A subjects only)
- •Subjects must meet the following criteria with respect to prior myeloma therapy:
- •a. Phase A and Phase A expansion:
Exclusion Criteria
- •Pregnant or lactating women
- •RETIRED WITH PROTOCOL V6
- •Active hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection.
- •Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.
- •NYHA Class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (\>30 seconds) ventricular tachyarrhythmias.
- •Have active auto-immune disease, including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy.
- •Have prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease, parenchymal masses) with myeloma. Screening for this (e.g. with lumbar puncture) is not required unless suspicious symptoms or radiographic findings are present. Subjects with calvarial disease that extends intracranially and involves the dura will be excluded, even if CSF is negative for myeloma.
Outcomes
Primary Outcomes
Adverse event reporting
Time Frame: 90 Days
The occurrence of adverse events that are possibly, probably or definitely related to CAR T cells.
Secondary Outcomes
- Maintenance therapy effects on persistence(28 days post infusion - 2 years)
- In vivo CAR T cell expansion as measured by flow cytometry(28 days post infusion - 2 years)
- Bioactivity by multiplex cytokine analysis(28 days post infusion - 2 years)
- Immune cell phenotyping(2 years)
- Duration of in vivo persistence of CAR T cells.(28 days post infusion - 2 years)
- Duration of Response(15 years)
- Evaluate effects of huCART19 on correlative parameters of CART BCMA resistance and clonogenic multiple myeloma cells, such as the following:(2 years)
- In vivo CAR T cell expansion as measured by qPCR(28 days post infusion - 2 years)
- Effects of maintenance therapy on CAR T cell pharmacokinetic parameters.(28 days post infusion - 2 years)
- Adverse event reporting(15 years)
- Clinical outcomes after each CAR T cell regimen(2 years)
- Progression-free Survival (PFS)(15 years)
- Overall Survival (OS)(15 years)
- Composition of investigative products(2 years)
- Cellular composition of CAR T cell products(28 days post infusion - 2 years)
- Impact of T Cells on systemic soluble immune factors in patients(2 years)