E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed Multiple Myeloma
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
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) |
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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 compare the efficacy of teclistamab in combination with lenalidomide (Tec-Len; Arm A) with that of lenalidomide (Len; Arm B) as assessed by PFS.
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E.2.2 | Secondary objectives of the trial |
To further compare the efficacy of Tec Len maintenance compared with Len. To assess the safety profile of Tec Len, characterize the PK of Tec Len, assess the immunogenicity of Tec Len, evaluate the impact of treatment with Tec Len on PROs compared with Len. EXPLORATORY OBJECTIVES: To evaluate the efficacy of Tec-Len in high-risk subgroups, explore pharmacodynamic biomarkers of antimyeloma and immune activity for Tec-Len, explore relationships between pharmacodynamic markers and clinical activity of Tec Len compared with Len, explore predictive biomarkers of response and resistance for Tec Len. To evaluate MRD negative conversion and CR or better conversion. To explore the relationships between PK, pharmacodynamic, AE profile, and clinical activity of Tec-Len. To explore time to symptomatic progression in both treatment arms. To explore the impact of treatment with Tec-Len on MRU compared with Len. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1 ≥18 years of age 2 Must have a new diagnosis of MM according to IMWG criteria and 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 6 and all treatment has completed prior to screening. 3 Must have received only one line of therapy and achieved at least a partial response (≥PR) as per IMWG 2016 response criteria. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria for ≥PR based on repeat imaging during screening utilizing the same modality. 4 Must not be intolerant to the starting dose of lenalidomide. 5 Must have received high-dose chemotherapy and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT at the time of first treatment dose. a) For participants who have not received consolidation therapy, the participant must be within 120 days post-transplant at the time of first treatment dose. b)For participants treated with consolidation therapy, the participant must be within 90 days of the last dose of consolidation therapy at the time of first treatment dose 6 Must not have received any maintenance therapy. 7 Have an ECOG performance status score of 0, 1, or 2 at screening and immediately prior to the start of administration of study treatment. 8 Have clinical laboratory values meeting the following criteria during the Screening Phase. In addition, these laboratory values must be re-evaluated within 72 hours prior to the first dose and the participant must also meet all criteria. If one or more criteria are not met within 72 hours prior to dosing, one repeat of laboratory testing is permitted. If >1 repeat laboratory test is necessary, the sponsor must be consulted prior to dosing. 9 A woman of childbearing potential must have a negative highly sensitive serum pregnancy test within 10-14 days prior to the start of study treatment and again either a serum or urine pregnancy test within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study. 10 A woman must be: a) Not of childbearing potential, or b) Of childbearing potential and 1) Practicing true abstinence; or 2) Practicing 2 reliable methods of contraception simultaneously including one highly effective method of contraception and one other effective method of contraception starting 4 weeks prior to dosing, throughout the study including during dose interruptions and for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 90 days after the last dose of teclistamab, whichever occurs later. For participants who are of childbearing potential, see Section 6.11.3 for details regarding concomitant use of estrogen containing products and lenalidomide. 11 A woman 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 minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 90 days after the last dose of teclistamab, whichever occurs later. 12 A man must wear a condom (with spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 90 days after the last dose of teclistamab, whichever occurs later. If his female partner is of childbearing potential, she must also be practicing a highly effective method of contraception. NOTE: If the male participant is vasectomized, he still must wear a condom (with spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception. 13 A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 90 days after teclistamab, whichever occurs later. 14 Must be willing and able to adhere to the lifestyle restrictions specified in this protocol. 15 Must sign an informed consent form ICF (or their legally acceptable representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
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E.4 | Principal exclusion criteria |
1 Received any prior BCMA-directed therapy. 2 Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy. 3 Discontinued treatment due to any AE related to lenalidomide as determined by the investigator. 4 History of allogeneic stem cell transplantation or prior organ transplant requiring immunosuppressive therapy. 5 Progressed on multiple myeloma therapy as per IMWG 2016 response criteria at any time prior to screening. 6 Radiotherapy within 14 days or focal radiation within 7 days of first treatment dose. 7 Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14 days prior to first treatment dose. 8 Received a live, attenuated vaccine within 4 weeks before first treatment dose. Non-live vaccines authorized for emergency use are allowed. 9 Myelodysplastic syndrome or active malignancies. The only allowed exceptions are: a)Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured b)Skin cancer treated within the last 24 months that is considered completely cured c) Noninvasive cervical cancer treated within the last 24 months that is considered completely cured d)Localized prostate cancer: 1) With a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance 2)With a Gleason score of 3+4 that has been treated >6 months prior to full study screening and considered to have a very low risk of recurrence or 3)History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence. e)Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence f)Other malignancy that is considered cured with minimal risk of recurrence. 10 Plasma cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome or primary light chain amyloidosis. 11 Central nervous system involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, brain MRI and lumbar cytology are required. 12 Stroke or seizure within 6 months of first treatment dose. 13 Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study treatment or its excipients . 14 Participant is pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study drug. 15 Participant plans to father a child while enrolled in this study or within 90 days after the last dose of study drug. 16 Presence of the following conditions: a)New York Heart Association stage III or IV congestive heart failure b)Myocardial infarction, or coronary artery bypass graft ≤6 months prior to first treatment dose c) History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration d) Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities. 17 HIV -positive participants with 1 or more of the following: -History of AIDS defining conditions -CD4 count <350 at screening -Detectable viral load during screening or within 6 months prior to screening -Not receiving highly ART -Had a change in antiretroviral therapy within 6 months of the start of screening -Receiving antiretroviral therapy that may interfere with study treatment as assessed after discussion with the Medical Monitor 18 Hepatitis B infection: In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status. 19 Active hepatitis C infection as measured by positive HCV- RNA Testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic HCV infection completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the participant is eligible for the study. 20 Concurrent medical or psychiatric condition or disease, that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study. 21 Major surgery within 2 weeks prior to the start of administration of study treatment, or has not fully recovered from an earlier surgery, or has major surgery planned during the time the participant is expected to participate in the study or within 2 weeks after administration of the last dose of study treatment. 22 Have received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks or 5 PK half-lives, whichever is longer, before first treatment dose or is currently enrolled in an interventional investigational study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is PFS, defined as the time from the date of randomization to the date of first confirmed disease progression, as defined in the IMWG criteria, or death due to any cause, whichever occurs first.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of randomization to the date of first confirmed disease progression or death due to any cause, whichever occurs first.
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E.5.2 | Secondary end point(s) |
CR or better (sCR+CR) is defined as participants who achieve a CR or better response per IMWG criteria. MRD negative CR is defined as participants who achieve CR or better and are MRD negative before initiation of subsequent therapy. Sustained MRD negativity is defined as the proportion of participants who achieve MRD-negative CR, confirmed minimum 1 year apart and without any examination showing MRD-positive status in between. OS will be measured from the date of randomization to the date of the participant’s death. If the participant is alive or the vital status is unknown, then the participant’s data will be censored at the date the participant was last known to be alive. PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as PD as assessed by investigator on the first subsequent line of antimyeloma therapy, or death from any cause, whichever occurs first. Those who are alive and for whom a second disease progression has not been observed will be censored at the last date of follow-up. Incidence and severity of AEs The PK of teclistamab will be assessed. Presence and activity of ADAs to teclistamab Time to worsening in overall HRQoL, symptoms, and functioning Change from baseline in overall HRQoL, symptoms, and functioning PFS, depth of response, etc will be determined in participants with high-risk molecular features as defined by IMWG criteria As part of the PROs, treatment effect will be assessed by change from baseline in overall HRQoL symptoms and functioning at each time point summarized by treatment arm. Time to worsening of symptoms will be measured as the interval from the date of randomization to the start date of worsening. Death due to disease progression will be considered as worsening. Participants who have not met the definition of worsening will be censored as of the last assessment date. The analysis methods for binary endpoints (eg, CR/sCR, and MRD negativity) will be conducted using stratified Cochran Mantel Haenszel test. The Mantel Haenszel odds ratio will be provided along with its 2-sided 95% CI and will be provided as the measure of treatment effect. For time-to-event endpoints (eg, PFS2, OS, and time of worsening symptoms), similar statistical methods will be applied as for PFS. EXPLORATORY ENDOPOINTS: To evaluate the efficacy of Tec-Len in high-risk subgroups To explore pharmacodynamic biomarkers of antimyeloma and immune activity for Tec-Len To explore relationships between pharmacodynamic markers and clinical activity of Tec-Len compared with Len To explore predictive biomarkers of response and resistance for Tec-Len, including prognostic and disease markers, at baseline, during treatment, and in relation to efficacy parameters To evaluate rate of conversion to CR and MRD negative CR To explore the relationships between PK, pharmacodynamic, AE profile, and clinical activity of Tec-Len To explore time to symptomatic progression in both treatment arms To explore the impact of treatment with Tec-Len on MRU compared with Len
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the entire duration of the study |
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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 | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenenicity evaluations, Exploratory Biomarker evaluations
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 62 |
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 |
Switzerland |
Korea, Democratic People's Republic of |
Australia |
Canada |
Serbia |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
Denmark |
Germany |
Greece |
Italy |
Netherlands |
Norway |
Türkiye |
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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
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The end of study is defined by the final OS analysis, which will occur when approximately 380 deaths have been observed, or 8 years after the last participant randomized, whichever is earlier.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |