| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation |
| Neu diagnostiziertes multiples Myelom bei Patienten, die für eine Stammzelltransplantation geeignet sind |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation |
| Neu diagnostiziertes multiples Myelom bei Patienten, die für eine Stammzelltransplantation geeignet sind |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 safety and tolerability of Tec-DRd and Tec-DVRd as induction and Tec-DR as maintenance therapy in participants with ND-TEMM |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate MRD negativity rates, conversion, and sustainability
-To evaluate the efficacy of Tec-DRd and Tec-DVRd as induction and Tec-DR as posttransplant maintenance therapy: Post induction , post ASCT, post maintenance and best overall: ORR, CR, VGPR, DOR, PFS
-To assess feasibility of successful transplantation (Stem cell yield and days to engraftment)
-To characterize the PK of teclistamab in participants with multiple myeloma before and after an ASCT and to characterize the PK of daratumumab after an ASCT (population PK approach)
-To assess the immunogenicity of teclistamab and daratumumab (ADA) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 to 70 years of age, inclusive
2. Have an ECOG performance status score of 0 to 2 at screening
3. Have clinical laboratory values meeting the following criteria during the Screening Phase.
Hematology:
Hemoglobin>=7.5 g/dL (>=4.65 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted)
Platelets: >=75×10E9/L in participants in whom <50% of bone marrow nucleated
cells are plasma cells and >=50×10E9/L in participants in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test)
Absolute neutrophil count: >=1.0×109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated-G-CSF)
Chemistry
AST and ALT: ≤2.5×ULN
eGFR: ≥30 mL/min based on Cockcroft-Gault formula or a 24-hour urine collection
Total bilirubin: ≤2.0×ULN; (isolated total bilirubin ≥ 1.5 x ULN with conjugated [direct] bilirubin <1.5xULN is allowed for those participants with known Gilbert’s syndrome).
Serum calcium corrected for albumin: ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)
4. A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening, and within 24 hours before start of study treatment, and must agree to further pregnancy tests during the study.
5. A participant must be either
a. Not of childbearing potential, or
b. Of childbearing potential and practicing 2 effective methods of contraception from the time of signing ICF until 6 months after the last dose of study treatment.
Contraception must begin 4 weeks prior to dosing of lenalidomide.
6. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment.
7. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 3 months after receiving the last dose of study treatment.
8. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 3 months after receiving the last dose of study treatment.
9. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol, including adherence to the global PPP or local PPP program for lenalidomide.
10. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Participants in Arm A, Arm A1 and Arm B must also satisfy all of the following criteria to be enrolled in the study:
1A. Documented multiple myeloma as defined by the criteria below:
a. Multiple myeloma diagnosis according to the IMWG diagnostic criteria
b. Measurable disease at screening as defined by any of the following:
1. Serum M-protein level ≥1.0 g/dL or
2. Urine M-protein level ≥200 mg/24 hours or
3. Serum immunoglobulin free light chain level ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
2A. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan.
Participants Arm C and C1 must also satisfy all of the following criteria
1B. diagnosed multiple myeloma according to IMWG criteria, see note
2B. Must have received 4 to 6 cycles of 3 or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post-ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 7.
3B. Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 response criteria based on the investigator’s assessment. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria for ≥PR based on repeat imaging utilizing the same modality.
4B. Must have received HDT and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT.
(7 months for participants who received consolidation at the time of enrollment).
|
|
| E.4 | Principal exclusion criteria |
1.a. Ongoing myelodysplastic syndrome or B-cell malignancy (other than MM)
b. History of malignancy (other than MM), considered high risk of recurrence requiring systemic therapy.
c. Active malignancy other than MM. Exceptions (details see protocol):
- Non-muscle invasive bladder cancer
- Non- melanoma skin cancer after curative therapy or localized melanoma after curative surgical resection alone
- Non-invasive cervical cancer
- Breast cancer: adequately treated lobular carcinoma in situ, or history of localized breast cancer
- Localized prostate cancer, treated locally only
2. CNS involvement or clinical signs of meningeal involvement of MM.
3. Stroke, transient ischemic attack or seizure within 6 months prior C1D1.
4. History of allogeneic stem cell transplant or organ transplantations requiring immunosuppressive therapy.
5. Any of the following
- Positive HIV, Hep B, active Hep C (details see protocol)
- COPD with a FEV1 <50% of predicted normal.
- Moderate/severe persistent asthma within the past 2 years or uncontrolled asthma.
6 Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures, or that in the investigator’s opinion would constitute a hazard for participants, such as:
a. Acute diffuse infiltrative pulmonary disease
b. Evidence of active systemic viral, fungal or bacterial infection, requiring systemic antimicrobial therapy
c. History of autoimmune disease, exc. vitiligo, type I diabetes, prior autoimmune thyroiditis currently euthyroid
d. Disabling psychiatric conditions, severe dementia, or altered mental status
e. History of noncompliance
7. Following cardiac conditions:
a. New York Heart Association stage III or IV congestive heart failure
b. Myocardial infarction or coronary artery bypass graft ≤6 months prior enrollment
c. History of clinically significant ventricular arrhythmia or unexplained syncope
d. Uncontrolled cardiac arrhythmia or clinically significant abnormal ECG.
8. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug/excipients.
9. Pregnant, breastfeeding, or planning pregnancy while enrolled in this study or within 6 months after the last dose of any study treatment.
10. Plans to father a child while enrolled in this study or within 3 months after the last dose of any study treatment.
11. significant traumatic injury or major surgery within 2 weeks prior to the start of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the study or within 2 weeks after the last dose of study treatment.
12. Received an investigational drug, used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/IMP before enrollment or is enrolled in an interventional study.
13. Have gastrointestinal disease that may significantly alter the absorption of oral drugs
14. Received a live, attenuated vaccine within 4 weeks before the first dose of study treatment.
17. Be unable or unwilling to undergo antithrombotic prophylactic treatment.
Arms A, A1, B
1. Prior or current systemic therapy or stem cell transplant for plasma cell dyscrasia, with the exc. of emergency use of a short course (equiv. of dexamethasone 40 mg/day for a max. 4 days) of corticosteroids before treatment.
2. Radiotherapy within 14 days or focal radiation within 7 days of enrollment. Radiotherapy on measurable soft-tissue plasmacytoma(s) is not permitted even in the setting of palliation for symptomatic management.
3. Plasmapheresis within 28 days of enrollment.
4. Plasma cell leukemia, smoldering MM, Waldenström’s macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.
5. Arm B only: Peripheral neuropathy or neuropathic pain Grade 2 or higher
6. Arm B only: received a strong CYP3A4 inducer within 5 half-lives prior to enrollment
Arms C and C1
1. Received any prior BCMA-directed therapy.
2. Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy (eg, CAR T cells, NK cells).
3. Discontinued treatment due to any AE related to lenalidomide as determined by the investigator.
4. Radiotherapy within 14 days or focal radiation within 7 days of enrollment.
5. Progressed on MM therapy any time prior to screening.
6. Received a cumulative dose of corticosteroids equivalent to ≥40 mg dexamethasone within the 14 day period before the start of study treatment.
7. Plasma cell leukemia, smoldering MM, Waldenström’s macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.
8. Intolerant to starting dose of lenalidomide.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence and severity of AEs and SAEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| any time during the study |
|
| E.5.2 | Secondary end point(s) |
To evaluate MRD negativity rates, conversion, and sustainability:
Post-induction, post-ASCT, post-maintenance, and best overall
- MRD negative CR
Sustained MRD negative CR (duration ≥12 months) after 18 cycles of maintenance treatment
MRD negative CR conversion and deepening during maintenance
To evaluate the efficacy of Tec-DRd and Tec-DVRd as induction and Tec-DR as posttransplant
maintenance therapy: Post-induction, post-ASCT, post-maintenance, and best overall:
- ORR (at least a PR or better)
- CR or better
- VGPR or better
DOR
PFS
To characterize the PK of teclistamab in participants with multiple myeloma before and after an ASCT and to characterize the PK of daratumumab after an ASCT: PK parameters using population PK approach
To assess the immunogenicity of teclistamab and daratumumab: Measure presence of ADAs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall
Sustained MRD negative CR: ≥12 months and after 18 cycles of maintenance treatment. Sustained MRD negative CR
- ORR (at least a PR or better)
- CR or better
- VGPR or better
Post-induction, post-ASCT, post-maintenance (assessments 3-monthly), and best overall:
DOR: 3-monthly response assessment
PFS: 3-monthly response assessment
PK analysis: over the course of the study |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 5 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 study is defined as when all participants have completed 18 cycles of maintenance treatment (or optional participants have completed 12 months of MRD negativity during maintenance phase) with Tec-DR and have been followed for an additional 6 months or when the sponsor decides to stop the study. |
|
| 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 |
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