This study has been transitioned to CTIS with ID 2024-511066-36-00 check the CTIS register for the current data. Double-blind Phase:Primary Objective:To evaluate the efficacy of birtamimab plus standard of care compared to placebo plus standard of…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Time to all-cause mortality during the Double-blind Phase
Secondary outcome
• Change from baseline to Month 9 of the Double-blind Phase in the 6-Minute
Walk Test (6MWT) distance
• Change from baseline to Month 9 of the Double-blind Phase in health related
quality of life using the Short Form 36 questionnaire Version 2 (SF 36v2)
Background summary
Subjects are being asked to take part in this study because they have been
newly diagnosed with Mayo Stage IV AL amyloidosis. This is a relatively rare
blood disease in which deposits of abnormal proteins, called amyloid, can build
up in the organs. This build up can cause progressive damage so that the organs
no longer work properly. Organs that can be affected include: heart, kidneys,
liver, spleen, digestive or gastrointestinal tract, and nervous system.
Antibodies are proteins that make up part of the immune system, the body*s own
natural defense system. They recognize foreign or unwanted material, such as
infections or even some cancers, and help destroy them without causing too much
harm to normal cells. Birtamimab is an antibody that was developed to destroy
the abnormal protein (amyloid) that is believed to be involved in AL
amyloidosis. Reduction in the amount of amyloid build up has been observed in
animal studies in which mice. In these studies mice were treated with a mouse
version of the birtamimab antibody. Birtamimab may reduce the amyloid build-up
and/or the damage caused by amyloid and may improve your abnormal organ
function.
Study objective
This study has been transitioned to CTIS with ID 2024-511066-36-00 check the CTIS register for the current data.
Double-blind Phase:
Primary Objective:
To evaluate the efficacy of birtamimab plus standard of care compared to
placebo plus standard of care when administered intravenously in Mayo Stage IV
subjects with AL amyloidosis by assessing time to all-cause mortality.
Secondary Objectives:
To evaluate birtamimab plus standard of care compared to placebo plus standard
of care on the following:
• Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance
• Change from baseline to Month 9 in health related quality of life using the
Short Form 36 questionnaire Version 2 (SF 36v2)
Exploratory Objectives:
None
Open-label Extension Phase:
Primary Objective:
To evaluate the long-term safety of birtamimab plus standard of care in Mayo
Stage IV subjects with AL amyloidosis
Secondary Objectives:
None
Exploratory Objectives:
To explore the long-term efficacy of birtamimab plus standard of care
Study design
This study comprises a multicenter, global, randomized, double-blind,
placebo-controlled, efficacy and safety evaluation in Mayo Stage IV subjects
with AL amyloidosis (i.e., Double-blind Phase), followed by a long-term,
open-label extension (i.e., Open-label Extension [OLE] Phase).
In the Double-blind Phase, newly diagnosed Mayo Stage IV subjects with AL
amyloidosis will be randomized in a 2:1 ratio to birtamimab or placebo. The
initial first-line chemotherapy regimen must include bortezomib.
Subjects will be stratified at randomization based on their 6MWT distance (<300
meters vs. >=300 meters) and initiation of daratumumab treatment at
randomization (yes vs. no).
Subjects will remain in the Double-blind Phase until its completion, which will
occur when approximately 47 primary endpoint events (all-cause mortality) have
been reached. After completion of the Double-blind Phase, eligible subjects may
enter the optional OLE Phase, in which all subjects will receive open-label
birtamimab treatment, regardless of Double-blind Phase randomized treatment
assignment. Treatment in the OLE Phase will continue for an additional 24
months or until birtamimab is commercially available in a subject*s country of
residence, whichever occurs first (in accordance with country-specific
regulations).
The primary efficacy endpoint is time to all-cause mortality during the
Double-blind Phase. The distribution of survival times will be compared between
treatment groups using a log rank test.
An interim analysis will be conducted when approximately 50% (or 24) of the
events have occurred. Using the O*Brien-Fleming group sequential methodology,
the interim analysis will be conducted with a significance level of 0.0108 and
the final analysis will be conducted with a significance level of 0.0984,
maintaining an overall study significance level of 0.10.
If a subject discontinues study drug prior to the end of the study, the subject
should have an Early Treatment Discontinuation (ETD) Visit within 28 to 35 days
after the last study drug administration (per Table 1 [Double-blind Phase] or
Table 2 [OLE Phase]). If a subject who discontinues study drug during the
Double-blind Phase is willing to continue to participate in study visits, they
will then have assessments every third month for the remainder of the
Double-blind Phase per Appendix 1.
Vital Status Assessment Follow-up phone calls (every 3 months) should be made
to all subjects (or their caregivers) who received a dose of study drug and are
no longer receiving study drug nor completing assessments in the clinic,
beginning approximately 3 months from the subject*s last visit. The subject*s
vital status (survival information) will be collected.
Intervention
Study Drug:
During the Double-blind Phase, study drug consists of birtamimab (24 mg/kg) or
placebo. The active study drug, birtamimab, is supplied as a sterile, single
use, lyophilized dosage form in a 20 mL vial containing 500 mg/vial birtamimab.
Each vial will be reconstituted with 9.6 mL sterile water for injection to a
concentration of 50 mg/mL resulting in a buffered, isotonic, preservative-free
solution. Birtamimab will be prepared in a 250-mL intravenous bag of 0.9%
saline. For subjects who are randomized to placebo, an IV infusion of 250 mL of
0.9% saline will be administered. All subjects will receive a flush of
approximately 30mL.
During the OLE Phase, study drug consists of birtamimab (24 mg/kg), which will
be supplied and prepared in the same manner as in the Double-blind Phase.
In both the Double-blind and OLE Phases, study drug will be administered once
every 28 days as an initial 120 (±20) minute intravenous infusion, including
flush. If the subject tolerates the initial infusion, subsequent infusions may
be administered over 60 (±10) minutes. The length of the infusion may be
extended over a longer period of time if and when it is clinically indicated. A
minimum of 21 days between doses is required.
Premedication:
All subjects will be premedicated for each dose of study drug with 25 mg
diphenhydramine (or equivalent dose of an H1 antihistamine) and 650 mg
acetaminophen (or equivalent paracetamol dose in accordance with local
practice) within 30 to 90 minutes prior to study drug administration.
Standard of Care Chemotherapy:
All subjects will receive concomitant standard of care chemotherapy, which must
include bortezomib administered subcutaneously on a weekly basis for the
initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may
be prescribed as per standard of care, at the Investigator*s discretion.
Antiviral prophylaxis is required. The initiation of daratumumab treatment at
randomization is allowed at the discretion of the Investigator; initiation at
any other time during the Double-blind Phase is prohibited. For subjects who
did not initiate daratumumab at randomization during the Double-blind Phase,
daratumumab may be initiated at any time during the OLE Phase at the
Investigator*s discretion.
Study burden and risks
See ICF section 7.0
Sir John Rogerson's Quay, Block C 77
Grand Canal Docklands, Dublin 2 D02 T804
IE
Sir John Rogerson's Quay, Block C 77
Grand Canal Docklands, Dublin 2 D02 T804
IE
Listed location countries
Age
Inclusion criteria
Double-blind Phase:
1.Aged >=18 years and legal age of consent according to local regulations
2.Newly diagnosed and AL amyloidosis treatment naive
3.Bone marrow demonstrating clonal plasma cells
4.Confirmed diagnosis of AL amyloidosis by the following:
-Histochemical diagnosis of amyloidosis determined by polarizing light
microscopy of green birefringent material in Congo red-stained tissue specimens
OR characteristic electron microscopy appearance AND
-Confirmatory immunohistochemistry OR immunoelectron microscopy OR mass
spectroscopy of AL amyloidosis
5.If the subject meets any of the following:
-Is black or of African descent
-Is over 75 years of age
-Has a history of familial transthyretin amyloidosis
-No cardiac tissue is available for typing, THEN the subject must have gene
sequencing consistent with transthyretin (TTR) wild type (i.e., no TTR mutation
present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2
propanodicarboxylic acid (99mTc DPD; Rapezzi 2011),
hydroxymethylenediphosphonate (99mTc HMDP; Galat 2015), OR pyrophosphate (99mTc
PYP; Bokhari 2013) scintigraphy
6.Cardiac involvement as defined by all of the following:
-Past documented or presently noted clinical signs and symptoms supportive of a
diagnosis of heart failure in the setting of a confirmed diagnosis of AL
amyloidosis in the absence of an alternative explanation for heart failure
-Either an endomyocardial biopsy demonstrating AL amyloidosis OR an
echocardiogram demonstrating a mean left ventricular wall thickness at diastole
>12 mm in the absence of other causes (e.g., severe hypertension, aortic
stenosis), which would adequately explain the degree of wall thickening OR
cardiovascular magnetic resonance imaging findings reported as characteristic
of amyloidosis
7.Confirmed Mayo Stage IV as defined by:
-NT-proBNP >=1800 pg/mL and
-Troponin-T >=0.025 ng/mL (mcg/L) or high sensitivity cardiac troponin T >=40
ng/L and
-Difference between involved and uninvolved free light chain >=18 mg/dL
8.Planned first-line chemotherapy contains bortezomib administered
subcutaneously weekly
9.Adequate bone marrow reserve, hepatic function, and renal function, as
demonstrated by:
-Absolute neutrophil count >=1.0 × 10e9/L
-Platelet count >=75 × 10e9/L
-Hemoglobin >=9 g/dL
-Total bilirubin <= 2 × the upper limit of normal (ULN) (except for subjects
with Gilbert*s syndrome, in which case direct bilirubin <=2 × ULN)
-Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase <=3 ×
ULN
-Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase <=3 × ULN
-Alkaline phosphatase (ALP) <=5 × ULN
-Estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2 as estimated by
the Chronic Kidney Disease Epidemiology Collaboration equation
10.Seated systolic blood pressure (BP) 90 to 180 mmHg
11.Distance walked during each Screening 6MWT is >30 meters and <550 meters
12.Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests
during Screening, the second within 24 hours prior to the first administration
of study drug, and must agree to use highly effective physician-approved
contraception from Screening to 90 days following the last study drug
administration
13. Male subjects must be surgically sterile or must agree to use a barrier
method, together with the use of highly effective physician-approved
contraception (Appendix 2) by their female partner of childbearing potential,
from Screening to 90 days following the last study drug administration
14.Ability to understand and willingness to sign an informed consent form (ICF)
prior to initiation of any study procedures
Open label extension phase:
To be eligible for the OLE Phase of the study, subjects must not have
discontinued treatment in the Double-blind Phase and must meet the following
criteria at the time of entry into the OLE Phase:
1. WOCBP must have a negative pregnancy test and must agree to use highly
effective contraception through 90 days following last study drug administration
2. Male subjects must be surgically sterile or agree to use highly effective
contraception through 90 days following last study drug administration
3. Ability to understand and willingness to sign an ICF prior to initiating the
OLE Phase
Exclusion criteria
Double-blind Phase:
1. Non-AL amyloidosis
2. NT-proBNP >8500 pg/mL
3. Meets the International Myeloma Working Group (IMWG) definition of multiple
myeloma, except for malignancy biomarker of involved/uninvolved serum free
light chain ratio >=100 (Appendix 3)
4. Subject is eligible for and plans to undergo ASCT or organ transplant during
the study
5. Symptomatic orthostatic hypotension that in the medical judgment of the
Investigator would interfere with the subject*s ability to safely receive
treatment or complete study assessments
6. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular
arrhythmias, or electrocardiographic (ECG) evidence of acute ischemia, within 6
months prior to the Month 1-Day 1 Visit
7. Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area
<1.0 cm2) or severe congenital heart disease
8. ECG evidence of acute ischemia or active conduction system abnormalities
with the exception of any of the following:
• First degree AV-block
• Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type)
• Right or left bundle branch block
• Atrial fibrillation with a controlled ventricular rate (uncontrolled [>110
bpm] ventricular rate is not allowed [determined by an average of 3 beats in
Lead II or 3 representative beats if Lead II is not representative of the
overall ECG])
9. Peripheral neuropathy assessed as National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2 with pain, Grade 3,
or Grade 4
10. Subject is receiving oral or intravenous antibiotics, antifungals, or
antivirals within 1 week of Month 1-Day 1 with the exception of prophylactic
agents
11. Prior treatment with hematopoietic growth factors, transfusions of blood or
blood products within 1 week of Month 1-Day 1
12. Prior radiotherapy within 4 weeks of Month 1-Day 1
13. Major surgery within 4 weeks of Month 1-Day 1 or planned major surgery
during the study
14. Active malignancy with the exception of any of the following:
• Adequately treated cutaneous basal cell carcinoma, squamous cell carcinoma,
or in situ cervical cancer
• Adequately treated Stage I cancer from which the subject is currently in
remission and has been in remission for 2 years
• Low-risk prostate cancer with Gleason score <7 prostate-specific antigen <10
ng/mL, and a stage of cancer at most cT2a, cN0, and CM0
• Any other cancer from which the subject has been disease-free for >=2 years
15. History of severe allergy to any of the components of birtamimab such as
histidine/L histidine hydrochloride monohydrate, trehalose dehydrate, or
polysorbate 20 or history of Grade >=3 infusion-related adverse events (AEs) or
hypersensitivity to another monoclonal antibody, or known hypersensitivity to
diphenhydramine (or an equivalent H1 antihistamine) or acetaminophen (or its
equivalent, paracetamol)
16. Known unresolved or active HIV, hepatitis B, hepatitis C, or SARS-CoV-2
infection
17. Prior treatment with plasma cell-directed chemotherapy, birtamimab,
daratumumab, 11-1F4, anti-serum amyloid P antibody, doxycycline for amyloid, or
other investigational treatment directed at amyloid
18. Treatment with another investigational agent within 30 days of Month 1-Day 1
19. Women who are pregnant or lactating
20. Any condition which could interfere with, or the treatment for which might
interfere with, the conduct of the study or which would, in the opinion of the
Investigator, unacceptably increase the subject*s risk by participating in the
study
21. Subject is under legal custodianship
22. History of uncontrolled epilepsy or seizure disorder
23. Waldenström's macroglobulinemia and/or immunoglobulin M monoclonal
gammopathy
Open label extension phase:
1. Any medical condition or clinically significant abnormality on physical,
neurological, laboratory, vital signs, or ECG examination that precludes
treatment with birtamimab or participation in the study, in the medical
judgment of the Investigator
2. Symptomatic orthostatic hypotension that in the medical judgment of the
Investigator would interfere with subject*s ability to safely receive treatment
or complete study assessments.
3. History of Grade >=3 infusion-related AEs during the Double-blind Phase or
hypersensitivity to birtamimab
4. Unable or unwilling to adhere to the study-specified procedures and
restrictions
5. Planning to receive any other investigational treatment during the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511066-36-00 |
| EudraCT | EUCTR2021-000037-14-NL |
| ClinicalTrials.gov | NCT04973137 |
| CCMO | NL77501.042.21 |