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Recurrent Plasma Cell MyelomaPhase 1NCT03502577

BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma

A Phase 1 study testing BCMA-specific CAR-expressing T Lymphocytes, Cyclophosphamide and Fludarabine in people with Recurrent Plasma Cell Myeloma and Refractory Plasma Cell Myeloma, run by Fred Hutchinson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This phase I trial determines the side effects and best dose of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T-cells when combined with gamma-secretase inhibitor LY3039478 (JSMD194), cyclophosphamide, and fludarabine in treating participants with multiple myeloma that that has come back or remains… Read more about this study

Who is it for?
Ages 21 years and older
What is being tested?
BCMA-specific CAR-expressing T Lymphocytes, Cyclophosphamide and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
1 siteUnited States
Study dates
23 May 2018to 20 Apr 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Eastern Cooperative Oncology Group (ECOG) performance status score =< 2
  • Have measurable disease by International Myeloma Working Group (IMWG) criteria based on one or more of the following findings:
  • Serum monoclonal immunoglobulin (M-protein) >= 1 g/dL
  • Urine M-protein >= 200 mg/24 hour
  • Involved serum free light chain (sFLC) level >= 10 mg/dL with abnormal kappa/lambda ratio
  • Measurable biopsy-proven plasmacytomas (>= 1 lesion that has a single diameter >= 2 cm)
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  • Bone marrow plasma cells >= 30%
  • Have a diagnosis of multiple myeloma (MM); the MM diagnosis must be confirmed by internal pathology review of a fresh biopsy specimen at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance (FHCRC/SCCA)
  • Have relapsed or treatment refractory disease with >= 10% CD138+ malignant plasma cells immunohistochemistry (IHC) on BM core biopsy, either:
  • Following autologous stem-cell transplantation (ASCT)
  • Or, if a patient has not yet undergone ASCT, the individual must:
  • Be transplant ineligible, due to age, comorbidity, patient choice, insurance reasons, concerns of rapidly progressive disease, and/or discretion of attending physician and principal investigator and,
  • Demonstrate disease that persists after > 4 cycles of induction therapy and that is double refractory (persistence/progression) after therapy with both a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) administered either in tandem, or in sequence, or demonstrate intolerance to both classes of agents (IMiD and PI); > 4 cycles of therapy are not required for patients with a diagnosis of plasma cell leukemia
  • Male and female patients of reproductive potential must be willing to use an effect contraceptive method before, during, and for at least 4 months after the BCMA CAR T cell infusion

Who cannot join

  • History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year (the following are exempt from the 1-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, curatively treated superficial bladder cancer and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear)
  • Active hepatitis B, hepatitis C at the time of screening
  • Patients who are human immunodeficiency virus (HIV) seropositive
  • Subjects with uncontrolled active infection
  • > 1 hospital admission for infection in prior 6 months
  • Presence of acute or chronic graft-versus-host disease (GVHD) unless limited to skin involvement and managed with topical steroid therapy alone
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  • History of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease as determined by the principal investigator (PI) or designee
  • History of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active central nervous system MM involvement and/or carcinomatous meningitis; subjects with previously treated central nervous systems involvement may participate, provided they are free of disease in the CNS (documented by flow cytometry performed on the cerebrospinal fluid [CSF] within 14 days of enrollment) and have no evidence of new sites of CNS activity
  • Pregnant or breastfeeding females
  • Allogeneic hematopoietic stem cell transplantation (HSCT) or donor lymphocyte infusion within 90 days of leukapheresis
  • Use of any of the following:
  • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis; physiologic replacement, topical, and inhaled steroids are permitted
  • Cytotoxic chemotherapeutic agents within 1 week of leukapheresis; oral chemotherapeutic agents are allowed if at least 3 half-lives have elapsed prior to leukapheresis
  • Lymphotoxic chemotherapeutic agents within 2 weeks of leukapheresis
  • Experimental agents within 4 weeks of leukapheresis unless progression is documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis
  • Daratumumab (or other anti-CD38 therapy) within 30 days of leukapheresis
  • Absolute neutrophil count (ANC) < 1000/mm^3, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Hemoglobin (Hgb) < 8 mg/dl, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Platelet count < 50,000/mm^3, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Active autoimmune disease requiring immunosuppressive therapy
  • Creatinine clearance < 20 ml/min
  • Significant hepatic dysfunction (serum glutamic-oxaloacetic transaminase [SGOT] > 5 x upper limit of normal; bilirubin > 3.0 mg/dL)
  • Forced expiratory volume in one second (FEV1) of < 50% predicted or carbon monoxide diffusing capacity (DLCO) (corrected) < 40% (patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing)
  • Anticipated survival of < 3 months
  • Contraindication to cyclophosphamide or fludarabine chemotherapy
  • Patients with known amyloidosis (AL) subtype amyloidosis
  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the investigator; or unwillingness or inability to follow the procedures required in the protocol
  • Documented malabsorptive syndromes including enteropathies, gastroenteritis (acute or chronic) or diarrhea (acute or chronic)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: A Phase I Study of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells in Combination With JSMD194, a Small Molecule Inhibitor of Gamma Secretase, in Patients With Relapsed or Persistent Multiple Myeloma

This phase I trial determines the side effects and best dose of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T-cells when combined with gamma-secretase inhibitor LY3039478 (JSMD194), cyclophosphamide, and fludarabine in treating participants with multiple myeloma that that has come back or remains despite treatment. Placing genes added in the laboratory into immune T-cells may make the T-cells recognize BCMA, a protein on the surface of cancer cells. JSMD194 may enhance the killing of cancer cells by increasing the BCMA expression on multiple myeloma cells, making the targeted BCMA CAR-T treatment more effective. JSMD194 also decreases the amount of BCMA found in the circulation (called soluble BCMA) that is not bound to the myeloma cells. JSMD194 can therefore reduce the potential for soluble BCMA to act as a decoy. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BCMA CAR T therapy with JSMD194, cyclophosphamide, and fludarabine may work better in treating participants with relapsed or persistent multiple myeloma.

Read the detailed description

OUTLINE: This is a dose escalation study of BCMA-specific CAR T-cells.

Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells intravenously (IV) over 20-30 minutes on day 0 and gamma-secretase inhibitor LY3039478 orally (PO) on days 2, 4, 7, 9, 11, 14, 16, and 18. Patients will also receive JSMD194 orally before the fludarabine and cyclophosphamide to evaluate the effect of this drug alone on multiple myeloma cell BCMA levels.

After completion of study treatment, participants are followed up every 6 months for years 1-5 and annually for years 6-15.

Being tested
BCMA-specific CAR-expressing T Lymphocytes, Cyclophosphamide, Fludarabine, Gamma-Secretase Inhibitor LY3039478, Laboratory Biomarker Analysis
Medical subject headings
Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BCMA-specific CAR-expressing T LymphocytesBiological

    Also called Anti-BCMA CAR T Cells, Anti-BCMA-CAR-transduced T Cells

    Receive CAR T infusion

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • FludarabineDrug

    Also called Fluradosa

    Given IV

  • Gamma-Secretase Inhibitor LY3039478Drug

    Also called LY 3039478, LY-3039478, LY3039478, JSMD194

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacokinetic StudyOther

    Also called PHARMACOKINETIC, PK Study

    Correlative studies

Study groups in NCT03502577
Study groupRoleWhat they receive
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)ExperimentalParticipants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Receives: Biological: BCMA-specific CAR-expressing T Lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Gamma-Secretase Inhibitor LY3039478; Other: Laboratory Biomarker Analysis; Other: Pharmacokinetic Study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells

    This is defined as the dose associated with a true dose-limiting toxicity (DLT) rate of 25% in each of the cohorts. DLTs are events that occur within the first 28 days following CAR T-cell infusion.

    Measured: Up to 28 days following CAR T-cell infusion

  2. Incidence of general toxicities

    This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

    Measured: Up to 1 year

Secondary outcomes (5)

  1. Objective response rate of complete remission and partial remission

    Measured: Up to 1 year

  2. Progression-free survival

    Measured: Up to 1 year

  3. Overall survival

    Measured: Up to 1 year

  4. Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells

    Measured: Up to 1 year

  5. Evaluation of the migration of adoptively transferred BCMA CAR T cells

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2018
  2. Study start23 May 2018
  3. Primary completion20 Apr 2022
  4. Study completion20 Apr 2022

Why it stopped: Closed per SRC Low Accrual Policy

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03502577
Sponsor's protocol ID
9952
Other IDs
NCI-2018-00514, 9952, RG9218033
Status last verified
Dec 2023
First submitted
11 Apr 2018
Last updated
8 Jan 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN 3rd, Coffey DG, Tuazon SA, Wood B, Gooley T, Wu VQ, Voutsinas J, Song X, Shadman M, Gauthier J, Chapuis AG, Milano F, Maloney DG, Riddell SR, Green DJ. gamma-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Jul;24(7):811-822. doi: 10.1016/S1470-2045(23)00246-2.

    PubMed 37414012

  • Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR. gamma-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019 Nov 7;134(19):1585-1597. doi: 10.1182/blood.2019000050.

    PubMed 31558469

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing BCMA-specific CAR-expressing T Lymphocytes, Cyclophosphamide and Fludarabine in people with Recurrent Plasma Cell Myeloma and Refractory Plasma Cell Myeloma, run by Fred Hutchinson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Closed per SRC Low Accrual Policy). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells (time frame: Up to 28 days following CAR T-cell infusion). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03502577, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jan 2024.

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