The primary hypothesis of this study is that the 6-month OS rate of patients with newly diagnosed stage 3B AL amyloidosis will exceed 50% after primary therapy with daratumumab
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to evaluate the overall survival rate at 6 months
following treatment with daratumumab in frontline AL patients with stage 3B
disease
Secondary outcome
The secondary objectives are:
• To evaluate the overall (ORR), very good partial (VGPR) and complete (CR)
hematologic response rates at 3 and 6 months
• To evaluate the Major Organ Deterioration Progression-Free Survival
(MOD-PFS). This is a composite endpoint of clinically observable endpoints and
will be defined from the start of study treatment (Cycle 1 Day 1) to any one of
the following events (whichever occurs first)
* Death
* Clinical manifestation of cardiac failure:
o Defined as development of dyspnea at rest (for at least 3 consecutive days
and solely due to amyloidosis cardiac deterioration) that requires
hospitalization for management, or need for cardiac transplant, or left
ventricular assist device (LVAD), or intra-aortic balloon pump (IABP).
* Clinical manifestation of renal failure:
o Defined as the development of end stage renal disease (need for hemodialysis
or renal transplant)
* Development of hematologic PD as per consensus guidelines (two consecutive
assessments are required, see section 9.2.1)
o From CHR, abnormal free light chain ratio (light chain ratio must double).
o From CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or 50%
increase in urine M-protein to >200 mg/day (a visible peak must be present)
o Free light chain increase of 50% to >100 mg/L
• To evaluate PFS based on all-cause mortality and progression of disease (PD,
including hematologic PD and organ (heart and kidney) PD according to consensus
guidelines)
• To evaluate the organ response rate (OrRR)
o Heart
o Kidney
o Liver
• To evaluate treatment effects on patient-reported outcomes (PROs) such as the
Short Form-36 Health Survey (SF-36), European Quality of Life-5 Dimensions
Questionnaire (EQ-5D-5L) and European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
• To characterize time to and duration of response
• To assess the safety and tolerability of daratumumab in patients with stage
3B AL amyloidosis
Background summary
AL amyloidosis is a rare disease with a poor prognosis. The median survival of
untreated patients is 13 months from diagnosis. The therapeutic options for AL
amyloidosis should include eradication of plasma cells that produce the toxic
protein deposits leading to organ failure. These plasma cells express CD38 and
could be targeted by antibodies such as daratumumab that binds and eliminates
CD38 expressing cells.
Based on the available safety data from single-agent daratumumab studies
(GEN501 & SIRIUS), and from combination studies of daratumumab with
lenalidomide or bortezomib or pomalidomide, the expected safety profile of
daratumumab in this combination therapy study is considered manageable. In
addition, the safety run-in phase of this study will provide information on the
safety of daratumumab in the stage 3B AL patient population.
In summary, there is a strong rationale for evaluating daratumumab in AL:
• There is a medical need for new treatments for stage 3B AL since no specific
standard of care therapy in frontline or relapsed setting exist
• There is high morbidity and mortality in stage 3B AL subjects and the current
treatment options are inadequate
• Preclinical data suggest that malignant plasma cells in AL express CD38 and
therefore can be targeted by daratumumab
• There is substantial evidence that daratumumab may be efficacious and with a
manageable safety profile in patients with AL
Study objective
The primary hypothesis of this study is that the 6-month OS rate of patients
with newly diagnosed stage 3B AL amyloidosis will exceed 50% after primary
therapy with daratumumab
Study design
This is an open-label, multicenter, Phase 2 study in subjects with newly
diagnosed stage 3B light chain (AL) amyloidosis. Approximately 40 subjects will
receive primary therapy with daratumumab. Subject participation will include a
Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a
Long-term Follow-up Phase
Intervention
Yes
Study burden and risks
Participants in this study should return to hospital day care every week the
first 8 weeks for IV/SC administration of Daratumumab. As soon as the amended
version of the protocol (protocol amd #1) is in force subjects that will start
will receive Daratumumab subcutaneously.
Adverse effects of daratumumab can lead to airway infection and changes in the
blood findings. Infusion related reactions may also occur.
These risks will be monitored extensively and compared to the fact that there
is currently no effective treatment for 3B light-chain amyloidosis
Riscs of Daratumumab are managed by staggered dosing. Subjects will also
receive pre-medication to lower the risk of known side effects. A DSMB is
implemented who will evaluate safety after the first 6 subjects have completed
one full cycle.
The reason for administering pre-infusion medications is to avoid infusion
related reactions (IRR). Signs and symptoms of IRRs may include respiratory
symptoms, such as stuffy nose, cough, throat irritation, as well as chills,
vomiting and nausea. Less common symptoms are having trouble breathing
(wheezing), runny nose, fever, chest discomfort, itching of the skin, low blood
pressure or high blood pressure and fluid in the lungs (pulmonary edema).The
IRR are mostly seen during infusion 1, in some patients also in 2 but not
anymore afterwards
With the current pre medication around 25% of patients will experience an IRR
during infusion 1.
The following medications to reduce the risk of known side effects of
daratumumab are depicted in the study protocol, section 6.2.3.1:
• Dexamethasone 20 mg IV or PO, Paracetamol (acetaminophen) 650 to 1000 mg PO
or IV
• An antihistamine (diphenhydramine 25 to 50 mg, or equivalent) either given IV
or PO
• Montelukast (leukotriene inhibitor): Pre-dose administration of a leukotriene
inhibitor (montelukast 10 mg PO or equivalent) is optional on Cycle 1 Day 1 and
can be administered up to 24 hours before the IV/SC infusion as per
investigator*s discretion. If necessary, oral pre-infusion medications may be
administered at the subject*s home on the day of the daratumumab treatment,
provided they are taken within 3 hours prior to the administration of
daratumumab IV/SC infusion.*
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
1. Men or women 18 years of age or older., 2. Diagnosis of amyloidosis, AL
type, based on:, a. Histopathological diagnosis of amyloidosis based on
detection by immunohistochemistry and polarizing light microscopy of green
bi-refringent material in Congo Red stained tissue specimens (excluding bone
marrow) or characteristic electron microscopy appearance, AND, b. Measurable
disease of amyloid light chain amyloidosis as defined by at least ONE of the
following: , - serum monoclonal protein >=0.5 g/dL by protein electrophoresis
(routine serum protein electrophoresis and immunofixation performed at local
lab), - serum free light chain (FLC) >=2.0 mg/dL (20 mg/L) with an abnormal
kappa:lambda ratio or the difference between involved and uninvolved free light
chains (dFLC) >=2mg/dL (20 mg/L). Serum FLCs will be measured using the Freelite
assay at a central laboratory., - Note: Measurable disease by Urine Bence-Jones
Proteinuria is not sufficient for study enrolment. , AND, c. Cardiac
involvement by AL amyloidosis according to consensus guidelines (See ATTACHMENT
3), 3. Mayo Stage 3B disease, defined as both A. increased cardiac troponin
(hsTnT >54 pg/ml) AND B. increased NT-proBNP >= 8500 pg/ml, 4. For subjects
with congestive heart failure, symptoms should be optimally managed and
clinically stable with no cardiovascular-related hospitalizations within 2
weeks prior to Cycle 1 Day 1, as assessed by the Principal Investigator. [See
also exclusion criteria 3], 5. Eastern Cooperative Oncology Group (ECOG)
Performance Status (PS) 0, 1,2 or 3 (ATTACHMENT 1), 6. Subject must have
pre-treatment clinical laboratory values meeting the following criteria during
the Screening Phase:, a. Absolute neutrophil count >=1.0 × 109/L;, b. Hemoglobin
level >=8.0 g/dL (>=5 mmol/L), c. Platelet count >=75 × 109/L; platelet
transfusions are NOT acceptable, d. Alanine aminotransferase level (ALT) <=2.5 x
ULN;, e. Aspartate aminotransferase (AST) <=2.5 x ULN, f. Total bilirubin level
<=1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case
direct bilirubin <= 2 × ULN, g. Estimated Glomerular Filtration Rate (eGFR) >=20
mL/min; Please note that the eGFR is measured by using the CKD-EPI equation ,
7. Women of childbearing potential 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 prior to dosing and
continue for 3 months after discontinuation of daratumumab. 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 3 months after receiving the last dose of daratumumab, female subjects 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 3 months after discontinuation of daratumumab. All men must not
donate sperm during the study and for 3 months after discontinuation of
daratumumab., 10. Female subjects of childbearing potential must have a
negative serum or urine pregnancy tests within 14 days prior to Cycle 1 Day 1.
For requirements during the Treatment Phase, please see the Time and Events
Schedule., 11. Each subject must sign an informed consent form (ICF) indicating
that he or she understands the purpose of the 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.
Exclusion criteria
1.Prior therapy for AL amyloidosis or multiple myeloma with the exception of
160 mg dexamethasone (or equivalent steroid) maximum exposure prior to Cycle 1
Day 1., 2.Previous or current diagnosis of symptomatic multiple myeloma
including the presence of lytic bone disease, plasmacytomas, >= 60% plasma cells
in the bone marrow, and/or hypercalcemia., 3.Evidence of significant
cardiovascular conditions as specified below:, a. New York Heart Association
(NYHA) classification of heart failure, stages IIIB or IV , b. Heart failure
that in the opinion of the investigator due to ischemic heart disease or
uncorrected valvular disease, and not due to AL amyloid cardiomyopathy., c.
Hospitalization for unstable angina or myocardial infarction or percutaneous
cardiac intervention with recent stent or coronary artery bypass grafting, all
within the last 6 months prior to the first dose , d. Subjects with a history
of sustained ventricular tachycardia or aborted ventricular fibrillation or
with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal
dysfunction for which a pacemaker/ICD is indicated but will not be placed
(subjects who do have a pacemaker/ICD are allowed in the study), e. Screening
12-lead ECG showing a baseline QT interval as corrected by Fridericia*s formula
(QTcF) >500 msec. Subjects who have pacemaker may be included regardless of
calculated QTc interval., f. 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. Subjects planning to undergo a stem cell transplant
during the first 6 cycles of protocol therapy are excluded. Stem cell
collection during the first 6 cycles of protocol therapy is permitted., 5.
Diagnosed or treated for malignancy other than AL, except:, a. Malignancy
treated with curative intent and with no known active disease present for >=24
months before Cycle 1 Day 1, b. Adequately treated non-melanoma skin cancer or
lentigo maligna without evidence of disease, c. Adequately treated carcinoma in
situ (e.g. cervical, breast) with no evidence of disease, 6. Subject has known
chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in
1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required
for subjects suspected of having COPD and subjects must be excluded if FEV1
<50% of predicted normal, 7. Subject has known moderate or severe persistent
asthma within the past 2 years or currently has uncontrolled asthma of any
classification. (Note that subjects who currently have controlled intermittent
asthma or controlled mild persistent asthma are allowed in the study)., 8.
Subject is known to be seropositive for human immunodeficiency virus (HIV). HIV
positive subjects who are stable on highly active antiretroviral therapy
(HAART) with no opportunistic infections within the last 6 months are
eligible. , 9. Subjects known: a. To be seropositive for hepatitis B (defined
by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with
resolved infection (ie, subjects who are HBsAg negative but positive for
antibodies to hepatitis B core antigen [antiH-Bc] and/or antibodies to
hepatitis B surface antigen [anti-HBs]) must be screened using real-time
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA
levels. Those who are PCR positive will be excluded. , b. To be seropositive
for hepatitis C, 10. Subject has any 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., 11. Any form of non-AL amyloidosis, including wild type or mutated
(ATTR) amyloidosis. , 12. Subject has known allergies, hypersensitivity, or
intolerance to monoclonal antibodies or human proteins, or their excipients, or
known sensitivity to mammalian-derived products., 13. Subject is 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 or that could prevent, limit,
or confound the protocol-specified assessments., 14. Subject is a woman who is
pregnant or breastfeeding or planning to become pregnant while enrolled in this
study or within 3 months following discontinuation of daratumumab., 15. Subject
has received an investigational drug or used an invasive investigational
medical device within 4 weeks prior to Cycle 1 Day 1, 16. Subject has had major
surgery within 2 weeks prior to 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 drug administration
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 |
|---|---|
| Other | Clinicaltrials.gov.uk |
| EudraCT | EUCTR2018-004333-33-NL |
| CCMO | NL68619.041.19 |