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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 23 March 2020
Main ID:  EUCTR2018-002761-19-CZ
Date of registration: 31/07/2019
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: 21/10/2019
Target sample size: 46
Recruitment status: Authorised-recruitment may be ongoing or finished
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 France Germany Greece Israel Italy Norway Poland
Spain United Kingdom United States
Contacts
Name: Clinical Trials Information Desk   
Address:  Västra Trädgårdsgatan 15 SE-111 53 Stockholm Sweden
Telephone:
Email: trials@oncopeptides.com
Affiliation:  Oncopeptides AB
Name: Clinical Trials Information Desk   
Address:  Västra Trädgårdsgatan 15 SE-111 53 Stockholm Sweden
Telephone:
Email: trials@oncopeptides.com
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 ECG with QRS < 120 msec, 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%.
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.
• Alkaline phosphatase = 3.5 x ULN.
• AST and ALT = 1.5 x ULN.
• Renal function: Estimated GFR (eGFR) by CKD-EPI formula = 45 mL/min (Appendix 11). A lower value may be acceptable after consultation and approval of the medical monitor.
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

Exclusion criteria:
1. Amyloidosis due to known mutations of the transthyretin gene or presence of another non-AL amyloidosis.
2. 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 is required to exclude clinically relevant conditions.
3. Cardiac risk stage 3 with NT-pro-BNP >5000 pg/mL (Appendix 7).
4. Low platelets values with evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. unable to maintain a platelet count =100,000 cells/mm3 [100 x 109/L]).
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 AV block (with the exception of Mobitz type I that is permitted), intermittent bundle branch block, ventricular arrythmias and sign of sick sinus syndrome.
7. Severe (symptomatic) orthostatic hypotension (a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within 3 minutes of standing compared with blood pressure from the supine position. 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 requiring parenteral or 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 B or C viral infection.
16. Concurrent symptomatic multiple myeloma (symptomatic defined as presence of bone lesion, extramedullary plasmacytoma or hypercalcemia (Rajkumar et al. 2014))
17. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes].
18. Previous cytotoxic therapies, including cytotoxic investigational agents, within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment (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 study treatment). Monoclonal antibodies (mAbs) within 4 weeks. Concomitant immunotherapy, investigational therapy, and anticoagulation therapy are not permitted (low dose acetylsalicylic aci


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
Patients with AL Amyloidosis
MedDRA version: 20.0 Level: PT Classification code 10002022 Term: Amyloidosis System Organ Class: 10021428 - Immune system disorders
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
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/g milligram(s)/gram
Concentration type: equal
Concentration number: 4-

Primary Outcome(s)
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
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)
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
Timepoint(s) of evaluation of this end point: During the course of the study
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)
OP201
Source(s) of Monetary Support
Oncopeptides AB
Secondary Sponsor(s)
Ethics review
Status: Approved
Approval date: 15/08/2019
Contact:
Results
Results available:
Date Posted:
Date Completed:
URL:
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