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

Study ID
STU 012013-006

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • UT Southwestern Ambulatory Services
  • UT Southwestern University Hospital—St. Paul
  • UT Southwestern University Hospital– Zale Lipshy
  • Parkland Health & Hospital System

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

Principal Investigator
Larry Anderson

Summary

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) 4) objective and measurable major organ involvement (ie, cardiac or renal) as defined by the standard international Society of amyloidosis (iSa) criteria. Patients may be proteasome inhibitor-exposed or naive, but cannot be refractory to proteasome inhibitor therapy.

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 [Less Than] 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) 3) proteasome inhibitor naive 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 (a list of the chemotherapy regimens that is offered as treatment options in patients diagnosed with relapsed or refractory aL amyloidosis)

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.

Participant Eligibility

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
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 deposits 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.
c. Patient may not be refractory to proteasome inhibitor therapy
d. 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
e. Must have recovered (ie, <= Grade 1 toxicity or patient[Single Quote]s baseline status) from the
reversible effects of prior therapy
f. 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 transplant
6. 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/[MICRO-SYMBOL]L
b. Platelet count > 75,000/[MICRO-SYMBOL]L
c. Total bilirubin <= 1.5 x ULN
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 line with the preferred and usual
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 line with the preferred and usual
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.