A Phase 3 Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physician's Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
- Conditions
- primary amyloidosisprimary systemic amyloidosis (PSA)10035227
- Registration Number
- NL-OMON50586
- Lead Sponsor
- Millenium Pharmaceuticals
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 7
1. Male or female patients 18 years or older., 2. Biopsy-proven diagnosis of AL
amyloidosis according to the following standard criteria:, a. Histochemical
diagnosis of amyloidosis, as based on tissue specimens with Congo red staining
with exhibition of an apple-green birefringence, b. If clinical and laboratory
parameters insufficient to establish AL amyloidosis or in cases of doubt,
amyloid typing may be necessary (see Section 15.1), 3. Measurable disease as
defined by serum differential free light chain concentration
(dFLC, difference between amyloid forming [involved] and nonamyloid forming
[uninvolved] free light chain [FLC]) >= 50 mg/L)., 4. Objective, measurable
major (cardiac or renal ) organ amyloid involvement as defined as follows
(amyloid involvement of at least 1 required):
a. Cardiac involvement is defined as the presence of a mean left ventricular
wall thickness on echocardiogram greater than 12 mm in the absence of other
potential causes of left ventricular hypertrophy (controlled hypertension is
allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy
in the presence of clinical or laboratory evidence of involvement. If there is
isolated cardiac involvement, then typing of amyloid deposists is recommended.
b. Renal involvement is defined as proteinuria (predominantly albumin) > 0.5
g/day in a 24- hour urine collection
Note: Amyloid involvement of other organ systems is allowed, but not required.,
5. Must be relapsed or refractory after 1 or 2 prior therapies.
For this protocol, relapsed is defined as PD documented more than 60
days after last dose; refractory is defined as documented absence of
hematologic response or hematologic progression on or within 60 days
after last dose of prior therapy.
a. Patient must not have been previously treated with proteasome
inhibitors. (The sponsor reserves the right to open the study to
proteasome inhibitor-exposed patients in the future, at some time point
after the first IA. In that case, the patient may not be refractory to
proteasome inhibitor therapy.), b. Given that the physician may select from an
offered list of regimens to treat a, specific patient, the patient may be
refractory to an agent/s listed within the list of offered treatment choices,
c. Must have recovered (ie, <= Grade 1 toxicity or patient*s baseline status)
from the reversible effects of prior therapy, d. If a patient has received a
transplant as his/her first-line therapy, he/she must be, at least 3 months
posttransplantation and recovered from the side effects of the, stem cell
transplant6. Patient must meet criteria for 1 of the following AL Amyloidosis
Risk Stages (as defined, by NT-proBNP cut off of < 332 pg/mL and troponin T
cut-off of 0.035 ng/mL as, thresholds):, a. Stage 1: both NT-proBNP and
troponin T under threshold, b. Stage 2: either NT-proBNP or troponin T [but not
both] over threshold;, c. Stage 3: both NT-proBNP and troponin T over threshold
(but NT-proBNP, < 8000 pg/mL), 7. ECOG Performance Status <= 2, 8. Clinical
laboratory values:, a. Absolute neutrophil count >= 1000/µL, b. Platelet count
>=75,000/µL
c. Total bilirubin <= 1.5 x ULN except for patients with Gilbert's syndrome
as defined by > 80% unconjugated bilirubin and total bilirubin <= 6
mg/dL, d. Alkaline phosphatase <= 5 x ULN,, e. ALT
Prospective patients will be excluded from this study if they meet ANY of the
following criteria:, 1. Amyloidosis due to mutations of the transthyretin gene
or presence of other, non-AL amyloidosis., 2. Female patients who are
lactating, breastfeeding, or pregnant., 3. Medically documented cardiac
syncope, uncompensated NYHA Class 3 or 4 congestive heart failure (Section
15.6), myocardial infarction within the previous 6 months, unstable angina
pectoris, clinically significant repetitive ventricular arrhythmias despite
antiarrhythmic treatment, or severe orthostatic hypotension or clinically
important autonomic disease., 4. Clinically overt multiple myeloma, according
to the IMGW criteria with at least 1 of the following:
a. Bone lesions
b. Hypercalcemia, defined as a calcium of > 11 mg/dL, 5. Inability to swallow
oral medication, inability or unwillingness to comply with the drug
administration requirements, or GI procedure that could interfere with the
oral, absorption or tolerance of treatment., 6. Requirement for other
concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered to be investigational or which would be considered as a treatment of
AL amyloidosis. However, patients may be on chronic steroids (maximum dose 20
mg/day prednisone or equivalent [Section 15.7]) if they are being given for,
disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid
arthritis, etc.)., 7. Comorbid systemic illnesses or other severe concurrent
disease which, in the judgment of the investigator, would make the patient
inappropriate for entry into this study or interfere significantly with the
proper assessment of safety and toxicity of the prescribed regimens., 8.
Ongoing or active infection, known HIV positive, active hepatitis B or C
infection., 9. Psychiatric illness/social situations that would limit
compliance with study requirements., 10. Known allergy to boron, MLN9708, any
of the study treatments, their
analogues, or excipients.
11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine,
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or
St. John's wort within 14 days before the first dose of study treatment., 12.
Diagnosed or treated for another malignancy with 3 years (or 5 years in France)
before study enrollment or previously diagnosed with another malignancy and
have any evidence of residual disease. Patients with non-melanoma skin cancer
or carcinoma in situ of any type are not excluded if they have undergone
complete resection.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or<br /><br>other study medication is the only endpoint being assessed. All other study<br /><br>endpoints will no longer be assessed.</p><br>
- Secondary Outcome Measures
Name Time Method <p>As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or<br /><br>other study medication is the only endpoint being assessed. All other study<br /><br>endpoints will no longer be assessed.</p><br>