| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 100000004864 |
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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 |
| The primary objective is to determine if the addition of daratumumab to VRd will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone. |
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| E.2.2 | Secondary objectives of the trial |
●To determine if the addition of daratumumab to VRd will improve clinical outcome as measured by:
-PFS
-MRD negativity rate at 1 year
-Durability of MRD negativity
-ORR of very good partial response (VGPR) or better, and rate of complete response (CR) or better
-Time to response
-Duration of response
-Time to next treatment
-Progression-free survival on the next line of therapy (PFS2; defined as time from randomization to progression on the next line of therapy or death, whichever comes first)
-Overall survival (OS)
●To evaluate medical resource utilization
●To evaluate the pharmacokinetics (PK) of daratumumab
●To determine the immunogenicity of daratumumab and recombinant human hyaluronidase PH20 (rHuPH20)
●To assess the safety profile of daratumumab + VRd (D-VRd)
●To evaluate clinical efficacy (ie, overall MRD negativity rate and PFS) of daratumumab when added to VRd in cytogenetic high-risk subgroups
●To evaluate patient-reported outcomes (PROs). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation due to:
●Being age ≥65years,or
●age 18-65years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with SCT or who refuse high-dose chemotherapy with SCT as initial treatment
2.Diagnosis of multiple myeloma as documented per International Myeloma Working Group Criteria:Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium,renal,anemia,bone(CRAB)criteria or biomarkers of malignancy criteria:
CRAB criteria:
1.Hypercalcemia:serum calcium >0.25mmol/L (>1mg/dL) higher than upper limit of normal (ULN) or >2.75mmol/L (>11mg/dL)
2.Renal insufficiency:creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2mg/dL)
3.Anemia:hemoglobin >2g/dL below the lower limit of normal or hemoglobin <10g/dL
Please see the complete list of criteria 2 in the Protocol Am on pg.38 and 39.
3.Must have measurable disease,as assessed by central laboratory,defined by any of the following:
- IgG,IgA,IgM,IgD,or IgE multiple myeloma:Serum monoclonal paraprotein (M-protein) level ≥1.0g/dL or urine M-protein level ≥200mg/24 hours;or
- Light chain multiple myeloma without measurable disease in serum or urine:Serum Ig FLC ≥10mg/dL and abnormal serum Ig kappa lambda FLC ratio
4.Eastern cooperative oncology group(ECOG) performance status score of 0,1 or2
5.Clinical laboratory values meeting the following criteria during the Screening Phase:
a.hemoglobin ≥ 7.5 g/dL (≥ 5 mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
b.absolute neutrophil count (ANC) ≥ 1.0 x 109/L (granulocyte colony stimulating factor [G-CSF] use is permitted)
c.platelet count ≥ 70x109/L for subjects in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count >50×109/L (transfusions are not permitted within 7 days)
d.aspartate aminotransferase (AST) ≤2.5 x ULN
e.alanine aminotransferase (ALT) ≤2.5 x ULN
f.total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia,such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)
g.Estimated creatinine clearance (CrCl) ≥30 mL/min.Creatinine clearance can be calculated using the Cockcroft-Gault formula (Appendix 8 [Section 10.8]) or eGFR (MDRD; Appendix 9 [Section10.9]), or CKD-epi formula or for subjects
with over- or underweight, CrCl may be measured from a 24-hours urine collection using the formula provided in Appendix 8 [Section 10.8]). If Cockcroft-Gault formula is used and body mass index (BMI) is ≥30 kg/m2 then adjusted body weight should be used in calculation (Appendix 8 [Section 10.8])
h.corrected serum calcium ≤13.5 mg/dL (≤3.4 mM/L);or free ionized calcium ≤6.5 mg/dL (≤1.6 mM/L)
6.Female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period,during any dose interruptions,and for 3months after the last dose of any component of the treatment regimen.Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug.This birth control method must include one highly effective form of contraception (tubal ligation,intrauterine device,hormonal [birth control pills,injections,hormonal patches,vaginal rings or implants]or partner’s vasectomy)and one additional effective contraceptive method (male latex or synthetic condom,diaphragm,or cervical cap).Contraception must begin 4weeks prior to dosing.Reliable contraception is indicated even where there has been a history of infertility,unless due to hysterectomy or bilateral oophorectomy
7.A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening,first within 10to14 days prior to dosing and the second within 24hours prior to dosing.For requirements during the Treatment Phase
8.A woman must agree not to donate eggs (ova, oocytes)for the purposes of assisted reproduction during the study and for a period of 3months after receiving the last dose of any component of the treatment regimen
9.Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3months after discontinuing study treatment (even after a successful vasectomy)
10.Male subjects of reproductive potential must not donate sperm during the study or for 3months after the last dose of study treatment
Please refer to Protocol for completed list of inclusion criteria |
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| E.4 | Principal exclusion criteria |
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
1. Frailty index of ≥2 according to Myeloma Geriatric Assessment score.
2.1 Prior therapy for multiple myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone or equivalent).
3. Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other noninvasive lesion that in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence within 3 years).
4. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.
5.1 Focal radiation therapy within 14 days of randomization with the exception of palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management.
6. Plasmapheresis within 28 days of randomization.
7. Clinical signs of meningeal involvement of multiple myeloma.
8. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is required for subjects suspected of having COPD).
9. Moderate or severe persistent asthma within the past 2 years, uncontrolled asthma of any classification. (Subjects who have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
10.2 Subject is:
a. Known to be seropositive for human immunodeficiency virus (HIV).
b. seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to total hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
c. Known to be seropositive for hepatitis C virus (HCV; anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy.
11. Concurrent medical or psychiatric condition or disease (such as but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard if enrolled in the study.
12. Has clinically significant cardiac disease, including:
● Myocardial infarction within 6 months before signing the informed consent form (ICF), or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV; Appendix 18)
● Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities
● Screening 12-lead ECG showing a baseline QT interval as corrected by Frederica’s formula (QTcF) >470 msec.
13. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization
14. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients, or sensitivity to mammalian-derived products or lenalidomide. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall MRD negativity rate, which is defined as the proportion of subjects who have achieved MRD negative status (at 10^-5) by bone marrow aspirate after randomization and prior to progressive disease (PD) or subsequent anti myeloma therapy. Subjects who have achieved MRD negative status on or after PD or after the switch to subsequent anti-myeloma therapy before PD, will not be considered MRD negative in the primary endpoint analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| One year after the last subject is administered their first dose of study treatment |
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| E.5.2 | Secondary end point(s) |
1. PFS defined as the duration from the date of randomization to either progressive disease (PD) or death, whichever comes first. Disease progression will be determined according to the International Myeloma Working Group (IMWG) criteria. For subjects who have not progressed and are alive, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy.
2. MRD negativity rate at 1 year.
3. Durable MRD negativity rate is defined as the proportion of subjects who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirate examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between.
4. Overall response rate is defined as the proportion of subjects who achieve PR or better responses prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria, during or after the study treatment.
5. VGPR or better rate is defined as the proportion of subjects achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment.
6. CR or better rate is defined as the proportion of subjects achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment.
7. Progression-free survival on the next line of therapy is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. Disease progression will be based on investigator judgment. Subjects who are still alive and not yet progressed on the next line of treatment will be censored on the last date of followup.
8. Overall survival is measured from the date of randomization to the date of the subject’s death due to any cause. If the subject is alive or the vital status is unknown, then the subject’s data will be censored at the date the subject was last known to be alive.
9. Time to response is defined as the time between the randomization and the first efficacy evaluation at which the subject meets all criteria for PR or better.
10. Duration of response is calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of PD, as defined in the IMWG evaluation before the start of any subsequent anti-myeloma therapy.
11. Clinical efficacy (i.e., overall MRD negativity rate and PFS) of D-VRd in high-risk molecular subgroups compared with VRd alone.
12. Pharmacokinetic concentrations of daratumumab.
13. Incidence of anti-daratumumab antibodies.
14. Prevalence and incidence of anti-rHuPH20 antibodies.
15. Mean change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) core 3-item (EORTC QLQ-C30) and the multiple myeloma 20-item (EORTC QLQ-MY20), and EuroQol Five Dimension Questionnaire (EQ-5D-5L) scales. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 7. & 11. From randomization to either PD or death, whichever comes first
2. At 1 year
3. From one year onwards
4. 5. 6. 9. & 10. Screening (within 28 days before randomization), Every 3 weeks of Cycles 1-8, Every 4 weeks for 30 months then every 8 weeks until PD (Cycles 9 and above)
8. From first dose of study drug until end of study (approximately 6 years 5 months)
12. Day (D)1 of Cycles 1-8, D1 of every 3rd cycle until PD & Every 16 weeks & start of subsequent therapy & 4 weeks after start of subsequent therapy
13. Predose on D1 of C1, C3, C9, C12, D4 on C1, C3 and at post-treatment week 4 & 8
14. & 15. Predose on D1 of C1, C9, C12 and at post-treatment week 4 & 8 |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity Analyses and Biomarkers Analyses |
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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 | No |
| 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 | 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 | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 |
| Brazil |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| United States |
| Turkey |
| Czechia |
| France |
| Germany |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
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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 as the later date between the primary PFS analysis (162 events observed) and 5 years after the last subject is randomized. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
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