As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or other study medication is the only endpoint being assessed. All other study endpoints will no longer be assessed.
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or
other study medication is the only endpoint being assessed. All other study
endpoints will no longer be assessed.
Secondary outcome
As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or
other study medication is the only endpoint being assessed. All other study
endpoints will no longer be assessed.
Background summary
As of protocol amendment 06, evaluation of the safety profile of MLN9708 and/or
other study medication is the only endpoint being assessed. All other study
endpoints will no longer be assessed. Please find the original study background
here:
Primary light chain (AL) amyloidosis is a rare, lethal plasma cell dyscrasia in
which fibril deposits containing toxic monoclonal immunoglobulin light chains
infiltrate tissues causing their dysfunction and failure. Unlike patients with
MM, patients with AL amyloidosis not only have a hematologic malignancy, but
also direct progressive involvement of 1 or more visceral organs. Given the
rarity of AL amyloidosis, there have not been any randomized controlled trials
in the relapsed disease setting, but rather there have been anecdotal case
reports, retrospective series, and small single institution trials utilizing
differing single-agent or combination therapy regimens shown active in a
similar yet different plasma cell dyscrasia multiple myeloma. The National
Comprehensive Cancer Network (NCCN) therefore recommends treatment in a
clinical trial because there are no regulatory approved treatments and data are
insufficient to identify an optimal therapy.(4) The treatment of patients with
relapsed and/or refractory systemic light-chain (AL) amyloidosis is an area of
unmet need. The current therapeutic approach to systemic amyloidosis is based
on the observation that amyloid deposits can be reabsorbed and organ function
restored if the concentration of the amyloidogenic protein precursor (known as
the involved free light chains [FLC]) is reduced. Therefore, the aim of
therapy in AL amyloidosis is to rapidly decrease the supply of errant
amyloid-forming FLC by suppressing the underlying clonal plasma cell while
using supportive measures to sustain and possibly preserve organ functions.
The clinical course of the disease is improved by arresting progressive organ
damage and allowing functional improvement of affected organs, thereby
providing clinical benefit.
While reduction in the amyloidogenic-involved free light chains can improve the
clinical course of the disease, the therapies that achieve these results are
not curative adding to the uniformly fatal prognosis for this disease with the
currently available approaches. When the patient*s disease relapses or does
not respond to first-line therapy, there is no standard therapy, and data are
limited even for those agents used in this setting.(4) Unfortunately, the
current choice of treatment is primarily based on nonrandomized studies and
investigator personal experience, which accounts for discrepancies in the
treatment strategies proposed by different investigators. Because there is no
consensus, the choice of treatment depends on a fine balance between the
perceived efficacy of the chosen regimen and the individual patient*s expected
ability to tolerate the treatment*s toxicity considering their age, organ
dysfunction, and pace of disease, and given the limited treatment options, may
mean exposure to an agent from the same drug class. Available treatment
options in AL amyloidosis have used advances made in the chemotherapy of MM,
including the use of corticosteriods, alkylating agents, proteasome inhibitors,
and immunomodulatory agents (IMiDs), more frequently as combination regimens
but also as single agents.
Recognizing that proteasome inhibition is an effective anticancer therapeutic
approach, Millennium developed MLN9708, which is a modified dipeptide boronic
acid proteasome inhibitor similar to VELCADE, with the aim of improving the
pharmacology of the agent, improving drug administration, while building on the
efficacy seen with VELCADE. This study has been designed based on the results
of VELCADE in previously treated AL amyloidosis,(80, 87) the emerging activity
seen with MLN9708 in the treatment of previously treated and untreated MM and
AL amyloidosis (see Section 1.3), and the urgent need for better treatment
options for this rare disease, especially in the relapsed setting where no
standard treatment exists.
Amyloidosis is a protein misfolding disease and may therefore be particularly
sensitive to proteasome inhibition. The hypothesis of this study, therefore,
is to compare a proteasome inhibitor, oral MLN9708, to oral agents of other
drug classes that are currently used in clinical practice. Given that the AL
amyloidosis population is predominantly a frail and elderly patient population,
the convenience of an oral regimen is expected to increase compliance and
possibly duration of treatment, which in turn should result in more durable
hematologic responses. This study is designed to determine the safety and
efficacy of oral MLN9708 with dexamethasone compared with treatment as chosen
by the investigator from a selected list of oral regimens routinely available
in clinical practice, dexamethasone alone or with an alkylating agent
(melphalan or cyclophosphamide) or dexamethasone with an IMiD (thalidomide or
lenalidomide) in patients with relapsed AL amyloidosis. Inclusion of patients
with amyloid involvement of heart and kidney was selected because these organs
represent the major organs most commonly involved in AL amyloidosis, but more
importantly, the criteria for involvement, response, and progression are based
on objective clinical laboratory and imaging tests which can be analyzed by
central laboratories to reduce variability and bias. The primary objective of
this study is to determine the overall hematologic response based on dFLC
(difference between the involved and uninvolved FLC) assessment and to
determine the rate of vital organ (that is heart and kidney) deterioration at 2
years. An improvement in hematologic response, as measured by reduction in FLC,
and a reduction in the rate of vital organ deterioration in patients with
relapsed or refractory systemic light chain amyloidosis would represent
clinical benefit.
Study objective
As of protocol Amendment 06, evaluation of the safety profile of MLN9708 and/or
other study medication is the only endpoint being assessed. All other study
endpoints will no longer be assessed.
Study design
This is a phase 3, randomized, controlled, open-label, multicenter study of the
oral formulation of dexamethasone plus MLN9708 compared with treatment chosen
by the investigator from a prespecified list of regimens available in clinical
practice. Treatment options will include: dexamethasone alone, dexamethasone
plus an alkylating agent (melphalan or cyclophosphamide), or dexamethasone plus
an immunomodulatory drug (IMiD, thalidomide or lenalidomide) in patients with
relapsed or refractory AL amyloidosis. Crossover to the investigational
treatment arm is not permitted during participation in this study.
Eligible patients must have: 1) biopsy-proven AL amyloidosis with relapsed or
refractory disease despite 1 or 2 prior therapies; 2) disease requiring further
treatment; 3) measureable disease as defined by serum differential free light
chain concentration (dFLC); and 4) objective and measurable major organ
involvement (ie, cardiac or renal) as defined by the standard International
Society of Amyloidosis (ISA) criteria. Patients must not have been previously
treated with proteasome inhibitors. (The sponsor reserves the right to open the
trial to proteasome inhibitor-exposed patients in the future, at some time
point after the first interim analysis.)
Physicians will choose a treatment regimen from a list of options provided by
the sponsor. Before randomization, physicians will declare which treatment
regimen they plan to select for each screened patient; the selection will be
recorded in the database. To maintain a balanced representation of the disease
characteristics, patients enrolled in this study will be stratified by: 1)
Cardiac Risk Stage: 1 versus 2 versus subgroup Cardiac Risk Stage 3 (ie, both
NT-proBNP and troponin T over threshold [but NT-proBNP < 8000 pg/mL]); 2)
relapsed versus refractory (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); and 3) proteasome inhibitor naïve versus exposed.
Eligible patients will be randomized in a 1:1 ratio into 1 of the 2 study arms:
Arm A: dexamethasone plus MLN9708
Arm B: physician*s choice
In both treatment arms, each patient will continue to receive sequential cycles
of therapy until disease progression, unacceptable toxicity, or until the study
is terminated, whichever occurs first.
Response to therapy will be evaluated by an AC which will include the
assessment of hematologic response and organ response according to the criteria
outlined in the Revised Consensus Response Criteria of the ISA. The AC will
also review specific data elements and corresponding data documentation to
support criteria of vital organ (that is heart or kidney) deterioration. An
independent data monitoring committee (IDMC) will review safety and efficacy
data at the interim analyses.
Safety will be assessed through adverse events (AEs), clinical laboratory
tests, and vital sign measurements. In addition, QOL and HU will be assessed
using questionnaires.
After disease progression, patients will be followed for survival, vital organ
deterioration, and subsequent therapy at least every 12 weeks
As of Amendment 6, however, the first IA has been conducted and the primary
endpoint of overall hematologic response rate (CR + VGPR + PR) did not reach
statistical significance. As such, the sponsor has decided to remove the
planned second IA and final analysis and discontinue the majority of study
assessments to ease the burden of protocol-mandated assessments on patients.
Ixazomib (MLN9708) and control drugs (if Takeda has been supplying them) will
continue to be provided for patients who continue to derive benefit.
Upon implementation of this amendment, data collection requirements will be
limited to the following safety assessments: all SAEs (regardless of causality,
including all deaths), any AE resulting in dose modification or discontinuation
of any study drug, Grade >=3 AEs, AEs of new primary malignancy, all reports of
drug exposure during pregnancy and pregnancy outcomes, product complaints, and
medication errors (including overdose). All other study assessments are no
longer required. Central laboratory and investigator assessments of response
and progression for protocol purposes are discontinued*AC review of response
data and IDMC review of efficacy and safety data will no longer be performed.
Patients will not be followed for the PFS or OS follow-up periods, as PFS and
OS are no longer being collected. Quality of Life (QOL) and pharmacokinetic
(PK) assessments will no longer be performed or recorded. Patients should
otherwise be treated by the investigator according to standard of care.
Intervention
Eligible patients will be randomized in a 1:1 ratio into 1 of the 2 study arms:
Arm A: dexamethasone plus MLN9708
Arm B: physician*s choice
Study burden and risks
Please refer to the Investigator Brochure for the Safety Information.
This trial will be conducted in compliance with the protocol, good clinical
practice (GCP), applicable regulatory requirements, and International
Conference on Harmonization (ICH) guidelines. Please refer to section E9 for a
detailled description of the risks and side effects.
Landsdowne Street 40
Cambridge, MA 02139
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Cambridge, MA 02139
US
Listed location countries
Age
Inclusion criteria
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 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 consent,
through 90 days after the last dose of study treatment, AND, b. Must also
adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR, c. Agree to practice true abstinence when this is
in line with the preferred and ususal lifestyle of the subject. (Periodic
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and
withdrawal are not acceptable methods of contraception.), Male patients, even
if surgically sterilized (ie, status post vasectomy), who:, a. Agree to
practice effective barrier contraception during the entire study treatment
period and through 90 days after the last dose of study drug, AND, b. Must also
adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR, c. Agree to practice true abstinence when this is
in line with the preferred and ususal lifestyle of the subject. (Periodic
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and
withdrawal are not acceptable methods of contraception.), 10. Voluntary written
consent must be given before performance of any study-related procedure not
part of standard medical care with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.
Exclusion criteria
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.
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 |
|---|---|
| EudraCT | EUCTR2011-005468-10-NL |
| ClinicalTrials.gov | NCT01659658 |
| CCMO | NL41603.028.12 |