| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis ) |
|
| 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. |
|
| 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 |
|
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the clinically observable endpoints for major organ deterioration (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:
- Progression-free survival (PFS)
- Organ response rate (OrRR)
- Overall survival (OS)
- Time 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 status in amyloidosis patients as a surrogate for PFS and OS or
as a biomarker for relapse
|
|
| 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 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 monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at central lab),
-serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥5mg/ dL.
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)Pre-treatment 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 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 4 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 4 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 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. |
|
| 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 (AV) 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.Seropositive for human immunodeficiency virus(HIV)
9.Known to have hepatitis B surface antigen positivity,or known to have a history of hepatitis C
10.Grade 2 sensory or Grade 1 painful peripheral neuropathy
11.Known hypersensitivity to bortezomib,boron or mannitol
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 or human proteins,or their excipients (refer to Investigator Brochure),or known sensitivity to mammalian-derived products
15.Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism,drug dependency,or psychological disorder)or the subject has any condition for which,in the opinion of the investigator, participation would not be in the best interest of the subject (eg,compromise their well-being)or that could prevent,
limit,or confound the protocol-specified assessments
16. Woman who is pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 1 year after discontinuation of cyclophosphamide or 3 months following discontinuation of daratumumab,whichever is longer
17.Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before Cycle1,Day 1
18. Major surgery within 2 weeks before Cycle1,Day1,or will not have fully recovered from surgery,or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration.Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is overall complete hematologic response rate. |
|
| 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. |
|
| 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, any detectable monoclonal protein or abnormal free light chain ratio (light chain ratio must double). Note: the development of a IgG Kappa spike on SPEP/IFE
will not be considered disease progression for subjects who have received daratumumab, DIRA testing may be indicated.
From 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
-Progression-free survival (PFS) is defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac, renal, or liver) progression, or death due to any cause, whichever occurs first according to central laboratory results and judged by international consensus guidelines. For those subjects who are still alive and have not yet progressed, the subject’s data will be censored at the last disease assessment.
- Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline organ involved subjects who achieve 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.
-Improvement in fatigue is defined as the change from baseline in the EORTC QLQ-C30 Fatigue scale score, improvement in mental functioning is defined as the change from baseline in the SF-36v2 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). 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 complete hematologic response (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). For subjects without a hematologic CR (or VGPR or better), data will be censored either at the date of progressive disease or, in the absence of progressive disease, at the last disease assessment.
-Duration of complete hematologic response (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 organ response is defined as the time between the date of randomization and the first efficacy evaluation at which the subject has each corresponding organ response. For subjects without organ response, data will be censored either at the date of the corresponding organ progressive disease or, in the absence of organ progressive disease, at the last disease assessment.
-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
|
|
| 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.
|
|
| 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 | 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 |
|
| 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 | 3 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The end of study is defined to be 5 years after the last subject is randomized. Please see Protocol Section 17.9.1. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
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