Recurrent Multiple Myeloma, Refractory Multiple Myeloma
Conditions
Keywords
ORCA-Q
Brief summary
This phase I trial tests the effect of allogeneic Orca-Q stem cell transplant in treating patients with high-risk multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). An allogeneic (donor) transplant uses blood forming stem cells (graft) from a matched donor. When the healthy blood forming (stem) cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease \[GVHD\]). Orca-Q includes some T cells (a type a white blood cell) that are thought to help prevent some of the known complications as well as help attack the cancer cells. However, Orca-Q removes a specific type of T cell called naive T lymphocytes. Naive T cells may contribute to GVHD and are not thought to be required for the success of the treatment. Removing these cells may help reduce the frequency or severity of GVHD. Giving chemotherapy, such as thiotepa, busulfan, and fludarabine, before a donor stem cell transplant helps kill cancer cells in the body and prepare the body to receive the transplant graft. Giving allogeneic Orca-Q may be safe, tolerable, and/or effective in treating patients with relapsed or refractory (R/R) high-risk multiple myeloma.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the safety of allogeneic ORCA-Q transplantation in subjects with R/R multiple myeloma with high-risk features. SECONDARY OBJECTIVES: I. To evaluate the efficacy of allogeneic ORCA-Q transplantation in subjects with R/R multiple myeloma with high-risk features. II. To further evaluate the safety of allogeneic ORCA-Q transplantation in subjects with R/R multiple myeloma with high-risk features. EXPLORATORY OBJECTIVE: I. To further evaluate the efficacy of allogeneic ORCA-Q transplantation in subjects with R/R multiple myeloma with high-risk features. OUTLINE: DONORS: Donors receive granulocyte colony-stimulating factor (G-CSF) or filgrastim subcutaneously (SC) daily (QD) on days -6 to -3 and undergo apheresis on day -2 or -1. Donors may also undergo a second apheresis on day -1 or 0. Additionally, donors undergo blood sample collection at screening. PATIENTS: Patients receive thiotepa intravenously (IV) over 3 hours on days -7 and -6, busulfan IV over 3 hours on days -5 to -3, fludarabine IV over 30 minutes on days -5 to -2, Orca-Q prime IV on day 0 followed by Orca-Q supplement IV on day 0 or 1 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo echocardiography or multigated acquisition scan (MUGA) and optional positron emission tomography (PET)/computed tomography (CT) or CT at screening and urine and blood sample collection, as well as bone marrow aspiration and biopsy throughout the study. After completion of study treatment, patients are followed up on days 1-7, 14, 21, 30, 60, 90, 180, and 365.
Interventions
BIOLOGICALAllogeneic Defined Hematopoietic Stem Cells/Immune Cells
Given Orca-Q prime IV
DRUGBusulfan
Given IV
BIOLOGICALFilgrastim
Given SC
DRUGFludarabine
Given IV
DRUGGranulocyte Colony-Stimulating Factor
Given SC
DRUGThiotepa
Given IV
Sponsors
University of California, Davis
National Cancer Institute (NCI)
Orca Biosystems, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Ability to understand and sign informed consent * Age ≥ 18 years and ≤ 65 years * Patients should be in very good partial response (VGPR) (5% or less plasma cells in the marrow) or better response status at the time of stem cell transplant with no evidence of central nervous system (CNS) disease. Patients in complete response (CR) should have minimal residual disease (MRD) positivity * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1; or Karnofsky performance status (KPS) of ≥ 70% * ≥ 60 days washout period from the last dose of an anti-CD38 antibody before the allogeneic transplant * ≥ 6 months washout period from the last autologous transplant before the allogeneic transplant * Related or unrelated donors available as follows: * Sibling donor who is a 7/8 mismatched or 8/8 matched for human leukocyte antigen (HLA)-A, -B, -C, -DRB1 * Matched unrelated donor who is a 7/8 mismatched or 8/8 matched for HLA-A, -B, -C, and -DRB1 * A diagnosis of relapsed or refractory defined as: * Primary refractory disease or relapse \< 12 months following initial therapy that includes an immunomodulatory agent, proteasome inhibitor, anti-CD38 monoclonal antibody, and corticosteroid * Relapse \< 12 months after first autologous stem cell transplant * Failing to achieve complete response or relapsing after chimeric antigen receptor (CAR)-T treatment or bispecific antibodies; or indicated but ineligible for either bispecific antibodies or CAR-T cells due to low blood counts * No appropriate standard of care therapy per investigator * A diagnosis of ultra-high risk multiple myeloma defined as having at least one or more of these criteria: * Biallelic TP53 inactivation * ≥ 2 HRCAs: del(17p), TP53 mutation, t(4;14), t(14;16), t(14;20), gain(1q), amp(1q), del(1p32) * Biallelic del(1p32) * High-risk gene expression profile signature * Extramedullary disease excluding intramedullary plasmacytoma with extraosseous extension and active CNS disease * ≥ 2% circulating plasma cells * Creatinine clearance of ≥ 50 mL/min as estimated by Cockcroft-Gault * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) except in subjects with Gilbert's syndrome in whom total bilirubin ≤ 3 times ULN * Alanine transaminase (ALT/serum glutamic pyruvic transaminase \[SGPT\]) and aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN if documented liver involvement by disease * Estimated glomerular filtration rate (eGFR) \> 50mL/minute. Creatinine clearance of ≥ 30 mL/min is allowed in patients eligible for no tacrolimus immunosuppression * Pulmonary function as defined by diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50% * Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram, or radionuclide scan (multigated acquisition scan \[MUGA\]) * Corrected diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50% * Individuals of childbearing potential or those with partners of childbearing potential must agree to use methods of contraception for the duration of study participation or be surgically sterilized * Stated ability and willingness to adhere to the study visit schedule and protocol requirements * DONOR: Ability to understand and sign informed consent * DONOR: Age ≥ 16 and ≤ 35 years at time of enrollment for unrelated donors and Age ≥ 16 and ≤ 50 years for related donors * DONOR: Either one of the following scenarios: * Sibling donor who is a 7/8 mismatched or 8/8 matched for HLA-A, -B, -C, and -DRB1, all typed using deoxyribonucleic acid (DNA)-based high-resolution methods * Unrelated donor who is 7/8 mismatched or 8/8 matched HLA-A, -B, -C, and -DRB1, all typed using DNA-based high-resolution methods * DONOR: Willing to donate stem cell mobilized mononuclear cells for up to two consecutive days * DONOR: Able to donate within the continental United States at a site that will employ a Spectra Optia Apheresis System for post-mobilization apheresis * DONOR: Meets federal eligibility criteria for donors of viable, leukocyte-rich cells or tissues and all relevant Food and Drug Administration (FDA) Guidance for Industry (Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products, 2007; Use of Donor Screening Tests to Test Donors of Human Cells, Tissues and Cellular and Tissue-Based Products for Infection with Treponema pallidum \[syphilis\], 2015; Use of Nucleic Acid Tests to Reduce the Risk of Transmission of Hepatitis B Virus from Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products, 2016; Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products \[HCT/Ps\], 2016) * DONOR: Donors determined to be ineligible, based on the results of required testing and/or screening, may nonetheless be included if either applies: * The donor is a first-degree blood relative of the recipient * Urgent medical need, meaning no comparable human cell product is available, and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the investigator * Meets any other criteria for donation as specified by standard National Marrow Donor Program (NMDP) guidelines (NMDP donors) or institutional standards (non-NMDP donors)
Exclusion criteria
* Prior allogeneic hematopoietic cell transplantation (HCT) * Planned pharmaceutical in vivo or ex vivo T cell depletion, e.g., post-transplant cyclophosphamide (Cy), peri-transplant anti-thymocyte globulin (ATG), or alemtuzumab * Positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either: * A positive crossmatch test of any titer; or * The presence of anti-donor HLA antibody to any HLA locus * Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) \> 4 * Uncontrolled bacterial, viral, or fungal infections (currently taking antimicrobial therapy and with no clinical improvement) at time of enrollment * Seropositive for HIV-1 or -2, human T-cell lymphotropic virus (HTLV)-1 or -2 * Documented allergy or documented hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins * Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers or any carcinoma in situ that have been curatively resected * History of idiopathic or secondary myelofibrosis * Individuals who are pregnant or breastfeeding * Any condition that would prohibit the understanding or rendering of informed consent * Any condition that in the opinion of the investigator would interfere with the subject's safety or compliance while on study * A diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome * DONOR: Evidence of uncontrolled, active infection * DONOR: Seropositive for HIV-1 or -2, HTLV-1 or -2 * DONOR: Positive for hepatitis B (HBV) surface antigen (HBsAg), total anti-hepatitis B core antibody (HBcAb, immunoglobulin \[I\]gG and IgM), HBV nucleic acid testing (NAT), anti-hepatitis C (HCV) antibody, or HCV NAT * DONOR: Aberrant CD45RA isoform expression * DONOR: Women who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of primary graft failure without grade II-IV acute graft-versus-host disease (GVHD) | From date of transplant and up to 30 days post-transplant | Frequency and proportions will be obtained. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary graft failure rate | Up to day 365 post-transplant | — |
| Occurrence of grade 3 or 4 treatment-emergent AEs | From date of transplant up to 100 days post-transplant | Will be classified by severity and graded according to the NCI CTCAE v 6.0. Frequency and proportions will be obtained. |
| Incidence of acute GVHD | From date of transplant up to 100 days post-transplant | — |
| Overall survival | From transplant to death from any cause, assessed up to day 365 post-transplant | The Kaplan-Meier (KM) method will be used to estimate the median and percentiles for time-to-event endpoints with 95% confidence intervals (CIs). |
| Progression-free survival | From transplant to progressive disease or death, assessed up to 365 days post-transplant | The KM method will be used to estimate the median and percentiles for time-to-event endpoints with 95% CIs. |
| Time to relapse | From transplant to disease progression, initiation of new anti-multiple myeloma treatment, or death, whichever occurs first, assessed up to 365 days post-transplant | — |
| Non-relapse mortality | From transplant to death from any cause not including disease progression, assessed up to 365 days post-transplant | Will be analyzed using the cumulative incidence function to account for the competing risk of disease relapse/progression. |
| Number of treatment-related adverse events (AEs) | From date of enrollment up to 100 days post-transplant | Will be classified by severity and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 6.0. Frequency and proportions will be obtained. |
| Incidence of GVHD free, relapse free survival | From date of transplant up to 365 days post-transplant | The KM method will be used to estimate the median and percentiles for time-to-event endpoints with 95% CIs. |
| Incidence of chronic GVHD | From date of transplant up to 100 days post-transplant | — |
Countries
United States
Contacts
CONTACTOffice of Clinical Research
PRINCIPAL_INVESTIGATORMehrdad Abedi
University of California, Davis
Outcome results
None listed