This study has been transitioned to CTIS with ID 2023-509848-10-00 check the CTIS register for the current data. Primary Objective: • Compare the efficacy of bb2121 to standard regimens in subjects with RRMM as measured by progression-free survival…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression-free Survival (PFS): Time from randomization to the first
documentation of progressive disease based on the International Myeloma Working
Group (IMWG) Uniform Response Criteria for Multiple Myeloma (Kumar, 2016)
assessed by an independent response committee (IRC) or death due to any cause
Secondary outcome
Key secondary
- Overall Response Rate (ORR): Percentage of subjects who achieved partial
response (PR) or better according to IMWG Uniform Response Criteria for
Multiple Myeloma (Kumar, 2016) as assessed by an IRC
- Overall Survival (OS): Time from randomization to time of death due to any
cause
Other secondary
- Event-free Survival (EFS): Time from randomization to the first documentation
of progressive disease, first day when subject receives another anti-myeloma
treatment or death due to any cause, whichever occurs first
- Minimal Residual Disease (MRD): Evaluate subjects for MRD status using next
generation sequencing (NGS)
- Complete Response (CR) Rate: Percentage of subjects who achieved CR or better
according to IMWG Uniform Response Criteria for Multiple Myeloma (Kumar, 2016)
as assessed by an IRC
- Duration of Response (DOR): Time from first documentation of response (PR or
better) to first documentation of disease progression or death from any cause,
whichever occurs first
- Time to Response (TTR): Time from randomization to the first documentation of
response (PR or better)
- Safety: Type, frequency, severity of adverse events (AEs), adverse events of
special interest (AESIs), and serious adverse events (SAEs)
- Pharmacokinetics (PK) - bb2121: Maximum peak in bb2121 chimeric antigen
receptor (CAR) T cells (Cmax), time to peak of bb2121 CAR T cells (tmax), area
under the curve of CAR T cells (AUC), time to last measurable CAR T cells
(tlast), area under the curve of CAR T cells from time zero to Day 28
(AUC0-28days) including maximum expansion and duration of persistence of bb2121
CAR T cells
- Primary Domains of Interest Health Related Quality of Life (HRQoL): Changes
in subject-reported health related quality of life and multiple myeloma-related
symptoms as measured by the selected domains of European Organization for
Research and Treatment of Cancer - Quality of Life C30 questionnaire
(EORTC-QLQ-C30), specifically GH/QoL, physical functioning, pain, fatigue, and
cognitive functioning and the disease symptoms and side effects of treatment
measured by European Quality of Life Multiple Myeloma Module (EORTC-QLQ-MY20)
- Time to next anti-myeloma treatment: Time from randomization to first day
when subject receives another anti-myeloma treatment
- Progression-free survival after next line therapy (PFS2): Time from
randomization to second objective disease progression or death from any cause,
whichever is first
Background summary
Disease background Multiple myeloma (MM) is a largely incurable blood cancer
characterized by the clonal proliferation of malignant plasma cells both within
the bone marrow (BM) and at localized extramedullary sites termed plasmacytomas
(Rajkumar, 2016). The major clinical features of MM reflect both the abnormal
plasma cell proliferation in local organs/tissues as well as pathologic
monoclonal proteins produced by the MM cells. These clinical manifestations
include infections, bleeding, anemia, hypercalcemia, bone pain/fractures
(related directly to bone/BM involvement by MM cells) as well as kidney damage
and hyperviscosity (related to pathologic monoclonal proteins). Multiple
myeloma is at the aggressive end of a spectrum of diseases referred to as
plasma cell dyscrasias (PCD) and is often preceded for months/years by an
asymptomatic condition known as monoclonal gammopathy of undetermined
significance (MGUS) (Rajkumar, 2016). Multiple myeloma accounts for
approximately 10% to 15% of all hematologic malignancies with a global
incidence of approximately 120,000 cases per year (Ludwig, 2014) and primarily
affects older individuals. The median age at onset is 66 years and it is very
rare in patients less than 30 years old (Moreau, 2013; Rajkumar, 2016; Kumar,
2017). Approximately 38,900 new cases and 24,300 deaths were estimated in
Europe in 2012, representing an age-standardized incidence rate of 2.6 per
100,000 (Ferlay, 2013). The point prevalence in the European Union (EU) is
estimated to be approximately 3.6 per 10,000 (bb2121 orphan designation,
EU/3/17/1863). According to the National Cancer Institute Surveillance,
Epidemiology, and End Results (SEER) Program in 2015 (National Cancer
Institute, 2019), there were an estimated 124,733 people living with myeloma in
the United States. In 2018, in the United States, 12,770 deaths from MM are
estimated to occur (National Cancer Institute, 2019). Progress has been made in
improving the overall survival (OS) in newly diagnosed MM (NDMM) patients. The
increase in survival has been driven by more effective combination induction
regimens composed primarily of proteasome inhibitors (PIs), immunomodulatory
(IMiD) compounds and dexamethasone coupled with consolidation using autologous
stem cell transplantation (ASCT) (Moreau, 2013; Rajkumar, 2016; Kumar, 2017).
Unfortunately, even with optimal up-front therapy, the vast majority of MM
patients progress or relapse and therefore further treatment is needed. For
these relapsed and refractory MM (RRMM) patients, treatment options have also
improved over time. With the introduction of newer classes of approved
anti-myeloma agents, including monoclonal antibodies (daratumumab and
elotuzumab), advanced generation proteasome inhibitors (PIs; carfilzomib,
ixazomib), IMiD compounds (eg, pomalidomide [POM]) and histone deacetylase
inhibitors (panobinostat), RRMM patients can expect some degree of response
(San-Miguel, 2014; Lonial, 2015; Stewart, 2015; Dimopoulos, 2016; Dimopoulos,
2016; Moreau, 2016; Palumbo, 2016; Botta, 2017). Despite these advances in the
treatment of MM, and regardless of treatment, the vast majority of the patients
will ultimately relapse. Additionally, with each relapse, tumors typically
recur more aggressively, leading to decreased response duration and ultimately
leading to refractory MM, which is associated with shortened survival times.
There are many factors that influence the choice of therapy in the RRMM
setting, including age, performance status, comorbidities, the type, efficacy
and tolerance of the previous treatment, the number of prior treatment lines,
the available remaining treatment options, the interval since the last therapy,
and the type of relapse (clinical versus biochemical) (Moreau, 2017). Although
there are several treatments available for relapsed patients, they have limited
ef*cacy. In particular patients who have had successive relapses or who are
refractory to treatment have poor survival (Kumar, 2017). A recent
retrospective analysis of real-world survival outcomes reported a median OS of
only 7.9 months in patients with > 3 prior lines of therapy, including a PI
or an IMiD compound, or who were double refractory to a PI and an IMiD compound
(Usmani, 2016). Compound Background bb2121 is defined as an autologous T
lymphocyte-enriched population that contains cells transduced with an
anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)
(anti-BCMA02 CAR) lentiviral vector encoding a chimeric antigen receptor
targeting human B cell maturation antigen. Anti-BCMA02 CAR lentiviral vector is
used to transduce autologous T cells. This vector uses the murine leukemia
virus-derived myeloproliferative sarcoma virus enhanced promoter to drive
expression of the chimeric receptor, a multi-domain protein consisting of the
extracellular antigen recognition domain (light chain variable domain [VL] and
heavy chain variable domain [VH]), the CD8α hinge domain, a transmembrane
domain (CD8 TM), and the intracellular CD137 co-stimulatory (4-1BB) and CD3zeta
chain signaling domains. Preclinical pharmacology of bb2121 showed desirable
specificity against BCMA and potent activity of the CAR T cells leading to
rapid and complete elimination of BCMA expressing tumors. In vitro, bb2121 was
cytotoxic against a range of MM cell lines with varying levels of BCMA
expression and this activity was not inhibited by soluble BCMA at physiologic
concentrations in the cultures. There was no tonic signaling of bb2121 in the
absence of BCMA target engagement and no in vitro cytotoxicity induced in cell
lines lacking BCMA, underscoring the specificity of bb2121 for BCMA-expressing
target cells. In vivo models showed a selective and higher anti-tumor activity
of bb2121 in comparison to bortezomib in treatment of immune-deficient mice
with large established BCMA-expressing tumors with complete remission and
survival rates as high as 100% in mice after a single dose of bb2121. Refer to
the bb2121 Investigator*s Brochure (IB) for detailed information concerning the
available pharmacology, toxicology, drug metabolism, clinical studies, and
adverse event (AE) profile of the investigational product (IP).
Study objective
This study has been transitioned to CTIS with ID 2023-509848-10-00 check the CTIS register for the current data.
Primary Objective:
• Compare the efficacy of bb2121 to standard regimens in subjects with RRMM as
measured by progression-free survival (PFS)
Secondary Objectives:
• Evaluate the safety of bb2121 compared to standard regimens in subjects with
RRMM
• Evaluate additional efficacy parameters of bb2121 compared to standard
regimens in subjects with RRMM
• Characterize the expansion and persistence of chimeric antigen receptor (CAR)
+ T cells, in the peripheral blood (cellular kinetics-pharmacokinetics [PK])
• Evaluate the percentage of subjects who attain minimal residual disease (MRD)
negative status by next generation sequencing (NGS)
• Evaluate the impact of bb2121 compared to standard regimens on the changes in
health-related quality of life (HRQoL)
• Evaluate the impact of bb2121 on health utility values compared with standard
regimens
Study design
This is a multicenter, randomized, open-label, Phase 3 study comparing the
efficacy and safety of bb2121 versus standard regimens in subjects with RRMM.
After informed consent has been obtained, subjects will undergo screening
procedures to determine eligibility. Eligible subjects will be randomized using
an Interactive Response Technology (IRT), stratified by the following factors:
1. Age: < 65 years versus >= 65 years 2. number of prior anti-myeloma
regimens: 2 prior anti-myeloma regimens versus 3 or 4 prior anti-myeloma
regimens 3. high risk cytogenetic abnormalities; t(4;14) or t(14;16) or del
17p: presence of these known (from baseline or historical cytogenetic results)
high risk cytogenetic abnormalities versus absence or unknown presence of these
high risk cytogenetic abnormalities Subjects randomized to Treatment Arm A will
undergo leukapheresis to enable bb2121 product generation. Subjects may receive
up to 1 cycle of DPd or DVd or IRd or Kd or EPd as bridging MM therapy (refer
to Section 7.2.11.2 for DPd, DVd, IRd, Kd and EPd dosing schedule) following
leukapheresis as long as the last dose is administered >= 14 days prior to
initiation of lymphodepleting (LD) chemotherapy. The choice of bridging therapy
will be dependent on the subject*s most recent anti-myeloma treatment regimen
based on the following criteria: • Subjects who have received DARA in
combination with POM with or without dexamethasone (DP±d) as part of their most
recent anti-myeloma treatment regimen, may receive up to 1 cycle of DVd, IRd,
Kd, or EPd as bridging therapy as per Investigator*s discretion • Subjects who
have received DARA in combination with BTZ with or without dexamethasone (DV±d)
as part of their most recent anti-myeloma treatment regimen, may receive up to
1 cycle of DPd, IRd, Kd or EPd as bridging therapy as per Investigator*s
discretion • Subjects who have received IXA in combination with LEN with or
without dexamethasone (IR±d) as part of their most recent anti-myeloma
treatment regimen, may receive up to 1 cycle of DPd, Kd, EPd, DVd as bridging
therapy as per Investigator*s discretion • Subjects who have received CFZ with
or without dexamethasone (K±d) as part of their most recent anti-myeloma
treatment regimen, may receive up to 1 cycle of DPd, DVd, IRd or EPd as
bridging therapy as per Investigator*s discretion • Subjects who have received
ELO in combination with POM with or without dexamethasone (EP±d) as part of
their most recent anti-myeloma treatment regimen, may receive up to 1 cycle of
DPd, DVd, IRd or Kd as bridging therapy as per Investigator*s discretion •
Subjects who have not received DP±d or DV±d or IR±d or K±d or EP±d as part of
their most recent anti-myeloma treatment regimen, may receive up to 1 cycle of
DPd, DVd, IRd, Kd or EPd as bridging therapy as per Investigator*s discretion
After bb2121 drug product has been successfully manufactured, additional
baseline evaluations, will be performed to assess continued eligibility and
safety at least 3 days prior to initiation of LD chemotherapy (including
disease staging assessments for those subjects who received bridging MM
therapy). Subjects eligible for treatment will receive 3 consecutive days of LD
chemotherapy with fludarabine and cyclophosphamide, followed by 2 days of rest
and subsequently bb2121 infusion on Day 1. Subjects will be followed for safety
and efficacy and, may continue on study treatment until assessment of disease
progression (PD) by the IRC based on IMWG criteria or, until withdrawal of
consent. Subjects are not expected to start any other anti-myeloma therapy
during the PFS follow-up period prior to PD. All subjects who received bb2121
will continue to be monitored for long-term safety after exposure to
gene-modified T cells under a separate Long-term Follow-up (LTFU) study
protocol for up to 15 years after bb2121 infusion, as per competent authority
guidelines. Subjects randomized to Treatment Arm B will receive study treatment
dependent on the subject*s most recent anti-myeloma treatment regimen: •
Intravenous (IV) DARA, Oral POM, Oral/IV dexamethasone (DPd) OR • IV DARA,
subcutaneous (SC) BTZ, Oral/IV dexamethasone (DVd) OR • Oral IXA, Oral LEN,
Oral dexamethasone (IRd) OR • IV CFZ, Oral/IV dexamethasone (Kd) OR • IV ELO,
oral POM, Oral/IV dexamethasone (EPd). The choice of study treatment will be
dependent on the subject*s most recent anti-myeloma treatment regimen based on
following criteria: • Subjects who have received DP±d as part of their most
recent anti-myeloma treatment regimen may receive DVd, Kd, EPd or IRd as per
Investigator*s discretion • Subjects who have received DV±d as part of their
most recent anti-myeloma treatment regimen may receive DPd, Kd, EPd or IRd as
per Investigator*s discretion • Subjects who have received IR±d as part of
their most recent anti-myeloma treatment regimen may receive DPd, Kd, EPd or
DVd as per Investigator*s discretion • Subjects who have received K±d as part
of their most recent anti-myeloma treatment regimen, may receive DPd, DVd, IRd
or EPd as per Investigator*s discretion • Subjects who have received EP±d as
part of their most recent anti-myeloma treatment regimen, may receive DPd, DVd,
IRd or Kd as per Investigator*s discretion • Subjects who have not received
DP±d or DV±d or IR±d or K±d or EP±d as part of their most recent anti-myeloma
treatment regimen may receive DPd, DVd, IRd, Kd or EPd as per Investigator*s
discretion. Subjects will be followed for safety and efficacy and may continue
on study treatment until assessment of disease progression (PD) by the IRC
based on IMWG criteria or, until withdrawal of consent. If requested by the
Investigator, subjects in Treatment Arm B may elect to receive bb2121 upon
assessment of disease progression by the IRC based on the IMWG criteria, and
confirmed eligibility (see Section 6.3.3). Subjects in Treatment Arm B who
receive bb2121 will be followed in the Post Treatment Follow-up period for
safety for 3 months after bb2121 infusion. Efficacy data including date of
initial response, best response and date of progression will be collected
similar to all other subjects enrolled in the study for subsequent therapy.
Intervention
Approximately 381 subjects will be randomized 2:1 between Treatment Arm A or
Treatment Arm B:
• ~ 254 subjects will be randomized to receive Treatment Arm A: bb2121
• ~ 127 subjects will be randomized to receive Treatment Arm B: standard
regimens dependent on the subject*s most recent anti-myeloma treatment regimen:
* Daratumumab (DARA) in combination with pomalidomide (POM) and
low-dose dexamethasone (dex) (DPd)
OR
* DARA in combination with bortezomib (BTZ) and low-dose dexamethasone
(DVd)
OR
* Ixazomib (IXA) in combination with lenalidomide (LEN) and low-dose
dexamethasone(IRd)
OR
* Carfilzomib (CFZ) in combination with low-dose dexamethasone (kd)
OR
* Elotuzumab (ELO) in combination with POM and low-dose dexamethasone
(EPd)
Study burden and risks
Based on the current knowledge of bb2121, and the safety monitoring, mitigation
management, precautions and guidance as described in the protocol, including
oversight by the Independent Data Monitoring Committee, it is considered that
the risks with the proposed study as specified in the protocol are commensurate
with the potential benefit that this study population with relapsed and
refractory multiple myeloma may derive from treatment with bb2121.
Morris Avenue 86
Summit NJ 07901
US
Morris Avenue 86
Summit NJ 07901
US
Listed location countries
Age
Inclusion criteria
1. Subject is >= 18 years of age at the time of signing the informed consent
form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any
study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other
protocol requirements within this protocol and for a subject randomized to
Treatment Arm A, subject agrees to continued follow-up for up to 15 years as
mandated by the regulatory guidelines for gene therapy trials.
4. Subject has documented diagnosis of MM and measurable disease, defined as:
• M-protein (serum protein electrophoresis [sPEP] or urine protein
electrophoresis [uPEP]): sPEP >= 0.5 g/dL or uPEP >= 200 mg/24 hours and/or
• Light chain MM without measurable disease in the serum or urine: Serum
immunoglobulin free light chain >= 10 mg/dL and abnormal serum immunoglobulin
kappa lambda free light chain ratio
5. Subject has received at least 2 but no greater than 4 prior MM regimens.
Note: induction with or without hematopoietic stem cell transplant and with or
without maintenance therapy is considered as one regimen.
6. Subject has received prior treatment with DARA, a proteasome inhibitor- and
an immunomodulatory compound-containing regimen for at least 2 consecutive
cycles.
7. Subject must be refractory to the last treatment regimen. Refractory is
defined as documented progressive disease during or within 60 days (measured
from the last dose of any drug within the regimen) of completing treatment with
the last anti-myeloma regimen before study entry.
8. Subject achieved a response (minimal response [MR] or better) to at least 1
prior treatment regimen.
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1.
10. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to
prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.
11. Adequate vascular access for leukapheresis.
12 and 13. Adequate contraceptive measures as outlined in the protocol.
Refer to protocol for additional inclusion criteria.
Exclusion criteria
1. Subject has any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in the
study. 2. Subject has any condition including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if he/she were to
participate in the study. 3. Subject has any condition that confounds the
ability to interpret data from the study. 4. Subject has nonsecretory MM. 5.
Subject has any of the following laboratory abnormalities: a. Absolute
neutrophil count (ANC) < 1,000/µL b. Platelet count: < 75,000/µL in
subjects in whom < 50% of bone marrow nucleated cells are plasma cells and
platelet count < 50,000/µL in subjects in whom >= 50% of bone marrow
nucleated cells are plasma cells (it is not permissible to transfuse a subject
to reach this level) c. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not
permissible to transfuse a subject to reach this level) d. Serum creatinine
clearance (CrCl) < 45 mL/min e. Corrected serum calcium > 13.5 mg/dL
(> 3.4 mmol/L) f. Serum aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) > 2.5 × upper limit of normal (ULN) g. Serum total
bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented
Gilbert*s syndrome h. International normalized ratio (INR) or activated partial
thromboplastin time (aPTT) > 1.5 × ULN, or history of Grade >= 2 hemorrhage
within 30 days, or subject requires ongoing treatment with chronic, therapeutic
dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa
inhibitors) 6. Subject has inadequate pulmonary function defined as oxygen
saturation (SaO2) < 92% on room air. 7. Subject has prior history of
malignancies, other than MM, unless the subject has been free of the disease
for >= 5 years with the exception of the following non-invasive malignancies: •
Basal cell carcinoma of the skin • Squamous cell carcinoma of the skin •
Carcinoma in situ of the cervix • Carcinoma in situ of the breast • Incidental
histologic finding of prostate cancer (T1a or T1b using the tumor, nodes,
metastasis [TNM] clinical staging system) or prostate cancer that can be
treated with curative intent 8. Subject has active or history of plasma cell
leukemia, Waldenstrom*s macroglobulinemia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, and skin changes) or
amyloidosis. 9. Subject with known central nervous system (CNS) involvement
with myeloma. 10. Subject has clinical evidence of pulmonary leukostasis and
disseminated intravascular coagulation. 11. Subject has known chronic
obstructive pulmonary disease (COPD) with a forced expiratory volume in 1
second (FEV1) 50% of predicted normal. Note that forced expiratory testing
(FEV1) is required for subjects suspected of having COPD and subjects must be
excluded if FEV1 is < 50% of predicted normal. 12. Subject has a history or
presence of clinically relevant CNS pathology such as epilepsy, seizure,
paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe
brain injuries, dementia, Parkinson's disease, cerebellar disease, organic
brain syndrome, or psychosis. 13. Subject was treated with DARA in combination
with POM with or without dexamethasone (DP±d) as part of their most recent
anti-myeloma treatment regimen, cannot receive DPd as bridging therapy but may
receive DVd, IRd, Kd or EPd as bridging as per Investigator*s discretion if
randomized to Treatment Arm A. 14. Subject was treated with DP±d as part of
their most recent anti-myeloma treatment regimen, cannot receive DPd if
randomized to Treatment Arm B but may receive DVd, IRd, Kd or EPd as per
Investigator*s discretion. 15. Subject was treated with DARA in combination
with BTZ with or without dexamethasone (DV±d) as part of their most recent
anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may
receive DPd, IRd, Kd or EPd as bridging as per Investigator*s discretion if
randomized to Treatment Arm A. 16. Subject was treated with DV±d as part of
their most recent anti-myeloma treatment regimen, cannot receive DVd if
randomized to Treatment Arm B but may receive DPd, IRd, Kd or EPd as per
Investigator*s discretion. 17. Subject was treated with IXA in combination with
LEN with or without dexamethasone (IR±d) as part of their most recent
anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may
receive DPd, DVd, Kd, EPd as bridging as per Investigator*s discretion if
randomized to Treatment Arm A., Refer to protocol for additional exclusion
criteria
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509848-10-00 |
| EudraCT | EUCTR2018-001023-38-NL |
| ClinicalTrials.gov | NCT03651128;U1111-1217-9988 |
| CCMO | NL66959.000.19 |