| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with AL Amyloidosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with AL Amyloidosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
•To explore the safety and tolerability
•To identify recommended Phase 2 dose (RP2D).
Phase 2
•To evaluate the hematologic ORR after 4 cycles at the RP2D determined in Phase 1 |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
•To assess pharmacokinetic profile of melflufen in this patient population
•To assess best hematologic response
•To assess duration of hematologic response
•To assess the proportion of organ system responses
•To assess duration of organ system responses
•To assess hematologic ORR
•To assess time to next AL amyloidosis treatment
•To assess OS
Phase 2
•To assess safety and tolerability
•To assess best hematologic response
•To assess duration of hematologic response
•To assess the proportion of organ system responses
•To assess duration of organ system responses
•To assess time to next AL amyloidosis treatment
•To assess OS
Exploratory
•To assess MRD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, age 18 years or older at the time of signing the informed consent.
2. Proven histochemical diagnosis of AL amyloidosis based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence confirmed with appropriate method of typing, e.g. mass spectrometry, immunofluorescence or immunohistochemistry (previous aspirate/biopsy tissue specimen result acceptable).
3. At least one prior line of therapy, defined as either one non-transplant regimen, one ASCT, or one regimen of induction therapy followed by a single ASCT (without hematologic progression between induction and ASCT). No more than 4 cycles of melphalan containing chemotherapy is allowed.
4. Measurable hematologic disease as defined by serum differential free light chain (dFLC) concentration ≥ 20 mg/L (dFLC is the difference between amyloid forming [involved] and non-amyloid forming [uninvolved] FLC).
5. Objectively measurable (cardiac, and/or renal and/or liver) organ amyloid involvement, as defined below (amyloid involvement of at least 1 required). See also Appendix 9:
a. Cardiac involvement: mean wall thickness >12 mm on echocardiogram, with no other cardiac cause or an elevated NT-ProBNP (>332 ng/L) in the absence of renal failure or atrial fibrillation.
b. Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
c. Hepatic involvement: Total liver span >15 cm in the absence of heart failure, or alkaline phosphatase >1.5 times institutional upper limit of normal (ULN).
Amyloid involvement of other organ systems is allowed, but not required.
6. ECOG performance status ≤ 2. See Appendix 5.
7. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test (See Appendix 4).
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
9. Less than 30% plasma cells in bone marrow aspirate or biopsy.
10. 12-lead screening safety ECG with PR < 220 msec and QTcF interval of ≤ 470 msec calculated by Fridericia Formula (Appendix 12) in patients with known cardiac amyloidosis involvement.
11. Echocardiogram (ECHO) with left ventricular ejection fraction (LVEF) ≥ 45%.
12. The following laboratory results must be met:
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
• Platelet count ≥ 100,000 cells/mm3 (100 x 109/L) without required transfusions during the 10 days prior to initiation of therapy).
• Hemoglobin ≥ 9.0 g/dl (RBC transfusions are permitted).
• Total Bilirubin ≤ 1.5 x ULN. Higher value may be accepted in participants diagnosed with Gilbert syndrome, if approved by the medical monitor.
• AST and ALT ≤ 1.5 x ULN.
• Renal function: Estimated GFR (eGFR) by CKD-EPI formula ≥ 45 mL/min (Appendix 11).
13. Male participant agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 90 days after the last dose of melflufen and refrain from donating sperm during this period.
OR
Female participant meets one of the following conditions:
i. Not of child bearing potential as defined in Appendix 4
ii. Not currently pregnant or breastfeeding and agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 30 days after the last dose of melflufen.
|
|
| E.4 | Principal exclusion criteria |
1.Amyloidosis due to known mutations of the transthyretin gene or presence of another non-AL amyloidosis
2.Cardiac risk stage 3 with NT-pro-BNP >5000 pg/mL (Appendix 7)
3.Evidence of gastro-intestinal bleeding
•Frank bleeding within 6 months prior to initiation of therapy
•Positive feces-hemoglobin/ fecal occult blood test within 6 months prior to initiation of therapy if clinically relevant. In case of a positive test within the last 6 months, a colonoscopy and upper endoscopy are required to exclude clinically relevant conditions. Should the first examination provide a satisfactory explanation to the GI-bleed, the second examination might be cancelled at the discretion of the investigator
4.Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by ≥10,000 cells/mm3 [10 x 109/L] after transfusion of an appropriate dose of platelets)
5.Medically documented cardiac syncope, NYHA (Appendix 8) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant ventricular arrhythmias, or atrioventricular (AV) block
6.Clinically significant finding on 24 h Holter recording performed at screening, including but not limited to high degree AV block (2nd degree type 2 or 3rd degree AV block), ventricular arrythmias and sign of sick sinus syndrome. (Bundle branch block is acceptable if clinically stable for ≥6 months)
7.Supine systolic blood pressure <90 mm Hg, or orthostatic hypotension defined as a decrease in systolic blood pressure upon standing of >20 mmHg or symptomatic orthostatic hypotension regardless of the amount of the drop in mmHg, despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion. See Section 8.3.2 for details on the assessment of orthostatic hypotension)
8.Clinically significant factor X deficiency
9.Clinically important autonomic disease
10.Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study
11.Known active infection that is uncontrolled (including symptomatic or asymptomatic COVID-19) or has required intravenous systemic therapy or has required oral anti-infective treatment within 14 days of initiation of treatment; Other wash out period may be considered after consultation and approval of the medical monitor
12.Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast, and very-low and low risk prostate cancer in active surveillance as defined in NCCN Guideline: Prostate Cancer (NCCN 2019)
13.Pregnant or breast-feeding females
14.Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
15.Known HIV or active hepatitis C viral infection
16.Known active hepatitis B viral infection (defined as HBsAg+)
•Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-)
•Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation
17.Concurrent symptomatic multiple myeloma (symptomatic defined as presence of bone lesion, extramedullary plasmacytoma or hypercalcemia)
18. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
19.Any of the following treatments, within the specified timeframe:
•Previous cytotoxic therapies, including cytotoxic investigational agents, within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy
•The use of live vaccines within 30 days before initiation of therapy
•Monoclonal antibodies within 4 weeks of initiation of therapy
•Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy
•Concomitant immunotherapy, investigational therapy and anticoagulation therapy are not permitted (low dose i.e. ≤ 150 mg OD acetylsalicylic acid permitted)
20.Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia, or neuropathy Grade 2, are permitted)
21.Prior autologous or allogeneic stem cell transplant within 12 weeks of initiation of therapy
22.Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD)
23.Prior major surgical procedure or radiation therapy within 4 weeks of the first dose of study treatment
24.Known intolerance to steroid therapy, known hypersensitivity to melphalan or melflufen, or known hypersensitivity to any of the excipients of melflufen or the dexamethasone product |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
• Frequency and grade of adverse events (AE) and laboratory values
• Dose-Limiting Toxicity (DLT) during Cycle 1 up to a maximum dose of melflufen of 40 mg
Phase 2
• The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study |
|
| E.5.2 | Secondary end point(s) |
Phase 1
• Melphalan plasma concentration post melflufen administration
• Best hematologic response (CR, VGPR, PR, NR, or PD)
• Duration of hematologic response (CR, VGPR, PR)
• Proportion of participants with kidney, cardiac or liver response, respectively
• Duration of organ system specific responses (separately for kidney, cardiac, and liver)
• The proportion of participants who achieve a hematologic CR, VGPR, or PR
• Time to next AL amyloidosis treatment
• OS
Phase 2
• Frequency and grade of AEs and laboratory values
• Best hematologic response (CR, VGPR, PR, NR, or PD)
• Duration of hematologic response (CR, VGPR, PR)
• Proportion of participants with kidney, cardiac or liver response, respectively
• Duration of organ system specific responses (separately for kidney, cardiac, and liver)
• Time to next AL amyloidosis treatment
• OS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Israel |
| United States |
| France |
| Germany |
| Greece |
| Italy |
| Norway |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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