| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and refractory multiple myeloma (RRMM), multiple myeloma (MM) with progression within 18 months of initial treatment, or MM with inadequate response post autologous stem cell transplant (ASCT) during initial treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bone marrow that recurs or is resistant to treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067095 |
| E.1.2 | Term | Multiple myeloma progression |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate the efficacy of bb2121 |
|
| E.2.2 | Secondary objectives of the trial |
• Evaluate the safety of bb2121
• Evaluate additional efficacy parameters of bb2121
• Characterize the expansion and persistence of chimeric antigen receptor (CAR) + T cells, in the peripheral blood (cellular kinetics-pharmacokinetics [PK])
• Evaluate the development of an anti-CAR antibody response
• Evaluate the percentage of subjects who attain minimal residual disease (MRD) negative status (by EuroFlow and/or next generation sequencing [NGS])
• Evaluate changes in health-related quality of life (HRQoL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
2. Subject has 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
3. Subjects with one of the following cohort specific requirements:
Cohort 1 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens:
• Subject must have received at least 3 prior anti-myeloma treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
• Subject must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen
• Subject must have received prior treatment with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody
• Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen
• Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen
Cohort 2 subjects with 1 prior anti-myeloma treatment regimen:
• Subject must have received only 1 prior anti-myeloma treatment regimen. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
• Subject must have the following HR factors:
Early relapse defined as:
▪ Cohort 2a: PD < 18 months since date of start of initial therapy. Initial therapy must contain induction, ASCT (single or tandem) and LEN containing maintenance
▪ Cohort 2b: PD < 18 months since date of start of initial therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone
▪ Cohort 2c: Subject must have received minimum 3 cycles of induction therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone. Subjects must have had ASCT (single or tandem)
AND
< VGPR (excluding PD) at first assessment between 70 to 110 days after last ASCT, with initial therapy without consolidation and maintenance
4. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
5. Subject must have recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy
6. Subject must have adequate vascular access for leukapheresis
7. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
8. Subject is willing and able to adhere to the study visit schedule and other protocol requirements as well as agrees to continued follow up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials
9. Female subjects of childbearing potential (FCBP) must:
• Have a negative pregnancy test as verified by the Investigator, one negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test result at screening, prior to LD chemotherapy. This applies even if the subject practices true abstinence* from heterosexual contact
• Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption, from screening through at least 1 year following last bb2121 infusion. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 12 months following bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
• Agree to abstain from breastfeeding during study participation and for at least 1 year post-bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
10. Male subjects must:
• Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing for at least 1 year post bb2121 infusion, even if he has undergone a successful vasectomy from screening until at least 1 year following last bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
• Must not donate sperm for at least 12 months following last bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
|
|
| E.4 | Principal exclusion criteria |
1. Subject used any investigational agents within 14 days of leukapheresis
2. Subject received any of the following within the last 14 days of leukapheresis:
a. Plasmapheresis
b. Major surgery (as defined by the investigator)
c. Radiation therapy other than local therapy for myeloma associated bone lesions
d. Use of any systemic anti-myeloma drug therapy
3. Subject with known central nervous system (CNS) involvement with myeloma
4. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation
5. 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.
6. Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis
7. Subject has nonsecretory MM
8. Subject has any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000/μL
b. Platelet count < 50,000 mm3 in the absence of transfusion support (platelet transfusion within 7 days of screening)
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 ratio (INR) or partial thromboplastin time (PTT) > 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)
9. Echocardiogram (ECHO) or multi-gated acquisition (MUGA) with left ventricular ejection fraction < 45%
10. Subject with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to starting study treatment
11. Inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on room air
12. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed
13. 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
14. Subject has received ASCT within 12 weeks prior to leukapheresis
15. Subject has history of primary immunodeficiency
16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C
17. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment
18. Subject with 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 noninvasive malignancies:
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
19. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during participation in the study
20. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab
21. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
22. 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. This includes systemic fungal, bacterial, viral, or other infection that is uncontrolled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management.
23. Subject has any condition that confounds the ability to interpret data from the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Overall response rate (ORR) (Cohort 1)
- Complete response (CR) rate (Cohort 2a, b and c)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Starting from M2, response will be assessed at every month for the first 6 months then every 3 months for a minimum of 24 months or until progressive disease (PD) up to 5 years after the last subject has received the first bb2121 infusion, whichever is longer |
|
| E.5.2 | Secondary end point(s) |
- Complete response (CR) rate (Cohort 1)
- Overall response rate (ORR) (Cohort 2a, b and c)
- Very good partial response (VGPR) rate (Cohort 2c)
- Time to response (TTR)
- Duration of response (DoR)
- Progression-free survival (PFS)
- Time to progression (TTP)
- Overall survival (OS)
- Safety
- Pharmacokinetics
- Immunogenicity
- Minimal Residual Disease (MRD) negative rate
- Health-related Quality of Life (HRQoL) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Starting M2, response will be assessed every month for the first 6 months then every 3 months for a minimum of 24 months or until progressive disease up to 5 years after the last subject has received the first bb2121 infusion, whichever is longer
- At the time of documented PD, all subjects will be followed for survival every 3 months until the end of the trial
- Safety: continuously
- PK: D3, D5, D8, D10, D12, D15, D18, D22, M2, M7, M10, M13, M16, M19, M22, M25, M31, every 6 months
- immunogenicity: D25, M2, M3, M4, M7, M10, M19, M31, every 12 months
- MRD: M2, M3, M4, M7, M13, M19, M25, every 12 months
- HRQoL: D1, M2-M7, M10, M13, M16, M19, M22, M25, M28, M31, M34, every 3 months
Refer to Table 3 in protocol for details for each Cohort |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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