| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| LIGHT CHAIN AMYLOIDOSIS (Amyloidosis AL) |
| Amyloidoza łańcuchów lekkich (Amyloidoza AL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Plasma cells produce an abnormal antibody (immunoglobulin) protein- the “light chains” that become misfolded, and the abnormal, misfolded result is the forming of amyloid. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10086183 |
| E.1.2 | Term | AL 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 |
Primary Objectives:
• To evaluate the efficacy based on the percentage of patients with a complete hematologic response (CHR)
• To assess the safety based on the percentage of patients with serious adverse events (SAEs)
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
• To evaluate overall hematologic response rate (OHRR)
• To evaluate organ response rate (OrRR)
• To evaluate minimal residual disease (MRD)
• To evaluate hematologic progression free survival (PFS)
• To evaluate overall survival (OS)
• To evaluate time to response
• To evaluate time to organ progression
• To assess the safety and tolerability of sargramostim in combination with D-VCd
• To assess patient-reported outcomes (PRO)
Exploratory Objectives:
• To evaluate the impact of bone marrow macrophages and monocytes on hematologic and organ responses
• To evaluate the impact of cytogenetic aberrations on treatment response
• To evaluate mass spectrometry (MS) in amyloid typing
• To evaluate immuno-electron microscopy (IEM) in amyloid typing
• To explore correlation of cardiac biomarkers with heart failure symptoms and cardiac function
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 years of age or older.
2. Histopathological diagnosis of AL amyloidosis based on detection by polarizing light microscopy of green bi-refringent material in Congo red-stained tissue specimens (in an organ other than bone marrow) and typing of AL amyloid in a tissue specimen by IHC or immune electron microscopy or mass spectrometry.
3. Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
a) serum M-protein ≥0.5 g/dL by protein routine serum protein electrophoresis and immunofixation (IFE),
b) 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. Note: Measurable disease by urine Bence-Jones proteinuria is not sufficient for study enrollment.
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 (ANC) ≥1.0 × 109 /L
b. Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed until 7 days before enrollment
c. Platelet count ≥50 × 109 /L; Platelet transfusions are acceptable without restriction during the Screening period
d. Alanine aminotransferase level (ALT) ≤2.5 times the upper limit of normal (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/1.73 m2. Please note the eGFR is measured by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
7. A woman of childbearing potential must have a negative serum or urine pregnancy test (serum preferred) result at screening and 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 C1D1 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, e.g., 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. 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, except for 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure.
2. Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, infiltration with ≥60% clonal plasma cells in the bone marrow, or hypercalcemia (serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
3. Evidence of significant cardiovascular conditions as specified below:
a. NT-ProBNP >8500 pg/ml (ng/L);
b.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 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 enrollment;
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 in the study);
g. Screening 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 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of 20 mmHg despite medical management in the absence of volume depletion.
4. Planned stem cell transplant and stem cell collection during 6 cycles of protocol therapy.
5. History of malignancy (other than AL amyloidosis) within 3 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other lesion that in the opinion of the investigator, with concurrence with the sponsor, is considered cured and/or with minimal risk of recurrence or progression within 3 years).
6. COPD with FEV1 < 50% of predicted normal.
7. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification.
8. Known to be seropositive for HIV/
9. Seropositive for hepatitis B. Subjects with resolved infection and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real time polymerase chain reaction (PCR) measurement of (HBV) DNA levels. Those who are PCR positive will be excluded.
10. 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).
11. Grade 2 sensory or Grade 1 painful peripheral neuropathy.
12. Known hypersensitivity or contraindication to any of the components of study drugs including sargramostim, daratumumab, bortezomib, boron, mannitol, or cyclophosphamide, dexamethasone or any of its metabolites. Patients with known hypersensitivity to GM-CSF and yeast-derived products or any component of the product. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, hyaluronidase, human proteins, or their excipients, or known sensitivity to mammalian-derived products.
13. Concurrent medical 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.
14. Any form of non-AL amyloidosis, including wild type or mutated ATTR amyloidosis.
15. Known or suspected of not being able to comply with the study protocol 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
16. Woman who is pregnant or breastfeeding 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 or used an invasive investigational medical device within 4 weeks before Cycle1 Day1.
18. Major surgery within 2 weeks before Cycle 1 Day 1, 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 treatment administration.
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
• Complete hematologic response rate (CHRR)
• Serious adverse events rate
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Complete hematologic response rate (CHRR) (from the first response evaluation to the end of combination treatment (EOCT) assessment)
2. Serious adverse events rate (measured from the date of informed consent form is signed to the EOCT assessment) |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1. Overall hematologic response rate (OHRR)
2. Organ response rate (OrRR) for heart, kidney, liver
3. Minimal residual disease (MRD) status
4. Hematologic progression free survival (PFS)
5. Overall survival (OS)
6. Time to very good partial or better hematologic response
7. Time to each organ response (heart, kidney, liver)
8. Time to each organ progression (heart, kidney, liver)
9. Incidence of adverse events
10. Change of quality of life
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from the first response evaluation to the EOT assessment
2. from the first response evaluation to the last assessment
3. measured at the time CHR is assessed
4. measured from C1D1 to the date of first documentation of hematologic progression, or death, whichever occurs first
5. measured from C1D1 to the date of subject’s death
6. measured from C1D1 to the date of first assessment in which the response criteria for VGPR or better are met
7. measured from C1D1 to the date of first assessment in which the response criteria for each corresponding organ are met)
8. easured from C1D1 to the date of progression for each corresponding organ)
9. measured from the date of informed consent form is signed to the EOCT assessment
10. from baseline in EORTC QLQ-C30 and EQ-5D-5L scales scores
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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 | No |
| 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 | 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) | 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.8.3 |
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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 30 |
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