Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

Study ID
C16011

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Clements University Hospital
  • UT Southwestern Ambulatory Services
  • Zale Lipshy University Hospital
  • Parkland Health & Hospital System

Contact
James Pond
214/648-7030
blake.pond@utsouthwestern.edu

Principal Investigator
Larry Anderson, M.D., Ph.D.

Official Title

A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physicians Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

Brief Overview


The purpose of this study is to determine whether dexamethasone plus IXAZOMIB improves
hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and
mortality rate versus a physician's choice of a chemotherapy regimen in participants
diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.

Summary


The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat
people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.

The study will enroll approximately 248 patients. Participants will be randomly assigned (by
chance, like flipping a coin) to one of the two treatment groups:

- IXAZOMIB 4 mg plus Dexamethasone 20 mg

- Physician's choice: Participants will receive one of the following treatment options as
selected by the physician:

1. Dexamethasone 20 mg

2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg

3. Dexamethasone 20 mg + Cyclophosphamide 500 mg

4. Dexamethasone 20 mg + Thalidomide 200 mg

5. Dexamethasone 20 mg + Lenalidomide 15 mg

6. All participants will be asked to take oral formulation of the drugs. In both
treatment arms, each participant will continue to receive sequential cycles of
therapy until disease progression, unacceptable toxicity, or until the study is
terminated, whichever occurs first. Participants in Arm B receiving melphalan and
dexamethasone will be treated to best response plus 2 additional cycles.

This multi-center trial will be conducted worldwide. The overall time to participate in this
study is 112 months (9.3 years), including 84 months of enrollment and 28 months of
follow-up after the last participant is enrolled.

Participant Eligibility


Inclusion Criteria:

1. Male or female participants 18 years or older.

2. Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis)
according to the following standard criteria:

1. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo
red staining with exhibition of an apple-green birefringence

2. If clinical and laboratory parameters insufficient to establish AL amyloidosis
or in cases of doubt, amyloid typing may be necessary.

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):

1. 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 deposits is recommended.

2. 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 progressive disease (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.

1. Participant must not have been previously treated with proteasome inhibitors.
(The sponsor reserves the right to open the study to proteasome
inhibitor-exposed participants in the future, at some time point after the first
interim analysis (IA). In that case, the participant may not be refractory to
proteasome inhibitor therapy.)

2. Given that the physician may select from an offered list of regimens to treat a
specific participant, the participant may be refractory to an agent/s listed
within the list of offered treatment choices

3. Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status)
from the reversible effects of prior therapy

4. If a participant has received a transplant as his/her first-line therapy, he/she
must be at least 3 months post transplantation and recovered from the side
effects of the stem cell transplant.

6. Must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by
N-terminal proBNP [NT-proBNP] cut-off of < 332 pg/mL and troponin T cut-off of 0.035
ng/mL as thresholds):

1. Stage 1: both NT-proBNP and troponin T under threshold

2. Stage 2: either NT-proBNP or troponin T (but not both) over threshold;

3. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP < 8000
pg/mL)

7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

8. Clinical laboratory values:

1. Absolute neutrophil count ≥ 1000/µL

2. Platelet count ≥ 75,000/µL

3. Total bilirubin ≤ 1.5 upper limit of normal (ULN), except for participants with
Gilbert's syndrome as defined by > 80% unconjugated bilirubin and total
bilirubin ≤ 6 mg/dL

4. Alkaline phosphatase ≤ 5 x ULN

5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN

6. Calculated creatinine clearance ≥ 30 mL/min

9. Female participants who:

1. 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

2. Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR

3. Agree to practice true abstinence when this is line with the preferred and usual
lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception.).

Male participants, even if surgically sterilized (ie, status post vasectomy), who:

1. Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, AND

2. Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR

3. Agree to practice true abstinence when this is line with the preferred and usual
lifestyle of the participant. (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 participant at any time without prejudice to future medical care.

Exclusion Criteria:

1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL
amyloidosis.

2. Female participants who are lactating, breast feeding, or pregnant.

3. Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA)
Class 3 or 4 congestive heart failure, 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 International Myeloma Working
Group (IMWG) criteria with at least 1 of the following:

1. Bone lesions

2. 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 gastrointestinal (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, participants may be on chronic steroids
(maximum dose 20 mg/day prednisone or equivalent) 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 participant 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 human immunodeficiency virus (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 (5 years for sites in
France) before study enrollment or previously diagnosed with another malignancy and
have any evidence of residual disease. Participants with nonmelanoma skin cancer or
carcinoma in situ of any type are not excluded if they have undergone complete
resection.