It is an early clinical trial to assess a new drug (Melflufen) when given together with a steroid (Dexamethasone) in the treatment of patients with a disease called the AL Amyloidosis Patients should also have received treatment in the past for the disease.

• Register: EUCTR
• Last refreshed on: 28 March 2022
• Main ID: EUCTR2018-002761-19-DE
• Date of registration: 12/08/2019
• Prospective Registration: Yes
• Primary sponsor: Oncopeptides AB
• Public title: It is an early clinical trial to assess a new drug (Melflufen) when given together with a steroid (Dexamethasone) in the treatment of patients with a disease called the AL Amyloidosis Patients should also have received treatment in the past for the disease.
• Scientific title: An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients with AL Amyloidosis Following at Least One Prior Line of Therapy
• Date of first enrolment: 06/03/2020
• Target sample size: 46
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002761-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Czech Republic, Czechia, France, Germany, Greece, Israel, Italy, Norway, Poland, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trials Information Desk
• Affiliation: Oncopeptides AB

• Name: Clinical Trials Information Desk
• Affiliation: Oncopeptides AB

Key inclusion & exclusion criteria

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).
11. Echocardiogram (ECHO) with left ventricular ejection fraction (LVEF) = 45% in patients with known cardiac amyloidosis involvement.
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
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 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 (in investigator's opinion)
9. Clinically important autonomic disease (in investigator's opinion)
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 (definded as HBsAg+)
• Patients with prior hepatitis B vaccination 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 consultation of risk of reactivation
17. Concurrent symptomatic multiple myeloma (definded as presence of bone

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Patients with AL Amyloidosis
MedDRA version: 20.0 Level: PT Classification code 10002022 Term: Amyloidosis System Organ Class: 10021428 - Immune system disorders

Intervention(s)

Product Name: Melflufen
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: melphalan fulfenamide hydrochloride
CAS Number: 380449-54-7
Other descriptive name: MELFLUFEN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Trade Name: Dexamethasone 4 mg JENAPHARM
Product Name: Dexamethasone
Product Code: H02AB02
Pharmaceutical Form: Tablet
INN or Proposed INN: DEXAMETHASONE
CAS Number: 50-02-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Primary Outcome(s)

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)

Timepoint(s) of evaluation of this end point: During the course of the study

Secondary Objective: 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

Main Objective: 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

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: During the course of the study

Secondary ID(s)

2018-002761-19-CZ

OP201

Source(s) of Monetary Support

Oncopeptides AB

Ethics review

Status: Approved
Approval date: 06/03/2020
Contact: