Multiple Myeloma
Conditions
Brief summary
This is a single center, single arm Phase Ib study with expansion cohort designed to establish the safety and physiologic effects of sirolimus pre-conditioning followed by T-cell engaging bispecific antibody therapy.
Detailed description
This is a Phase Ib trial with expansion cohort to assess the safety and estimate the preliminary efficacy of sirolimus pre-conditioning prior to treatment with a T-cell engaging bispecific antibody in patients with relapsed / refractory multiple myeloma previously exposed to T-cell engager therapy. Following Phase Ib, the study will enroll an expansion cohort to test the hypothesis that sirolimus pre-conditioning will result in an increase in the Teffector: Texhausted -cell ratio.
Interventions
DRUGSirolimus
Sirolimus is an immunosuppressant drug. Sirolimus binds to FK binding protein 12 and inhibits mTOR. This then suppresses T-cell proliferation and inhibits progression from G1 to S phase of the cell cycle.
BIOLOGICALTeclistamab
Teclistamab is a bispecific antibody that binds the CD3 receptor on T-cells and the B-cell maturation antigen on multiple myeloma cells and healthy B-lineage cells.
BIOLOGICALTalquetamb
Talquetamab is a bispecific antibody that binds the CD3 receptor on T-cells and the GPRC5d receptor on multiple myeloma cells.
Sponsors
Christopher Strouse
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible to participate in this study, an individual must meet all of the following criteria: * Willingness and ability to provide signed and dated informed consent form. * Stated willingness to comply with all study procedures and availability for the duration of the study. * Aged 18 years of older. * Diagnosis with multiple myeloma, per IMWG Consensus Criteria.20 * Planned for treatment with teclistamab, or talquetamab per standard of care, label indications.15 * Prior exposure to any of the following types of T-cell engaging therapies. 1. Anti-BCMA x CD3 bispecific antibody (for example: teclistamab, elranatamab) 2. Anti-GPRC5d x CD3 bispecific antibody (for example: talquetamab) 3. Anti-GPRC5d x CD3 x CD38 trispecific antibody 4. Anti-BCMA x CD3 x CD38 trispecific antibody 5. Anti-BCMA x CD3 x GPRC5d trispecific antibody 6. Anti-BCMA chimeric antigen T-cell (for example: idecabtagene vicleucel, ciltacabtagene autoleucel) 7. Anti-FcRL5 x CD3 bispecific antibody * Required clinical laboratory values during screening phase Hematologic Parameters Hemoglobin ≥7.0 g/dL; Platelets ≥25 x 109/L; Absolute Lymphocyte Count ≥0.2 x 109/L Chemistries AST/ALT \< 5 x the ULN; Total Bilirubin \< 3 x the ULN * Ability to take oral medication and be willing to adhere to the sirolimus pre-conditioning regimen. * ECOG performance status of 0, 1, or 2 (KPS of \>50). * For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner per section5.3. * Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: * Participants whose multiple myeloma is progressing at a rapid pace requiring immediate anti-myeloma therapy per assessment by the principal investigator or enrolling investigator are excluded. * Excluded concomitant medication exposures: * Exposure to corticosteroids within 1 week of treatment start * Exposure to calcineurin inhibitor or mTOR inhibitors (tacrolimus, everolimus, temsirolimus, sirolimus) * Immunomodulatory monoclonal antibodies targeting tumor necrosis factor alpha (e.g. infliximab), interleukin 6 (e.g. siltuximab), * Janus kinase inhibitors (e.g. ruxolitinib) * Any other investigational drug within 28 days * History of allogeneic hematopoietic cell transplantation. * Excluded concurrent medical conditions: * Active uncontrolled infection within 7 days prior to treatment start * Uncontrolled thrombotic event within 3 months of treatment start * Acute myocardial infarction or acute coronary syndrome within 6 months of start of treatment * Uncontrolled inflammatory bowel disease * Active hepatitis B virus, hepatitis C virus, or Human Immunodeficiency Virus infection * Uncontrolled rheumatologic conditions * Use of ACE-inhibitor therapy within 1 week of treatment start * Patients found to be taking ace-inhibitor therapy during screening can be included if the ace-inhibitor is substituted for an angiotensin receptor blocking agent. (https://drug-interactions.medicine.iu.edu/main-table) * CYP3A4/p-gp inhibitors and inducers for 7 days prior to sirolimus doses and 7 days after sirolimus doses(see appendix A for list) * Any other current active malignancy or history of metastatic malignancy that has the potential to interfere with the safety or efficacy assessment of the investigational intervention * Pregnancy or lactation. * Known allergic reactions to study agent (sirolimus).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Dose limiting toxicities (DLTs) as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | From treatment initiation through 30 days post last dose of study treatment | The incidence of treatment-emergent adverse events will be summarized by system organ class and/or preferred term, type of adverse event, severity (based on NCI CTCAE v5.0) grades), and relation to study treatment. The most severe grade per participant will be reported. Adverse events leading to premature discontinuation from the study intervention and serious treatment-emergent adverse events will be presented in tabular form. |
| Expansion Cohort: Participants change in the Teffector: Texhausted cell ratio | From treatment initiation through 3 months | Testing the null hypothesis H0: ΔPost-Pre = 0 versus the alternative H1: ΔPost-Pre ≠ 0. Results will be used as preliminary estimates to inform a subsequent larger trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participant change in the following T-cell subsets: T-regulatory; T-Effector Memory (T-EM); T-Effector Memory expressing RA (T-EMRA) | From treatment initiation through 3 months | The within participant change in the following T-cell subsets will be estimated: T-regulatory, T-EM, T-EMRA. Mixed effects regression models will be utilized to estimate changes. Random effects will be included to account for the longitudinally correlated nature of repeated measurements. Graphical plots of the estimated mean and associated 95% confidence intervals by time point in the study will be produced. |
| The proportion of participants with grade 3 or higher CRS | From treatment initiation through 3 months | The rate of grade ≥3 CRS will be defined as the proportion of participants who develop grade 3 or higher CRS. The rate of grade ≥3 CRS will be reported as a binomial proportion along with a two-sided 95% confidence interval. |
| The proportion of participants with grade 3 or highter ICANS | From treatment initiation through 3 months | The rate of grade ≥3 ICAN will be defined as the proportion of participants who develop grade 3 or higher ICAN. The rate of grade ≥3 ICAN will be reported as a binomial proportion along with a two-sided 95% confidence interval. |
| The proportion of participants with a very good partial response (VGPR) or better at 3 months | Three months after the initiation of treatment | The 3-month response rate will be defined as the proportion of participants with a very good partial response (VGPR) or better at 3 months. The 3-month response rate will be reported as a binomial proportion along with a two-sided 95% confidence interval. |
Countries
United States
Contacts
CONTACTChristopher Strouse, MD
PRINCIPAL_INVESTIGATORChristopher Strouse, MD
University of Iowa
Outcome results
None listed