Lymphodepleting Total Body Irradiation (TBI) Plus Cyclophosphamide Prior to Ciltacabtagene Autoleucel (Carvykti; Cilta-cel) for Multiple Myeloma (MM) Patients With Impaired Renal Function

Official title

A Pilot Safety and Feasibility Study of Lymphodepleting Total Body Irradiation (TBI) Plus Cyclophosphamide Prior to Ciltacabtagene Autoleucel (Carvykti; Cilta-cel) for Multiple Myeloma (MM) Patients With Impaired Renal Function

Overview

Treatment for relapsed/refractory multiple myeloma continues to evolve with the approval of highly effective anti-BCMA CAR T therapies in recent years. However, despite the high prevalence of renal insufficiency in this population, pivotal clinical trials have excluded patients with impaired renal function, leading to an urgent, unmet clinical need to develop safe and effective lymphodepleting regimens prior to CAR T administration for this population. In addition, renal insufficiency is linked to poor disease-related outcomes and is highly associated with several underserved populations. This study is testing the hypotheses that: 1. low-dose total body irradiation (TBI) in combination with cyclophosphamide (Cy) as lymphodepletion prior to administration of cilta-cel will be safe and tolerable in patients with multiple myeloma who have impaired renal function 2. low-dose TBI-Cy as lymphodepletion prior to cilta-cel will result in comparable CAR T expansion/persistence and disease response rates as those seen with standard lymphodepleting chemotherapy (fludarabine / cyclophosphamide).

Interventions

• Drug Cyclophosphamide
  Standard of care
• Drug Ciltacabtagene Autoleucel
  Standard of care
• Radiation Total body irradiation
  Radiation doses delivered to the entire body

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: Through 28 days post cilta-cel]

Secondary outcome measures (12)

• Incidence of treatment related adverse events (TEAEs) [Time frame: Through completion of follow-up (estimated to 1 year and 1 week)]
• Incidence of cytokine release syndrome (CRS) [Time frame: Through day 100]
• Incidence of immune effector cell associated neurotoxicity syndrome (ICANS) [Time frame: Through day 100]
• Best overall response by IMWG criteria [Time frame: Through completion of follow-up (estimated to 1 year and 1 week)]
• Response rate by IMWG criteria [Time frame: Day 28 post cilta-cel]
• Response rate by IMWG criteria [Time frame: Day 100 post cilta-cel]
• Response rate by IMWG criteria [Time frame: 1 year post cilta-cel]
• Measurable residual disease (MRD) as measured by ClonoSeq [Time frame: Day 28 post cilta-cel]
• Measurable residual disease (MRD) as measured by ClonoSeq [Time frame: Day 100 post cilta-cel]
• Measurable residual disease (MRD) as measured by ClonoSeq [Time frame: 1 year post cilta-cel]
• Median duration of response (DoR) [Time frame: Through completion of follow-up (estimated to 1 year and 1 week)]
• Duration of response [Time frame: Through completion of follow-up (estimated to 1 year and 1 week)]

Eligibility criteria

Inclusion criteria

• Histologically confirmed diagnosis of multiple myeloma.
• Renal insufficiency, defined as eGFR < 45 by MDRD formula.
• At least 18 years of age.
• ECOG performance status ≤ 1.
• Meets standard of care indication for cilta-cel (per FDA approval).
• ANC ≥ 1.0 k/cumm. If neutropenia is present at initial screening but is judged to be attributable to bridging and/or leading therapies, patients can be re-tested within the screening period to confirm eligibility.
• Patients with a history of prior autologous hematopoietic cell transplant (AHCT) must have received a graft containing ≥2.0 x 106 CD34+ cells/kg body weight.
• Availability of adequate cryopreserved autologous stem cells (≥2.0 x 106 CD34+ cells/kg body weight) to allow for an autologous stem cell boost in case of prolonged cytopenias.
• Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. 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

• 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 any other investigational agents.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmia. 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 pregnancy test within 14 days of study entry.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Washington University School of Medicine — St Louis

Identifiers

NCT: NCT06623630 · 202410010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗