Clinical trial NCT01659658: Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Relapsed or Refractory Systemic Light Chain Amyloidosis
Keywords: MLN9708
Amyloidosis
Light Chain
IXAZOMIB
Tourmaline AL1
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-08-08
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to provide continued access of ixazomib and/or other study medications and to continue collecting relevant safety data to monitor participant's safety, 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.

Detailed description: 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 177 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 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.

Eligibility criteria: 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 (or 5 years for participants 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.

Primary outcomes:
measure: Percentage of Participants With Overall Hematologic Response
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: 2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
timeFrame: Up to 2 years
Secondary outcomes:
measure: Percentage of Participants With Complete Hematologic Response
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Overall Survival
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Progression Free Survival (PFS)
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Hematologic Disease Progression Free Survival
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
timeFrame: From randomization to time of vital organ deterioration or death (up to 115 months)
measure: Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Vital Organ Progression Free Survival
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Duration of Hematologic Response
timeFrame: From time of first documented response to disease progression (up to 115 months)
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
measure: Time To Treatment Failure (TTF)
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
measure: Time To Subsequent Anticancer Treatment
timeFrame: From first dose of study drug until subsequent anticancer treatment (up to 115 months)
measure: Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up
timeFrame: Baseline, Week 28 of the PFS Follow-up
measure: Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up
timeFrame: Baseline, Week 28 of the PFS Follow-up
measure: Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up
timeFrame: Baseline, Week 28 of the PFS Follow-up
measure: Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up
timeFrame: Baseline, Week 28 of the PFS Follow-up
measure: Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score
timeFrame: At Week 28 of the OS follow-up
measure: EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score
timeFrame: At Week 28 of the OS follow-up
measure: Plasma Concentration of Ixazomib
timeFrame: Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days)
measure: Number of Hospitalizations
timeFrame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert and The Medical College of Wisconsin
state: Wisconsin
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Florianopolis
country: Brazil
facility: Centro de Pesquisas Oncologicas
state: Santa Catarina
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Clementino Fraga Filho (UFRJ)
city: Sao Paulo
country: Brazil
facility: Irmandade Da Santa Casa de Misericordia de Sao Paulo
city: Sao Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
state: Moravskoslezsk Kraj
city: Praha
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
state: Praha, Hlavni Mesto
city: Aahus
country: Denmark
facility: Arhus Universitetshospital Arhus Sygehus
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Nantes
country: France
facility: Hotel Dieu
state: Loire-Atlantique
city: Lille
country: France
facility: Hopital Claude Huriez
city: Limoges
country: France
facility: Centre Hospitalier et Universitaire de Limoges
city: Paris
country: France
facility: Hopital Saint Louis
city: Toulouse
country: France
facility: Hopital de Rangueil
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg Eppendorf
city: Heidelberg
country: Germany
facility: Universitat Heidelberg
city: Patras
country: Greece
facility: University General Hospital of Patras
state: Achaia
city: Athens
country: Greece
facility: Alexandra Hospital
city: Haifa
country: Israel
facility: Rambam Health Corporation
city: Jerusalem
country: Israel
facility: Hadasit Medical Research Services and Development Ltd
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center - PPDS
city: Ramat-Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Bologna
country: Italy
facility: Institute of Hematology "Seragnoli" University of Bologna
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital at Yonsei University Health System - PPDS
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center - PPDS
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St Mary's Hospital
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord-Holland
city: AZ Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: London
country: United Kingdom
facility: Royal Free and University College Medical School
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schonland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 May 26.