| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and Refractory Multiple Myeloma |
|
| 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 | 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.1.2 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy, defined as overall response rate (ORR), of bb2121 in subjects with relapsed and refractory multiple myeloma (RRMM) |
|
| E.2.2 | Secondary objectives of the trial |
- Assess additional efficacy outcomes, including complete response (CR) rate, time to response (TTR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP) and overall survival (OS)
- Assess the safety of bb2121 in subjects with RRMM
- Characterize the expansion of chimeric antigen receptor (CAR)+ Tcells in the peripheral blood (cellular kinetics- pharmacokinetics [PK])
- Evaluate the development of an anti-CAR antibody response
- Evaluate the proportion of subjects who attain minimal residual disease (MRD) negative status by next generation sequencing (NGS)
- Describe changes in health-related quality of life (HRQol) using the European Organization for Research and Treatment of Cancer- Quality of life C30 questionnaire (EORTC-QLQ-C30), the European Quality of LIfe-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) and the European Quality of Life Multiple Myeloma Module(EORTC-QLQ-MY20) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility is determined prior to leukapheresis. Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. 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. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose) of completing treatment with the last anti-myeloma drug regimen before study entry.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. 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
- Bone marrow plasma cells > 30% of total bone marrow cells
5. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy.
6. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
7. Subject is willing and able to adhere to the study visit schedule and other protocol requirements within this protocol as well as agrees to continued follow-up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials.
8. Females of childbearing potential (FCBP (see note 1 below)) 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 lymphodepleting chemotherapy. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with bb2121. Any decision regarding contraception after bb2121 infusion should be discussed with the treating physician.
- Agree to abstain from breastfeeding during study participation . There is insufficient exposure data to provide any recommendation concerning the total duration of abstaining from breastfeeding following treatment with bb2121. Any decision regarding breastfeeding after bb2121 infusion should be discussed with the treating physician.
- Refrain from tissue donation including egg donation or any other tissue/blood/organ donations for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with bb2121. Any decision regarding tissue donation after bb2121 infusion should be discussed with the treating physician.
Male subjects must:
- Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1-year post lymphodepleting chemotherapy, even if he has undergone a successful vasectomy. Subjects will be followed from screening until at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with bb2121. Any decision regarding contraception after bb2121 infusion should be discussed with the treating physician.
- Refrain from tissue donation including sperm or any other tissue/blood/organ donation for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with bb2121. Any decision regarding tissue donation after bb2121 infusion should be discussed with the treating physician.
Note: Highly effective methods are defined in the protocol. True abstinence is defined in the protocol. A female of childbearing potential is defined in the protocol.
|
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a subject from enrollment:
1. Subjects with known central nervous system involvement with myeloma.
2. History or presence of clinically relevant central nervous system (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. (Note: this criterion does not apply to subjects undergoing retreatment unless Grade 4 neurotoxicity was observed following prior treatment with bb2121).
3. Subjects 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.
4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease.
5. Inadequate hepatic function defined by AST and/or ALT > 2.5 × upper limit of normal (ULN) and total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome and direct bilirubin is ≤ 1.5 x ULN).
6. Inadequate renal function defined by CrCl ≤ 45 ml/min using Cockcroft-Gault equation.
7. 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 anti-coagulants (eg, warfarin, low molecular weight heparin, or Factor Xa inhibitors).
8. Inadequate bone marrow function defined by absolute neutrophil count (ANC) < 1000 cells/mm3 in the absence of growth factor support (filgrastim within 7 days or peg-filgrastim within 14 days of screening) and platelet count < 50,000 mm3 in the absence of transfusion support (platelet transfusion within 7 days of screening).
9. Echocardiogram or MUGA with left ventricular ejection fraction < 45%.
10. Inadequate pulmonary function as defined as oxygen saturation (Sa02) < 92 % on room air.
11. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed.
12. 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.
13. Evidence of human immunodeficiency virus (HIV) infection.
14. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV)
- Subjects who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA negative are eligible
- Subjects who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible
- Subjects who are seropositive because of hepatitis B virus vaccine are eligible
- Subjects with known HBV infection should have undetectable HBV viral load and be maintained on anti-viral therapy to prevent HBV reactivation.
15. Seropositive for and with active viral infection with hepatitis C virus (HCV)
- Subjects who had hepatitis C but have received an antiviral treatment and show no detectable HCV viral RNA for 6 months are eligible.
16. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to starting study treatment.
17. 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; exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, or incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor nodes, metastasis clinical staging system]) or prostate cancer that is curative.
18. Subjects who are pregnant, or who intend to become pregnant during participation in the study.
19. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine or tocilizumab.
20. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
21. 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.
22. 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):
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 independent response committee (IRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
When all bb2121 treated subjects have completed a
minimum of 10 months of post bb2121 infusion follow up. An updated analysis will be performed following a minimum of 24 months of post bb2121 infusion follow up and additional ad hoc analyses will be performed as appropriate. |
|
| E.5.2 | Secondary end point(s) |
*Key Secondary
- Complete Response (CR) Rate:
Percentage of subjects who achieved CR or sCR according to IMWG Uniform Response Criteria for Multiple Myeloma (Kumar, 2016) as assessed by an IRC
*Other Secondary
- Time to Response: Time from first bb2121 infusion to first documentation of response of PR or better
- Duration of Response (DOR): Time from first documentation of response of PR or better to first documentation of disease progression or death from any cause, whichever occurs first
- Progression-free Survival (PFS): 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): Time from first bb2121 infusion to first documentation of PD
- Overall Survival (OS): Time from first bb2121 infusion to time of death due to any cause
- Safety: Type, frequency, and severity of adverse events (AEs), adverse events of special interest (AESI), serious adverse events (SAEs), cytokine release syndrome, neurotoxicity, infection and laboratory abnormalities
- PK: Maximum transgene level (Cmax), time to peak transgene level (Tmax), area under the curve of transgene level (AUC), including maximum expansion and duration of persistence of bb2121 CD3+ cells
- Immunogenicity: Evaluate the development of an anti-CAR antibody response
- Minimal Residual Disease (MRD): Evaluate subjects for MRD status using next generation sequencing (NGS)
- Health Related Quality of Life (HRQoL): Subject-reported outcomes as measured by EORTC-QLQC30, EQ-5D-5L and EORTC-QLQ-MY20. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| When all bb2121 treated subjects have completed sufficient follow-up, e.g. a minimum of 6 months post bb2121 infusion follow up. An updated analysis will be performed at 24 months after the last subject has received bb2121 infusion, or at other timepoints as needed. |
|
| 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 | Yes |
| 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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Canada |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
|
| 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 pre-specified 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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