Multiple Myeloma, Multiple Myeloma in Relapse, Multiple Myeloma, Refractory
Conditions
Keywords
Cytokines, Interleukin-7, Cellular therapy, Chimeric antigen receptor T cell therapy
Brief summary
CAR-T cell therapy is an emerging treatment modality in relapsed and refractory multiple myeloma (MM). CAR-T therapy in MM relies on directing autologous T-cells to detect and clear myeloma cells expressing B-cell Maturation Antigen (BCMA). While BCMA CAR-T cell-treated patients achieve an excellent overall response rate, their response is often not durable. NT-I7 promotes CAR-T cell expansion and efficacy in pre-clinical lymphoma models. In patients receiving CD19-directed CAR-T therapy for lymphoma, NT-I7 augmented CAR-T expansion while being safe and tolerable. The impact of NT-I7 on BCMA CAR-T cells in multiple myeloma is unknown. This is a two-stage, multicenter, phase IB study, with a dose escalation stage leading into a two-arm, double blind, placebo-controlled, randomized dose expansion stage testing the safety and toxicity of adding NT-I7 to BCMA CAR-T therapy in patients with relapsed and refractory multiple myeloma. The hypothesis is that NT-I7 will promote CAR-T expansion and persistence which will enhance clearance of MM, while maintaining a favorable safety and toxicity profile. Patients receiving standard of care BCMA CAR-T (cilta-cel) will be randomized to either NT-I7 or placebo. Correlative studies will evaluate CAR-T cell expansion, persistence, immune-phenotype, function and correlate with clinical outcomes.
Interventions
DRUGNT-I7
NT-I7 will be supplied by NeoImmuneTech Inc
DRUGPlacebo
Placebo will be supplied by NeoImmuneTech Inc
Sponsors
Washington University School of Medicine
NeoImmuneTech
Swim Across America
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Sequential for the dose-escalation portion and parallel for the dose expansion portion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma with measurable disease by IMWG criteria. * Eligible for standard of care, FDA-approved BCMA CAR-T cell therapy with ciltacabtagene autoleucel. * Patients enrolling in the dose escalation stage must have received at least two prior lines of treatment and be penta-drug exposed (i.e. exposure to at least 5 active anti-myeloma drugs, excluding corticosteroids and melphalan and including, at minimum, a proteasome inhibitor, an immunomodulatory drug, and a CD38 monoclonal antibody). * Life expectancy ≥ 12 weeks per assessment from the enrolling physician. * At least 18 years of age. * ECOG performance status ≤ 2 * Adequate organ function as defined below: * Total bilirubin ≤ 1.5 x IULN * AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN * Creatinine clearance \> 30 mL/min by Cockcroft-Gault * The effects of NT-I7 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry until 90 days after completion of NT-I7 therapy/placebo (corresponding to Day 125 post CAR-T). Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately. * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion criteria
* Received prior BCMA-directed therapy. * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial. * Currently receiving or have received any other investigational agents within 14 days prior to CAR-T infusion. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to NT-I7or other agents used in the study. * Uncontrolled intercurrent illness including but not limited to: ongoing or active infection (bacterial, fungal, viral, or tuberculosis, including known hepatitis A, B, or C, or HIV (testing not required)), symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia (except well-controlled atrial fibrillation). Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to starting CAR-T therapy. * Receipt of live, attenuated vaccine within 30 days prior to first day of treatment. * Had an allogeneic tissue/solid organ transplant or allogeneic stem cell transplant. * Not able to receive intramuscular therapy. * Prior history of T cell malignancy. * Prior history of congenital immunodeficiency syndrome. * Prior history of autoimmune disease with significant disease activity in the past 2 years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sézary syndrome, vasculitis or glomerulonephritis, Bell's palsy, Guillain-Barré syndrome, or multiple sclerosis. * Prior history of plasma cell leukemia, systemic amyloidosis, POEMS syndrome, or multiple myeloma with CNS involvement. * Planning to start maintenance therapy prior to Day 100 post-CAR-T therapy. * A history of clinically significant pulmonary disorders, such as severe asthma, severe COPD, restrictive lung disease, symptomatic pulmonary embolism within 3 months prior to study enrollment, or active or prior interstitial lung disease/pneumonitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of non-hematologic grade ≥3 treatment-related adverse events (excluding expected conditioning-related AEs) | From Day 14 to Day 100 | Graded per CTCAE v 5.0. |
| Recommended phase II dose (Dose escalation stage only) | Through day 65 for all dose escalation stage patients (estimated to be 3 months and 65 days) | The recommended phase II dose (RP2D) is defined as the highest tested dose level or the dose level immediately below the dose level at which 2 or more patients experience dose-limiting toxicity during the dose-limiting toxicity (DLT) assessment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MRD negativity by clonoSEQ (10^5 cutoff) | At Day 100 | — |
| MRD negativity by clonoSEQ (10^6 cutoff) | At Day 100 | — |
| Number of participants with stringent complete response (sCR) by IMWG criteria | At Day 100 | * Stringent complete response requires all of the following: * CR as defined below * Normal free light chain ratio (0.26-1.65) * Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence * Complete response (CR) requires all of the following: * Negative immunofixation on the serum and urine * \<5% plasma cells in the bone marrow aspirate * Disappearance of any soft tissue plasmacytomas * Normalization of the serum free light chain ratio in patients who lack measurable M protein in the serum and urine at baseline |
| Progression-free survival (PFS) | At Day 365 | * PFS is defined as the length of time between randomization and disease progression or death from any cause. * Progressive disease per IMWG criteria. |
| Number of participants with Grade ≥2 CRS and ICANS according to ASTCT consensus grading | From Day 0 through Day 100 | — |
| Number of participants with Grade ≥3 CRS and ICANS according to ASTCT consensus grading | From Day 0 through Day 100 | — |
| Rate of non-relapse mortality (NRM) | By Day 365 | For the purposes of this study, NRM is death following CAR-T cell infusion without evidence of progressive myeloma. |
Countries
United States
Contacts
CONTACTMichael Slade, M.D., M.S.C.I.
PRINCIPAL_INVESTIGATORMichael Slade, M.D., M.S.C.I
Washington University School of Medicine
Outcome results
None listed