A study to assess the safety and efficacy of dexamethasone plus MLN9708 or physician choice of treatment in patients with relapsed or refractory amyloidosis.
- Conditions
- Relapsed or Refractory Systemic Light Chain (AL) AmyloidosisTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2011-005468-10-GB
- Lead Sponsor
- Millennium Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 177
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. 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 or AST =3 x ULN
f. Calculated creatinine clearance = 30 mL/min
9. Female patients who:
a. If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed conse
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 within 3 years (or 5
years for patients in France) before study enrolment 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 clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: As of this amendment, the objectives are to provide continued access of<br>MLN9708 and/or other study medications and to continue collecting<br>relevant safety data to monitor patient safety. All other study objectives<br>will no longer be assessed;Secondary Objective: As of this amendment, the objectives are to provide continued access of<br>MLN9708 and/or other study medications and to continue collecting<br>relevant safety data to monitor patient safety. All other study objectives<br>will no longer be assessed. ;Primary end point(s): As of this amendment, evaluation of the safety profile of MLN9708<br>and/or other study medication is the only endpoint being assessed. All<br>other study endpoints will no longer be assessed ;Timepoint(s) of evaluation of this end point: As of this amendment, evaluation of the safety profile of MLN9708<br>and/or other study medication is the only endpoint being assessed. All<br>other study endpoints will no longer be assessed.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): As of this amendment, evaluation of the safety profile of MLN9708<br>and/or other study medication is the only endpoint being assessed. All<br>other study endpoints will no longer be assessed. <br><br>;Timepoint(s) of evaluation of this end point: AEs - Recorded from the first dose of study drug through 30 days after<br>last dose of study drug. Only AEs leading to dose modification or<br>discontinuation, Grade = 3 AEs, AEs of new primary malignancy, all<br>reports of drug exposure during pregnancy and pregnancy outcomes,<br>product complaints, and medication errors are to be reported upon<br>implementation of Amendment 6 through 30 days after the last dose of<br>study drug.<br>SAEs - Will be reported from signing of the informed consent form<br>through 30 days after the last dose of study drug.