E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis ) |
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E.1.1.1 | Medical condition in easily understood language |
Amyloidosis refers to a disease in which abnormally folded protein (amyloid) deposits in various organs and tissues in the body. |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002022 |
E.1.2 | Term | Amyloidosis |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD alone in the treatment of newly diagnosed AL amyloidosis patients. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the clinically observable composite endpoints for major organ deterioration progression-free survival (MOD-PFS) following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
To evaluate the following efficacy measures following treatment with daratumumab in combination with CyBorD compared with CyBorD alone:
- Organ response rate (OrRR)
- Overall survival (OS)
- Time to and duration of response
To evaluate fatigue, mental functioning, and health-related quality of life following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
To assess the safety and tolerability of daratumumab when administered in combination with CyBorD
To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab and rHuPH20
To explore minimal residual disease (MRD) status in amyloidosis patients as a surrogate for
hematologic progression-free survival (HemPFS) and OS or as a biomarker for relapse |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) or older.
2) Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) and polarizing light microscopy of green bi-refringent material in congo red-stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance
Considerations for specific populations where other types of amyloidosis may be encountered:
- For male subjects 70 years of age or older who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
-serum M-protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation (IFE) performed at a central laboratory),
-serum free light chain ≥50 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥50 mg/L.
4) One or more organs impacted by AL amyloidosis according to consensus guidelines
5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
6) Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a. Absolute neutrophil count ≥1.0 ×1000000000 /L;
b. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
c. Platelet count ≥50 × 1000000000/L; Platelet transfusions are acceptable without restriction during the Screening period
d. Alanine aminotransferase level (ALT) ≤2.5 times the ULN
e. Aspartate aminotransferase (AST) ≤2.5 times the ULN
f. Total bilirubin level ≤1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin ≤2 × ULN
g. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73m2. Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
7)Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes 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 4 weeks prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
8)During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9) A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control; eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
10) A woman of childbearing potential must have a negative serum or urine pregnancy test (serum preferred) result within 14 days prior to randomization.
11) Each subject, or legally acceptable representative, must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. |
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E.4 | Principal exclusion criteria |
1.Prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure prior to randomization
2.Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, ≥60% plasma cells in the bone marrow, or hypercalcemia
3.Evidence of significant cardiovascular conditions as specified below:
a.NT-ProBNP >8500 ng/L
b.New York Heart Association (NYHA) classification IIIB or IV heart failure
c.Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (eg prior myocardial infarction with documented history of cardiac enzyme elevation and ECG changes)or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
d.Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months prior to first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months
e.For subjects with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks prior to randomization
f.Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed on study)
g.Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc interval
h.Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management (eg, midodrine, fludrocortisones)in the absence of volume depletion
4.Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded.Stem cell collection during the first 6 cycles of protocol therapy is permitted
5.History of malignancy (other than AL amyloidosis)within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin,carcinoma in situ of the cervix or breast, or other non-invasive 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)
6.Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal.Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
7.Moderate or severe persistent asthma within the past 2 years,or currently has uncontrolled asthma of any classification.(Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
8.Know to be seropositive for human immunodeficiency virus (HIV)
9.Any of the following:
a. 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 hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using realtime 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.
b. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
10.Grade 2 sensory or Grade 1 painful peripheral neuropathy
11.Known hypersensitivity or contraindication to any of the study drugs including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites
12.Concurrent medical condition or disease (eg, active systemic infection)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
13.Any form of non-AL amyloidosis,including wild type or mutated (ATTR)amyloidosis
14.Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients (refer to IB), or known sensitivity to mammalian-derived products
19. Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the first dose of study treatment.
For a complete list of the exclusion criteria, please refer to the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is overall complete hematologic response (CHR) rate. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria. |
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E.5.2 | Secondary end point(s) |
- Major organ deterioration progression-free survival (MOD-PFS). This is a composite endpoint of clinically observable endpoints and will be defined from randomization to any one of the following events, whichever comes first:
1. Death
2. Clinical Manifestation of Cardiac Failure: Defined as development of dyspnea at rest (for at least 3 consecutive days) and due solely to amyloidosis cardiac deterioration, or need for cardiac transplant, left ventricular assist device (LVAD), or intra-aortic balloon pump (IABP)
3. Clinical Manifestation of Renal Failure: Defined as the development of end-stage renal disease (need for hemodialysis or renal transplant)
4. Development of hematologic PD as per consensus guidelines
From CHR, abnormal free light chain ratio (light chain ratio must double) or from CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or 50% increase in urine M-protein to >200 mg/day (a visible peak must be present)
Free light chain increase of 50% to >100 mg/L
- Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline organ involved subjects who achieve confirmed organ response in each corresponding organ.
-Overall survival (OS) is measured from the date of randomization to the date of the subject’s death. 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.
-CHR rate at 6 months is defined as the proportion of subjects who achieve a complete hematologic response at 6 months, according to the consensus guidelines for AL amyloidosis, during or after the study treatment.
- Improvement in fatigue is defined as the change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Fatigue scale score, improvement in mental functioning is defined as the change from baseline in the 36-Item Short Form Survey version 2 (SF-36v2) Mental Component Summary (MCS), and improvement in health-related quality of life is defined as change from baseline in the EORTC QLQ-C30 Global Health Status scale score.
-Time to next treatment (TNT) defined as the time from the date of randomization to the start date of subsequent AL amyloidosis (non-protocol) treatment. Death due to PD prior to subsequent therapy is considered as an event. Otherwise, TNT is censored at the date of death or the last date known to be alive.
-Hematologic VGPR or better rate is defined as the proportion of subjects who achieve hematologic CR or VGPR.
-Time to CHR (or VGPR or better) is defined as the time between the date of randomization and the first efficacy evaluation at which the subject has met all criteria for hematologic CR (or VGPR or better).
-Duration of CHR (or VGPR or better) is defined as the time between the date of initial documentation of CHR (or VGPR or better) to the date of first documented evidence of hematologic progressive disease. For subjects who have not progressed, data will be censored at the last disease assessment.
-Time to cardiac response, time to renal response, and time to liver response. Defined as the time between the date of randomization and the first efficacy evaluation at which the subject has each corresponding organ response.
- Duration of organ response is defined as the time between the date of initial documentation of each corresponding organ response to the date of first documented evidence of the corresponding organ progressive disease. For subjects who have not had organ progression, data will be censored at the last disease assessment.
- Time to cardiac progression, time to renal progression, and time to liver progression.
Defined as the time from the date of randomization to the date of each corresponding organ progression per consensus guidelines. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria.
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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 | Yes |
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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
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 |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
United Kingdom |
United States |
Belgium |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Netherlands |
Poland |
Romania |
Spain |
Sweden |
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 to be 5 years after the last subject is randomized. Please see Protocol Section 17.9.1. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 |