| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma is a cancer formed by malignant plasma cells that starts in the bone marrow (the spongy tissue inside the bones). |
|
| 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) |
|
| 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 of cevostamab based on investigator assessed Objective response rate (ORR)
• To evaluate the safety and tolerability of cevostamab
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of cevostamab based on IRC assessed ORR, DOR, CR or better, rate of VGPR or better, OS, PFS, time to first response, time to best response, proportion of participants experiencing a clinically meaningful improvement and time to deterioration assessed
by EORTC QLQ-C30 and EORTC QLQ-MY20
• To characterize the PK of cevostamab in participants with MM
• To evaluate the immune response to cevostamab, potential relationships between cevostamab exposure and pharmacodynamic biomarkers
• To make a preliminary assessment of the efficacy of tocilizumab in ameliorating the symptoms of CRS following treatment with cevostamab
• To identify biomarkers that may be:
o Able to provide evidence of cevostamab activity and to increase the knowledge and understanding of disease biology
o Predictive of response to cevostamab
o Associated with progression to a more severe disease state, acquired resistance to cevostamab and susceptibility to developing AEs |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age >= 18 years
• Documented diagnosis of multiple myeloma (MM) based on standard International Myeloma Working Group (IMWG) criteria
• Evidence of progressive disease based on investigators determination of response by IMWG criteria on or after their last dosing regimen
• Prior B cell maturation antigen (BCMA) antibody-drug conjugate (ADC) or chimeric antigen receptor T (CAR-T) Cohort: participants who have received a BCMA-targeted CAR-T or ADC therapy and are triple-class relapsed or refractory
• Prior BCMA Bispecific Cohort: participants who have received a BCMAtargeting T-cell-dependent bispecific (TDB) antibody and are triple-class relapsed or refractory
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Life expectancy is at least 12 weeks
• Agreement to protocol-specified assessments, including bone marrow biopsy and aspirate samples as detailed in the protocol
• Resolution of adverse events from prior anti-cancer therapy to Grade =< 1
• Measurable disease, defined as at least one of the following:
– Serum M-protein >= 0.5 g/dL (>= 5 g/L)
– Urine M-protein >= 200 mg/24 hours
– Serum-free light chain (sFLC) assay: involved sFLCs >= 10 mg/dL (>=100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65)
– If central laboratory assessments are not available, relevant local laboratory measurements must exceed the minimum required level by at least 25%
• Adequate laboratory values
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 5 months after the final dose of cevostamab and for 3 months after the last dose of tocilizumab was administered
• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm during the treatment period and for at least 2 months after the final dose of tocilizumab (if applicable) to avoid exposing the
embryo |
|
| E.4 | Principal exclusion criteria |
• Inability to comply with protocol-mandated hospitalization
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of cevostamab or within 3 months after the last dose of tocilizumab
• Prior treatment with cevostamab or another agent with the same target
• Prior BCMA ADC or CAR-T Cohort: prior treatment with any T cell dependent bispecific antibody (TDB) antibody including non BCMA targeting TDB
• Prior BCMA Bispecific Cohort: treatment with TDB antibody within 12 weeks prior to enrollment in the study
• Prior use of any monoclonal antibody (mAb), radioimmunoconjugate, or ADC as anti-cancer therapy within 4 weeks before first study treatment, except for the use of non-myeloma therapy
• Prior treatment with systemic immunotherapeutic agents
• Prior treatment with CAR-T cell therapy within 12 weeks before first cevostamab infusion
• Known treatment-related, immune-mediated adverse events associated with prior checkpoint inhibitors as follows:
– Prior PD-L1/PD-1 or CTLA-4 inhibitor: Grade >= 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy
– Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation
• Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anti-cancer agent within 4 weeks or 5 halflives of the drug, whichever is shorter, prior to first study treatment
• Autologous stem cell transplantation (SCT) within 100 days prior to first study treatment
• Prior allogeneic SCT
• Circulating plasma cell count exceeding 500/ microliter (μL) or 5% of the peripheral blood white cells
• Prior solid organ transplantation
• History of autoimmune disease
• History of confirmed progressive multifocal leukoencephalopathy
• History of severe allergic or anaphylactic reactions to mAb therapy
• Known history of amyloidosis
• Lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare
• History of other malignancy within 2 years prior to screening, except those with negligible risk of metastasis or death, such as ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, lowgrade, localized prostate cancer not requiring treatment or appropriately
treated Stage I uterine cancer
• Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM
• Significant cardiovascular disease that may limit a potential participant's ability to adequately respond to a cytokine release syndrome (CRS) event
• Symptomatic active pulmonary disease or requiring supplemental oxygen
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV (intravenous) antimicrobials where the last dose of IV antimicrobial was given within 14 days prior to first study treatment
• Active symptomatic coronavirus disease 2019 (COVID-19) infection at study enrollment or requiring treatment with IV antiviral where last dose of IV antiviral treatment was given within 14 days prior to first study treatment. Patients with active COVID-19 infection must have
clinical recovery and two negative antigen tests at least 24 hours apart prior to first study treatment
• Positive and quantifiable EBV PCR or CMV PCR prior to first study treatment
• Known or suspected chronic active Epstein-Barr virus (EBV) infection
• Known history of Grade >= 3 CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior bispecific therapies
• Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
• Recent major surgery within 4 weeks prior to first study treatment
• Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection
• Acute or chronic hepatitis C virus (HCV) infection
• Known history of human immunodeficiency virus (HIV) seropositivity
• Administration of a live, attenuated vaccine within 4 weeks before first study treatment or anticipation that such a live attenuated vaccine will be required during the study
• Treatment with systemic immunosuppressive medications, with the exception of corticosteroid treatment <= 10 mg/day prednisone or equivalent, within 2 weeks prior to first study treatment
• History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
• Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. ORR, defined as the proportion of participants with an objective response [stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR)], based on investigator-assessed response, according to IMWG criteria
2. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) for CRS and of immune effector cell associated neurotoxicity syndrome (ICANS) grading |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-2. Up to approximately 2 years |
|
| E.5.2 | Secondary end point(s) |
1. ORR, defined as the proportion of participants with an objective response based on independent review committee (IRC)-assessed response
2. Duration of response (DOR), defined as the time from the first occurrence of an objective response until the date of disease progression or death from any cause (whichever occurs first), as determined separately by the IRC and the investigator
3. Rate of CR or better, defined as the proportion of participants who achieve a response of sCR or CR, as assessed separately by IRC and the investigator
4. Rate of VGPR or better, defined as the proportion of participants who achieve a response of VGPR or better, as assessed separately by IRC and the investigator
5. Overall survival (OS), defined as the time from initiation of study treatment to death from any cause
6. Progression-free survival (PFS), defined as the time from initiation of study treatment to the first occurrence of disease progression, relapse, or death from any cause (whichever occurs first), as assessed separately by IRC and the investigator
7. Time to first response (for participants who achieve an objective response), defined as time from initiation of study treatment to first achieving an objective response (separate analyses by IRC and investigator)
8. Time to best response (for participants who achieve an objective response), defined as time from initiation of study treatment to achieving the deepest response (separate analyses by IRC and investigator)
9. Proportion of participants experiencing a clinically meaningful improvement in the fatigue domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core-30 Questionnaire (QLQC-30) and EORTC QLQ-MY20
10. Time to deterioration in the fatigue domain of the EORTC QLQ-C30 and/or disease symptoms domain of the EORTC QLQ-MY20
11. Serum concentration of cevostamab at specified timepoints
12. Pharmacokinetics (PK) parameters of cevostamab, as data allow
13. Prevalence of anti-drug antibodies (ADAs) against cevostamab at baseline and incidence of ADAs against cevostamab during the study
14. CRS outcome following administration of tocilizumab (e.g., time to CRS resolution, doses of tocilizumab administered, relationship between serum concentration or other PK parameters for tocilizumab and pharmacodynamic biomarkers)
15. Relationship between serum concentration or other PK parameters for cevostamab and pharmacodynamic biomarkers, including, but not limited to, cytokine release, T cell number, and T-cell activation state
16. Relationship between biomarkers in blood, bone marrow biopsies and aspirates, and tumor tissue and efficacy, safety, PK, immunogenicity, or other biomarker endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-10. Up to approximately 2 years
11-13. At Cycles 1, 2, 3, 4, 6, 8 and every other cycle until the end of treatment / disease progression
14-16. Up to approximately 2 years |
|
| 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 | No |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Spain |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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