Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

Phase 2

Completed

Conditions: Multiple Myeloma

Interventions: Biological: bb2121

Registration Number: NCT03361748

Lead Sponsor: Celgene

Brief Summary: This is an open label, single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory multiple myeloma. A leukapheresis procedure will be performed to manufacture bb2121 chimeric antigen receptor (CAR) modified T cells. Prior to bb2121 infusion subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide.

Detailed Description: Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 149

Inclusion Criteria

Eligibility is determined prior to leukapheresis. Subjects must satisfy the following criteria to be enrolled in the study:

Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
Documented diagnosis of multiple myeloma
- Must have received at least 3 prior MM treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen.
- Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen.
- Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.
- Must be refractory to the last treatment regimen.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Subjects must have measurable disease, including at least one of the criteria below:
- Serum M-protein greater or equal to 1.0 g/dL
- Urine M-protein greater or equal to 200 mg/24 h
- Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal
Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy.

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment:

Subjects with known central nervous system involvement with myeloma.
History or presence of clinically relevant central nervous system (CNS) pathology.
Subjects with active or history of plasma cell leukemia.
Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease
Inadequate organ function
Ongoing treatment with chronic immunosuppressants
Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy
Evidence of human immunodeficiency virus (HIV) infection.
Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV)
Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV)
Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months.
Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission
Pregnant or lactating women.
Subject with known hypersensitivity to any component of bb2121 productThe presence of any of the following will exclude a subject from enrollment:
Subjects with known central nervous system involvement with myeloma. 2. History or presence of clinically relevant central nervous system (CNS) pathology.
Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5. Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy 8. Evidence of human immunodeficiency virus (HIV) infection. 9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) 10. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. 11. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission 12. Pregnant or lactating women. 13 Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, or tocilizumab.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Administration of bb2121	bb2121	bb2121 autologous CAR T cells will be infused at a dose ranging from 15 - 450 x 10\^6 CAR+ T cells after receiving lymphodepleting chemotherapy.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	From first dose to 24 Months	Number of participants who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an independent response committee (IRC).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Safety Related Events	From screening to the end of follow up (approximately 5 years and 2 months)	Number of participants with adverse events (AEs), adverse events of special interest (AESI), serious adverse events (SAEs), cytokine release syndrome, neurotoxicity, infection and clinically signifcant laboratory abnormalities.
Complete Response Rate	From first dose to 24 Months	Percentage of participants who achieved CR or sCR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC.
Cmax	From first dose to the end of follow up (Approximately 5 years)	Cmax is defined as the maximum transgene level at Tmax Tmax: The time of maximum observed transgene level, obtained directly from the observed transgene level - time.
Time to Response	From first dose to initial response (approximately on average 1.2 months, max of 8.8 months)	Time from first bb2121 infusion to first documentation of response of PR or better.
Duration of Response	From first dose to 24 months after first dose	Time from first documentation of response or PR or better to first documentation of disease progression or death from any cause, whichever occurs first.
Progression Free Survival (PFS)	From first dose to 24 months after first dose	Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first.
Time to Progression (TTP)	From first dose to 24 months after first dose	Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first.
AUC 0-9M	at 9 months post first dose (Approximtately 9 Months)	The AUC of the transgene level from the time of dosing to 9 months
Tmax	From first dose to the end of follow up (Approximately 5 years)	Tmax: The time of maximum observed transgene level, obtained directly from the observed transgene level - time.
Number of Participants With Anti-CAR-Antibodies	From first dose to the end of follow up (Approximately 5 years)	Number of Participants with Anti-CAR-Antibodies. Pre-postive is defined by last value before or on bb2121 infusion date is positive Post-positve is defined by at least one positive value post bb2121 infusion.
Overall Survival	From screening to the end of follow up (approximately 5 years and 2 months)	Time from first bb2121 infusion to time of death due to any cause.
Mean Change From Baseline on the EORTC QLQ-C30 - Physical Functioning	At Day 1 and at specific time points up to month 24	The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100 and an average will be taken. This average is the overall score. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning.
Percentage of Participants Who Achieved >= VGPR and MRD Negative Status	From screening to the end of follow up (Approximately 5 years and 2 months)	Percentage of participants who achieved ≥ VGPR and MRD negative status at a sensitivity of 10-⁵ at any time point within 3 months prior to achieving at least VGPR until the time of PD/death. MRD in the bone marrow will be measured using both next generation sequencing (NGS) techniques measuring immunoglobulin gene rearrangements of the malignant clone. MRD will be reported with a sensitivity of 10-⁴, 10-⁵, and 10-⁶ nucleated cells. The primary analysis for MRD negative response will use the sensitivity of 10-⁵. MRD = Minimal Residual Disease PD = Progressive Disease VGPR = Very good partial response.
Mean Change From Baseline on the EORTC QLQ-C30 - Fatigue.	At Day 1 and at specific time points up to month 24	Mean change from baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-C30 - Pain	At Day 1 and at specific time points up to month 24	Mean change from baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-C30 - Cognitive Functioning	At Day 1 and at specific time points up to month 24	The QLQ-C30 employs a week recall period for all items. All items will be scored from 0 to 100 and an average will be taken. This average is the overall score. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning.
Mean Change From Baseline on the EORTC QLQ-C30 - Global Heath/QoL	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-C30 The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A higher scale score represents a higher level of well-being and better ability of daily functioning. Thus, a high score for a functional scale represents a high/healthy level of functioning; a high score for the global health status/HRQoL represents a high HRQoL.
Mean Change From Baseline on the EORTC QLQ-MY20 - Disease Symptoms	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-MY20 The EORTC has developed a myeloma module referred to as QLQ- MY20, to be administered alongside the core QLQ-C30. The QLQ-MY20 is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EORTC QLQ-MY20 - Side Effects	At Day 1 and at specific time points up to month 24	Mean change from baseline on the EORTC QLQ-MY20 The EORTC has developed a myeloma module referred to as QLQ- MY20, to be administered alongside the core QLQ-C30. The QLQ-MY20 is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality. All items will be scored from 0 to 100. The average of the scores will represent the symptoms score. A high score for a symptom scale/item represents a high level of symptomatic problem.
Mean Change From Baseline on the EQ-5D-5L Index	At Day 1 and at specific time points up to month 24	The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index (HUI) is assessed using the Crosswalk algorithm for France based on the individual responses to the 5 EQ-5D-5L domains ranging from -0.530 to 1.000. The smallest change considered clinically meaningful, is defined as a score difference of 0.08 points.

Trial Locations

Locations (48): University of California - San Francisco
🇺🇸
San Francisco, California, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Mayo Clinic
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Rochester, Minnesota, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Mt. Sinai Medical Center
🇺🇸
New York, New York, United States
Sarah Cannon Research Institute
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Nashville, Tennessee, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Universitaire Ziekenhuizen Leuven
🇧🇪
Leuven, Flemish Brabant, Belgium
Princess Margaret Cancer Centre
🇨🇦
Toronto, Canada
Centre Hospitalier Regional Universitaire de Lille-Hopital Calude Huriez Service des Maladies du Sang
🇫🇷
Lille, Hauts-de-France, France
Centre Hospitalier Universitaire de Nantes - Hotel Dieu
🇫🇷
Nantes, Pays De La Loire, France
Universitatsklinikum Heidelberg Medizinische Klinik Krehl-Klinik Haematologie, Onkologie, Rheumato
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Heidelberg, Baden-Württemberg, Germany
University of Tübingen
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Tübingen, Baden-Württemberg, Germany
Universitatsklinikum Würzburg
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Würzburg, Bavaria, Germany
Azienda Ospedaliero Universitaria Di Bologna Policlinico
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Bologna, Emilia-Romagna, Italy
Ospedali Riuniti di Bergamo
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Bergamo, Italy
Tokai University Hospital
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Isehara, Kanagawa, Japan
Jichi Medical University Hospital
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Shimotsuke, Tochigi, Japan
Japan Red Cross Medical Center
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Shibuya-ku, Tokyo, Japan
Tokyo Women's Medical University Hospital
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Shinjuku City, Japan
Hospital Universitari Germans Trias i Pujol Can Ruti
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Badalona, Barcelona, Spain
Clinica Universidad de Navarra
🇪🇸
Pamplona, Navarre, Spain
Local Institution - 108
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San Francisco, California, United States
Local Institution - 103
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Atlanta, Georgia, United States
Local Institution - 107
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Boston, Massachusetts, United States
Local Institution - 106
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Boston, Massachusetts, United States
Local Institution - 105
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Rochester, Minnesota, United States
Local Institution - 102
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Hackensack, New Jersey, United States
Local Institution - 109
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New York, New York, United States
Local Institution - 101
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Nashville, Tennessee, United States
Local Institution - 104
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Dallas, Texas, United States
Local Institution - 201
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Leuven, Belgium
Local Institution - 301
🇨🇦
Toronto, Ontario, Canada
Local Institution - 402
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Lille, France
Local Institution - 401
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Nantes, France
Local Institution - 502
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Heidelberg, Germany
Local Institution - 503
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Tübingen, Germany
Local Institution - 501
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Würzburg, Germany
Local Institution - 602
🇮🇹
Bergamo, Italy
Local Institution - 601
🇮🇹
Bologna, Italy
Local Institution - 803
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Isehara City, Kanagawa, Japan
Local Institution - 801
🇯🇵
Shibuya-ku, Japan
Local Institution - 802
🇯🇵
Shimotsuke, Japan
Local Institution - 804
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Shinjuku City, Japan
Local Institution - 702
🇪🇸
Badalona (Barcelona), Spain
Local Institution - 701
🇪🇸
Pamplona, Spain