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Anti-BCMA Chimeric Antigen Receptor T Cells for Relapsed or Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05577000
Recruitment Status : Recruiting
First Posted : October 13, 2022
Last Update Posted : January 10, 2023
Sponsor:
Collaborators:
Actavis Inc.
University of California, Davis
Eugia Pharma Specialities Limited
Information provided by (Responsible Party):
Thomas Martin, MD, University of California, San Francisco

Brief Summary:
This is an open-label study to determine the safety of anti-B-cell maturation antigen (BCMA) Chimeric antigen receptor T-cell (CAR T) therapy in participants with Relapsed or Refractory Multiple Myeloma (RRMM).

Condition or disease Intervention/treatment Phase
Refractory Multiple Myeloma Relapsed Multiple Myeloma Biological: Manufactured Anti-BCMA CAR-T cells Drug: Fludarabine Drug: Cyclophosphamide Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

  1. To evaluate the safety of administering chimeric antigen receptor (CAR)-T cells targeting BCMA to participants with RRMM (Dose Escalation).
  2. To determine the maximum tolerated dose (MTD) for anti-BCMA CAR-T cells (Dose Escalation).
  3. Determine whether administering chimeric antigen receptor T cells targeting BCMA to participants with RRMM increases the overall response rate (ORR) in RRMM compared with historical data for non-CAR agents per International Myeloma Working Group (IMWG) response criteria (Dose Expansion).

SECONDARY OBJECTIVES:

Dose Expansion Only:

  1. To describe the efficacy of CAR-T cells targeting BCMA in participants with RRMM.
  2. To evaluate the feasibility of manufacturing anti-BCMA CAR-T cells locally and ability to produce adequate quantities of vector positive T-cells.
  3. To evaluate the safety and toxicity of CAR-T cells targeting BCMA to participants with RRMM

OUTLINE:

Participants will be enrolled sequentially to each dose level dependent on analysis of dose-limiting toxicities at the previous dose level. A dose expansion will occur at the maximum tolerated dose (MTD). Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells drug product (DP), participants will undergo lymphodepleting chemotherapy with fludarabine (and cyclophosphamide. Participants will undergo an additional evaluation of eligibility on Day -1 or 1 prior to infusion of anti-BCMA CAR-T cell product. A single infusion of anti-BCMA CAR-T cells at the starting dose will be given on Day 1. Following treatment with DP, participants will be followed up at 12 months and annually for up to 15 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Clinical Trial of Anti-BCMA Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : October 18, 2021
Estimated Primary Completion Date : October 31, 2025
Estimated Study Completion Date : October 1, 2039

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Fludarabine

Arm Intervention/treatment
Experimental: Dose Escalation (150 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the starting dose of 150 x 10^6 flat dose will then be given on Day 1.
Biological: Manufactured Anti-BCMA CAR-T cells
Given IV
Other Name: Anti-BCMA CAR-T cells

Drug: Fludarabine
Given IV
Other Name: Fludara

Drug: Cyclophosphamide
Given IV
Other Name: Cytoxan

Experimental: Dose Escalation (450 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 450 x 10^6 flat dose will then be given on Day 1.
Biological: Manufactured Anti-BCMA CAR-T cells
Given IV
Other Name: Anti-BCMA CAR-T cells

Drug: Fludarabine
Given IV
Other Name: Fludara

Drug: Cyclophosphamide
Given IV
Other Name: Cytoxan

Experimental: Dose Escalation (600 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 600 x 10^6 flat dose will then be given on Day 1.
Biological: Manufactured Anti-BCMA CAR-T cells
Given IV
Other Name: Anti-BCMA CAR-T cells

Drug: Fludarabine
Given IV
Other Name: Fludara

Drug: Cyclophosphamide
Given IV
Other Name: Cytoxan

Experimental: Dose Expansion: Maximum Tolerated Dose (MTD)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the MTD will then be given on Day 1.
Biological: Manufactured Anti-BCMA CAR-T cells
Given IV
Other Name: Anti-BCMA CAR-T cells

Drug: Fludarabine
Given IV
Other Name: Fludara

Drug: Cyclophosphamide
Given IV
Other Name: Cytoxan




Primary Outcome Measures :
  1. Proportion of participants with treatment-emergent adverse events (AE) (Dose Escalation) [ Time Frame: From initiation of study treatment (day 1) to 29 days following CAR-T infusion ]
    Proportion of participants with treatment-emergent adverse events of CAR-T as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, revised cytokine release syndromeCRS grading criteria (for CRS), and American Society of Transplantation and Cellular Therapy (ASTCT) Immune Effector Cell Associated Neurotoxicity (ICANS) Consensus Grading for Adults (for neurotoxicity).

  2. Proportion of participants who experience a dose-limiting toxicity (DLT) (Dose Escalation) [ Time Frame: From initiation of study treatment (day 1) to 29 days following CAR-T infusion ]
    The DLT evaluable analysis set includes all participants in the dose-finding part of the study who have received the anti-BCMA CAR-T cell product, and who have either experienced a DLT or were followed for the full DLT evaluation period (within 28 days following infusion of CAR-T cells targeting BCMA). The MTD is defined as the dose level immediately below that in which >=2/6 participants experience a DLT and will be used to determine the recommended Phase 2 dose for future studies.

  3. Overall Response Rate (ORR) [ Time Frame: Up to 12 months following CAR- T infusion ]
    Overall response rate includes participants with a demonstrated Stringent Complete Response (sCR), Complete Response (CR), Partial Response (PR), or Very Good Partial Response (VGPR) per International Myeloma Working Group (IMWG) criteria reported as proportion with 90% binomial confidence interval for the expansion cohort including the patients on MTD in the dose escalation cohort


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: Up to 12 months following CAR- T infusion ]
    This is measured, only in responders, from the documented beginning of response (sCR, CR, PR or VGPR) to the time of progression per IMWG criteria for the expansion cohort including the patients on MTD in the dose escalation cohort

  2. Progression-free Survival (PFS) [ Time Frame: Up to 12 months following CAR- T infusion ]
    PFS is defined as the rate of survival from the the time from entry onto study until MM progression by IMWG criteria, or death from any cause for the expansion cohort including the patients on MTD in the dose escalation cohort.

  3. Overall Survival [ Time Frame: Up to 15 years ]
    Overall Survival is defined as the time from entry onto study until multiple myeloma progression or death from any cause. and will be be analyzed by Kaplan-Meier method for the expansion cohort including the patients on MTD in the dose escalation cohort.

  4. Proportion of participants for whom BCMA CAR T-cell therapy is manufactured successfully [ Time Frame: From initiation of CAR T-cell manufacturing to end of infusion, up to 21 days ]
    Participants who have anti-BCMA CAR T-cells successfully manufactured locally and are able to produce adequate quantities of vector positive T-cells which meet pre-specified release criteria.

  5. Proportion of participants who complete study treatment [ Time Frame: From initiation of CAR T-cell manufacturing to end of infusion, up to 21 days ]
    Participants who have anti-BCMA CAR T-cells successfully manufactured locally and are able to produce adequate quantities of vector positive T-cells which meet pre-specified release criteria which are then infused with the drug product.

  6. Proportion of participants with treatment-emergent adverse events (AE) (Dose Expansion) [ Time Frame: From initiation of CAR T-cell manufacturing to end of first follow-up, approximately 13 months ]
    Proportion of participants with treatment-emergent adverse events of CAR-T as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, revised cytokine release syndrome CRS grading criteria (for CRS), and American Society of Transplantation and Cellular Therapy (ASTCT) Immune Effector Cell Associated Neurotoxicity (ICANS) Consensus Grading for Adults (for neurotoxicity).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligibility for enrollment:

Inclusion Criteria:

  1. Voluntarily sign informed consent form
  2. >=18 years of age at the time of signing informed consent
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  4. Diagnosis of MM with relapsed or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor (PI; e.g., bortezomib or carfilzomib) immunomodulatory therapy (IMiD; e.g., lenalidomide or pomalidomide), and anti-CD38 antibody therapy
  5. Participants must have measurable disease, including at least one of the criteria below:

    1. Serum M-protein greater or equal to 0.5 g/dL.
    2. Urine M-protein greater or equal to 200 mg/24 h.
    3. Serum free light chain (FLC) assay: involved FLC level of >= 100 mg/L.
  6. Adequate organ function, defined as:

    1. Hemoglobulin >8 gm/dl (transfusions allowed).
    2. Platelets >50,000/microliter (uL) (in the absence of platelet transfusion within 7 days of apheresis, but transfusion permitted prior to lymphodepleting chemotherapy).
    3. Absolute neutrophil count (ANC) > 1000/uL in the absence of growth factor support (filgrastim within 7 days or pegfilgrastim within 14 days of apheresis, but growth factor permitted prior to lymphodepleting chemotherapy).
    4. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x institutional upper limit of normal (ULN).
    5. Total bilirubin =< 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome.
    6. Serum creatinine clearance (CrCl) >= 45 mL/min using Cockcroft-Gault formula.
    7. Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA).
  7. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-BCMA CAR-T cells.
  8. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method.

Exclusion Criteria:

  1. Autologous transplant within 6 weeks of planned CAR-T cell infusion.
  2. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast). Any fully treated malignancies or indolent, clinically insignificant malignancies can be discussed among the study team to determine eligibility.
  3. HIV seropositivity.
  4. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded).
  5. Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pulmonary abnormalities, or psychiatric illness/social situations that would limit compliance with study requirements.
  6. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
  7. Patients with currently symptomatic central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia, and Parkinson's disease.
  8. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.

Eligibility for Infusion of Investigational Product:

Includes the inclusion/exclusion criteria required for enrollment with the following exceptions and additions.

Inclusion criteria exceptions:

  1. Hematologic function parameters will not be included as a pre-infusion eligibility criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).
  2. Laboratory result abnormalities that are considered not clinically significant by the principal investigator, AND are not the result of a demonstrated active infection or an active central nervous system condition.

Exclusion criteria additions:

  1. Use of anti-multiple myeloma therapy, including systemic corticosteroids within 14 days prior to lymphodepletive chemotherapy.
  2. Neurologic symptoms suggestive of an active central nervous system condition.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05577000


Contacts
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Contact: HDFCCC Cancer Immunotherapy Program 877-827-3222 HDFCCC.CIP@ucsf.edu

Locations
Layout table for location information
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: HDFCCC Cancer Immunotherapy Program    877-827-3222    HDFCCC.CIP@ucsf.edu   
Contact       cancertrials@ucsf.edu   
Principal Investigator: Thomas Martin, MD         
Sponsors and Collaborators
Thomas Martin, MD
Actavis Inc.
University of California, Davis
Eugia Pharma Specialities Limited
Investigators
Layout table for investigator information
Principal Investigator: Thomas Martin, MD University of California, San Francisco
Layout table for additonal information
Responsible Party: Thomas Martin, MD, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT05577000    
Other Study ID Numbers: 22702
22-37359 ( Other Identifier: University of California, San Francisco )
First Posted: October 13, 2022    Key Record Dates
Last Update Posted: January 10, 2023
Last Verified: January 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Thomas Martin, MD, University of California, San Francisco:
CAR-T Therapies
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Idecabtagene vicleucel
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological