A Study of Oral Ixazomib Maintenance Therapy in Participants With Newly Diagnosed Multiple Myeloma (NDMM) Not Treated With Stem Cell Transplantation (SCT)

Multiple Myeloma Clinical Trial

Official title:

A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02312258
• Other study ID #: C16021
• Secondary ID: U1111-1160-17022
• Status: Completed
• Phase: Phase 3
• Start date: April 9, 2015
• Est. completion date: August 26, 2022

Study information

• Verified date: August 2023
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in participants with NDMM who have had a major response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to initial therapy and who have not undergone SCT.

Description:

The drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow progressive disease (PD) and improve overall survival in people who have NDMM who have had a major positive response to initial therapy and have not undergone SCT. This study will look at the effect of ixazomib citrate has on the length of time that participants are free of PD and their overall survival. The study will enrol approximately 700 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 3:2 ratio to Ixazomib or matching placebo groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): - Ixazomib citrate initiates at 3 mg which will be escalated to 4 mg with cycle 5 day 1 - Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle. The treatment period will be approximately 24 months (equivalent to 26 cycles) or until patients experience PD or unacceptable toxicities, whichever occurs first. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 78 to 106 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make follow-up visits every 4 weeks until the next line of therapy begins. Participants will also be contacted by telephone every 12 weeks after last treatment visit for a follow-up assessment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 706
• Est. completion date: August 26, 2022
• Est. primary completion date: August 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic newly diagnosed multiple myeloma (NDMM) according to standard criteria.

2. Completed 6 to 12 months (± 2 weeks) of initial therapy, during which the participant was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached.

3. Documented major response (PR, VGPR, CR) according to the International Myeloma Working Group (IMWG) uniform response criteria, version 2011, after this initial therapy.

4. Female participants who:

• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• 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 drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

Male participants, even if surgically sterilized (that is, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study drug, OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)

5. 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.

6. Complete documentation of the details of the initial therapy before randomization including cytogenetics and International Staging System (ISS) is available.

7. Eastern Cooperative Oncology Group Performance Status of 0 to 2.

8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken.

9. Is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration.

10. Must meet the following clinical laboratory criteria at study entry:

• Absolute neutrophil count (ANC) greater than or equal to (=) 1,000 per cubic millimeter (/mm^3) without growth factor support and platelet count =75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before randomization.
• Total bilirubin less than or equal to (=) 1.5*the upper limit of the normal range (ULN).
• Alanine aminotransferase and aspartate aminotransferase = 3*ULN.
• Calculated creatinine clearance = 30 milliliter per minute (mL/min) (using the Cockcroft-Gault equation).

Exclusion Criteria:

1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy.

2. Prior SCT.

3. Radiotherapy within 14 days before randomization.

4. Diagnosed or treated for another malignancy within 5 years before randomization or previous diagnosis with another malignancy. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

5. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.

6. Major surgery within 14 days before randomization.

7. Central nervous system involvement.

8. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before randomization.

9. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS), plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.

10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

11. Systemic treatment with strong cytochrome P450 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or St. John's wort within 14 days before randomization.

12. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.

13. Comorbid systemic illnesses or other severe concurrent disease that, 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 (example, PN that is Grade 1 with pain or Grade 2 or higher of any cause).

14. Psychiatric illness or social situation that would limit compliance with study requirements.

15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.

16. 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.

17. Treatment with any investigational products within 30 days before randomization.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Placebo
Ixazomib placebo-matching capsules.
• Ixazomib
Ixazomib capsules.

Locations

Country	Name	City	State
Argentina	Centro de Educacion Medica e Investigaciones Clinicas "Norberto Quirno" (CEMIC)	Buenos Aires	Ciudad Autonoma De BuenosAires
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires	Ciudad Autonoma De BuenosAires
Argentina	Hospital Universitario Austral	Buenos Aires	Ciudad Autonoma De BuenosAires
Argentina	Sanatorio Allende S.A.	Cordoba
Argentina	Hospital Iturraspe	Santa Fe
Australia	St Vincents Hospital Melbourne - PPDS	Fitzroy	Victoria
Australia	Frankston Hospital	Frankston	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Austria	Universitatsklinikum Innsbruck	Innsbruck	Tirol
Austria	Paracelsus Medizinische Privatuniversitat	Salzburg
Austria	Klinikum Wels-Grieskirchen GmbH	Wels
Austria	Medizinische Universitat Wien (Medical University of Vienna)	Wien
Belgium	Universitair Ziekenhuis Brussel - PIN	Brussel	Brussels
Belgium	UZ Brussel	Brussel	Brussels
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles	Brussels
Brazil	Fundacao PIO XII	Barretos	Sao Paulo
Brazil	Hospital Das Clinicas Da UFMG	Belo Horizonte	Minas Gerais
Brazil	Universidade Estadual de Campinas	Campinas	Sao Paulo
Brazil	Universidade de Caxias do Sul	Caxias Do Sul	Rio Grande Do Sul
Brazil	Liga Paranaense de Combate Ao Cancer - Hospital Erasto Gaertner	Curitiba	Parana
Brazil	Hospital Das Clinicas Da Universidade Federal de Goias	Goiania	Goias
Brazil	Associacao Hospital de Caridade Ijui	Ijui	Rio Grande Do Sul
Brazil	Hospital Amaral Carvalho	Jau	Sao Paulo
Brazil	Instituto Joinvilense de Hematologia E Oncologia	Joinville	Santa Catarina
Brazil	Liga Norte Riograndense Contra O Cancer	Natal	Rio Grande Do Norte
Brazil	American Oncology Partners of Maryland, PA	Passo Fundo	Rio Grande Do Sul
Brazil	Hospital de Clinicas de Porto Alegre (HCPA) - PPDS	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital Moinhos de Vento	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)	Porto Alegre	Rio Grande Do Sul
Brazil	Mae de Deus Center Hospital Giovanni Battista	Porto Alegre	Rio Grande Do Sul
Brazil	Fundação Antônio Prudente - AC Camargo Câncer Center	Rio De Janeiro
Brazil	HEMORIO - Unidade de Pesquisa Clinica	Rio De Janeiro
Brazil	Instituto Nacional de Cancer	Rio de Janeiro
Brazil	Del-pesti Centrumkorhaz- Orszagos Hematologiai és Infektologiai Intezet	Salvador	Bahia
Brazil	Faculdade de Medicina Do ABC	Santo Andre	Sao Paulo
Brazil	Hospital de Base Da Faculdade de Medicina de Sao Jose Do Rio Preto	Sao Jose Do Rio Preto
Brazil	Clinica Sao Germano	Sao Paulo
Brazil	Ealing Hospital	Sao Paulo
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo	Sao Paulo
Brazil	Hospital Israelita Albert Einstein	Sao Paulo
Brazil	Hospital Santa Marcelina	Sao Paulo
Brazil	Hospital Sirio Libanes	Sao Paulo
Brazil	Instituto de Ensino E Pesquisa Sao Lucas	Sao Paulo
Canada	Royal Victoria Regional Health Centre	Barrie	Ontario
Canada	William Osler Health Centre	Brampton	Ontario
Canada	McGill University Health Center	Montreal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
Chile	Centro Internacional de Estudios Clinicos	Santiago
Chile	Instituto Nacional Del Cancer	Santiago
Chile	Hospital Amaral Carvalho	Temuco	Araucanía
Chile	Centro de Investigaciones Clinicas Vina del Mar	Vina Del Mar
China	Beijing Chaoyang Hospital Capital Medical University	Beijing
China	Peking Union Medical College Hospital	Beijing
China	Peking University Third Hospital	Beijing
China	The First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang
China	The First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou
China	Hospital de Clinicas de Passo Fundo	Nanjing	Jiangsu
China	Renji Hospital Shanghai Jiaotong University School of Medicine	Shanghai
China	Ruijin Hospital Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai
China	Shanghai Chang Zheng Hospital	Shanghai
China	Hospital São Rafael	Shenyang
China	Second Hospital of Shanxi Medical University	Taiyuan
China	James Lind Centro de Investigación del Cáncer	Wuhan
Colombia	Hospital Universitario San Ignacio	Bogota	Distrito Capital De Bogota
Colombia	Instituto Nacional de Cancerologia Colombia	Bogota	Cundinamarca
Colombia	Hospital Pablo Tobon Uribe	Medellin	Antioquia
Croatia	Clinical Hospital Center Rijeka	Rijeka
Croatia	Clinical Hospital Center Zagreb - PPDS	Zagreb
Croatia	Clinical Hospital Dubrava	Zagreb	Grad Zagreb
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove	Kralovehradeck Kraj
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultni nemocnice Kralovske Vinohrady	Prague	Praha, Hlavni Mesto
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Denmark	Aarhus Universitetshospital Århus Sygehus	Aarhus N
Denmark	Regionshospitalet Holstebro	Holstebro
Denmark	Jiangsu Province Hospital (the First Affiliated Hospital With Nanjing Medical University)	København	Capital
Denmark	Odense Universitetshospital	Odense
France	Hopital Antoine Beclere	Clamart	Hauts-de-Seine
France	CHRU Dijon Complexe Du Bocage	Dijon
France	CHRU Lille	Lille
France	Hopital Saint Vincent de Paul GHICL	Lille
France	Hotel Dieu	Nantes	Loire-Atlantique
France	Groupe Hospitalier Necker Enfants Malades	Paris
France	Hopital de la Pitie Salpetriere	Paris
France	Hopital Haut Leveque	Pessac
France	Hopital Jean Bernard	Poitiers
France	CHRU Rennes	Rennes
France	CHRU Nancy	Vandoeuvre-les-nancy	Meurthe-et-Moselle
Germany	Onkologie Aschaffenburg	Aschaffenburg
Germany	Hamatologische Onkologische Gemeinschaftspraxis Dr. Brudler, Dr. Heinrich, Dr. Bangerter	Augsburg	Bayern
Germany	Charite - Universitatsmedizin Berlin	Berlin
Germany	Medizinisches Versorgungszentrum Onkologischer Schwerpunkt	Berlin
Germany	Universitatsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Internistisch Hamatologische und Internistische Praxis	Herrsching am Ammersee	Bayern
Germany	Universitat Des Saarlandes	Homburg	Saarland
Germany	Klinikum Landshut	Landshut
Germany	Universitatsmedizin der Johannes Gutenberg-Universitat Mainz	Mainz	Rheinland-Pfalz
Germany	Klinikum rechts der Isar der Technischen Universitat Munchen	Munchen
Germany	LMU Klinikum der Universitat Munchen	Munchen	Bayern
Germany	Gemeinschaftspraxis fur Hamatologie und Onkologie	Munster	Nordrhein-Westfalen
Germany	Pius Hospital Oldenburg	Oldenburg	Niedersachsen
Germany	Praxis Pihusch Medizinisches Versorgungszentrum GbR	Rosenheim
Germany	Universitatsklinikum Ulm	Ulm	Baden-Wurttemberg
Germany	Schwarzwald Baar Klinkum Villingen-Schwenningen GmbH	Villingen-Schwenningen	Baden-Wurttemberg
Germany	Gemeinschaftspraxis Dr. med. R. Schlag & Dr. med. B. Schottker & Dr. med. J. Haas	Wurzburg
Greece	Evangelismos General Hospital of Athens	Athens
Greece	University of Athens Medical School - Regional General Hospital Alexandra	Athens	Attiki
Greece	University General Hospital of Ioannina	Ioannina
Greece	University General Hospital of Larissa	Larissa
Greece	Georgios Papanikolaou General Hospital of Thessaloniki	Thessaloniki
Greece	Theageneio Anticancer Oncology Hospital of Thessaloniki	Thessaloniki
Hungary	Klinika Hematologii, Szpital Uniwersytecki Nr 2 im. Jana Biziela w Bydgoszczy	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged
Israel	Shamir Medical Center Assaf Harofeh	Be'er Sheva
Israel	Rigshospitalet	Beer Yaakov
Israel	Bnai Zion Medical Center	Haifa
Israel	Hadassah Medical Center - PPDS	Jerusalem
Israel	Meir Medical Center	Kfar Saba
Israel	Rabin Medical Center - PPDS	Petah Tikva
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Assuta Medical Centers	Tel Aviv
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Israel	Baruch Padeh Poriya Medical Center	Tiberias
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G.M. Lancisi G. Salesi	Ancona
Italy	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna	Emilia-Romagna
Italy	ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia - INCIPIT - PIN	Brescia	Lombardia
Italy	Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele	Catania	Sicilia
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	IRCCS Az. Osp. Universitaria San Martino- IST	Genova	Liguria
Italy	ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda	Milano	Lombardia
Italy	AORN A Cardarelli	Napoli	Campania
Italy	Azienda Ospedaliero Universitaria di Parma	Parma
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa	Toscana
Italy	Ospedale Santa Maria Delle Croci	Ravenna
Italy	Ospedale Infermi di Rimini	Rimini	Emilia-Romagna
Italy	Ospedale Casa Sollievo Della Sofferenza IRCCS	San Giovanni Rotondo	Puglia
Italy	Azienda Ospedaliera S Maria Di Terni	Terni	Umbria
Italy	Azienda Ospedaliera Citta della Salute e della Scienza di Torino	Torino
Japan	Juntendo University Hospital	Bunkyo	Tokyo
Japan	National Hospital Organization Kyushu Medical Center	Fukuoka
Japan	Fukushima Medical University Hospital	Fukushima-City
Japan	Hitachi General Hospital	Hitachi	Ibaraki
Japan	National Hospital Organization Mito Medical Center	Ibaraki
Japan	Nara Hospital Kinki University Faculty of Medicine	Ikoma-City	Nara
Japan	Kobe City Medical Center General Hospital	Kobe-City	Hyogo
Japan	Kurume University Hospital	Kurume
Japan	Shizuoka Cancer Center	Nagaizumi-cho
Japan	Japanese Red Cross Nagoya Daiichi Hospital	Nagoya
Japan	Nagoya City University Hospital	Nagoya
Japan	Japanese Red Cross Narita Hospital	Narita-shi
Japan	Niigata Cancer Center Hospital	Niigata-city
Japan	Ogaki Municipal Hospital	Ogaki	Gihu
Japan	National Hospital Organization Okayama Medical Center	Okayama-city	Okayama
Japan	Osaka Saiseikai Nakatsu Hospital	Osaka
Japan	Japanese Red Cross Medical Center	Shibuya-ku	Tokyo
Japan	National Hospital Organization Disaster Medical Center	Tachikawa
Japan	Toyohashi Municipal Hospital	Toyohashi
Japan	Yamanashi Prefectural Central Hospital	Yamanashi
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggido
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Samsung Medical Center - PPDS	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System - PPDS	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Mexico	Centro de Investigacion Farmaceutica Especializada de Occidente, SC - PPDS	Guadalajara	Jalisco
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City
Mexico	Hospital Universitario Dr. Jose Eleuterio Gonzalez	Monterrey	Nuevo Leon
Mexico	Hospital Y Clinica OCA Sociedad Anonima de Capital Variable	Monterrey	Nuevo Leon
Mexico	Oaxaca Site management Organization (OSMO) - PPDS	Oaxaca
Poland	Shengjing Hospital of China Medical University	Bydgoszcz	Kujawsko-pomorskie
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich	Chorzow
Poland	MTZ Clinical Research Sp z o o - PRATIA - PPDS	Warszawa	Mazowieckie
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw
Portugal	Hospital Garcia de Orta	Almada
Portugal	Hospital de Braga	Braga
Portugal	Champalimaud Cancer Center	Lisboa
Portugal	Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E.	Lisbon	Lisboa
Portugal	Centro Hospitalar de Sao Joao EPE	Porto
Portugal	Centro Hospitalar do Porto - Hospital de Santo Antonio	Porto
Portugal	Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS	Porto
Russian Federation	State Medical and Preventive Treatment Institution Kirov Regional Clinical Oncology Dispensary	Kirov
Russian Federation	Stavropol Regional Clinical Oncology Centre Pyatigorsk Affiliate	Pyatigorsk
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	City Center of MS Treatment based on Saint-Petersburg City Clinical Hospital #31	St. Petersburg
Russian Federation	Russian Research Institute of Hematology and Blood Transfusion	St. Petersburg
Serbia	Clinical Hospital Center ''Bezanijska Kosa''	Belgrade
Serbia	Tongji Hospital Tongji Medical College Huazhong University of Science and Technology	Belgrade
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	Soroka University Medical Centre	Nis
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital (SGH)	Singapore
South Africa	Medical Oncology Centre of Rosebank	Johannesburg	Gauteng
South Africa	Albert Alberts Stem Cell Transplant Centre	Pretoria	Gauteng
South Africa	Mary Potter Oncology Centre	Pretoria	Gauteng
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de La Santa Creu i Sant Pau	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario HM Sanchinarro CIOCC	Madrid
Spain	Hospital Universitario Infanta Leonor	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital General Universitario Morales Meseguer	Murcia
Spain	Clinica Universidad Navarra	Pamplona	Navarra
Spain	Hospital Universitario Quironsalud Madrid	Pozuelo De Alarcon	Madrid, Communidad Delaware
Spain	Complejo Asistencial Universitario de Salamanca H. Clinico	Salamanca
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Sweden	Sahlgrenska Universitetssjukhuset	Goteborg	Vastra Gotalands Lan
Sweden	Skanes Universitetssjukhus Lund	Lund
Sweden	Karolinska Universitetssjukhuset Huddinge	Stockholm	Sodermanlands Lan
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm	Sodermanlands Lan
Switzerland	Spital STS AG	Thun
Taiwan	Kaohsiung Medical University Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Thailand	Chulalongkorn University	Bangkok
Thailand	Ramathibodi Hospital	Bangkok	Krung Thep Maha Nakhon
Thailand	Maharaj Nakorn Chiang Mai Chiang Mai University	Chiangmai
Turkey	Ankara University Medical Faculty PPDS	Ankara
Turkey	Hacettepe Universitesi Tip Fakultesi Hastanesi	Ankara
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi	Istanbul
Turkey	Dokuz Eylul University Medical Faculty	Izmir
United Kingdom	Royal United Hospital	Bath
United Kingdom	Belfast City Hospital	Belfast	Antrim
United Kingdom	Ulster Hospital	Belfast
United Kingdom	Royal Bournemouth Hospital	Bournemouth	Dorset
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	Bristol, City Of
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Kent and Canterbury Hospital	Canterbury	Kent
United Kingdom	University Clinical Center Nis	Cardiff
United Kingdom	West Middlesex University Hospital	Isleworth
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Barts Health NHS Trust	London	London, City Of
United Kingdom	Chelsea and Westminster NHS Trust	London
United Kingdom	Hammersmith Hospital	London	London, City Of
United Kingdom	Kings College Hospital	London	London, City Of
United Kingdom	University College London	London	London, City Of
United Kingdom	Manchester Royal Infirmary - PPDS	Manchester
United Kingdom	Northwick Park Hospital	Middlesex
United Kingdom	The Royal Oldham Hospital - PPDS	Oldham
United Kingdom	Churchill Hospital	Oxford	Oxfordshire
United Kingdom	Queen Alexandra Hospital	Portsmouth	Hampshire
United Kingdom	University Clinical Center of Serbia - PPDS	Southall
United Kingdom	Royal Marsden Hospital - Surrey	Sutton	Surrey
United Kingdom	Singleton Hospital - PPDS	Swansea
United Kingdom	Hillingdon Hospital	Uxbridge	London, City Of
United Kingdom	Birmingham Heartlands Hospital	West Malling	Birmingham
United Kingdom	New Cross Hospital	Wolverhampton	Staffordshire
United States	Cancer Care of WNC PA	Asheville	North Carolina
United States	Winship Cancer Institute, Emory University	Atlanta	Georgia
United States	Saint Agnes Hospital - Baltimore - Hunt - PPDS	Baltimore	Maryland
United States	University Hospital of Wales -	Bethesda	Maryland
United States	Tufts Medical Center - PPDS	Boston	Massachusetts
United States	John H. Stroger Jr. Hospital of Cook County	Chicago	Illinois
United States	Robert A Moss MD FACP Inc	Fountain Valley	California
United States	Appalachian Regional Healthcare	Hazard	Kentucky
United States	Herbert-Herman Cancer Center	Lansing	Michigan
United States	UCLA Medical Hematology and Oncology	Los Angeles	California
United States	W VA University Mary Babb Randolph Cancer Center	Morgantown	West Virginia
United States	Clinical Research Alliance Inc	New York	New York
United States	New York Presbyterian Hospital - Weill-Cornell	New York	New York
United States	North County Oncology Medical Clinic Inc	Oceanside	California
United States	Ventura County Hematology Oncology Specialists	Oxnard	California
United States	UPMC Cancer Pavillion	Pittsburgh	Pennsylvania
United States	Emad Ibrahim, MD, Inc	Redlands	California
United States	Global Cancer Research Institute (GCRI), Inc.	San Jose	California
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	New England Cancer Specialists	Scarborough	Maine
United States	Swedish Cancer Institute	Seattle	Washington
United States	Siouxland Hematology - Oncology Associates LLP	Sioux City	Iowa
United States	HOPE Cancer Center of East Texas	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  China,  Colombia,  Croatia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Poland,  Portugal,  Russian Federation,  Serbia,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD is defined as, increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase =0.5 g/ deciliter (dL)); or urine M-component (absolute increase =200 mg/24-hour); difference between involved and uninvolved free light chains (FLC) levels (absolute increase >10 mg/dL); or bone marrow plasma cell percentage (absolute plasma cell percentage =10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia (corrected serum calcium >11.5mg/dL).	From randomization until PD or death (up to 52 months)
Secondary	Overall Survival (OS)	OS was measured as the time from the date of randomization to the date of death.	From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)
Secondary	Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period	Response was assessed according to IMWG criteria based on IRC assessment. Best response included PR, VGPR and CR. PR= >=50% reduction of serum M protein and >=90% or <200 mg reduction urinary M protein in 24-hour, or >50% decrease in difference between involved and uninvolved FLC levels, or >50% reduction in bone marrow plasma cells, if bone marrow plasma cells >30% and >50% reduction in size of soft tissue plasmacytomas at baseline. VGPR= >90% reduction (<100 mg/24-hour) in serum M-protein + urine M-protein detectable by immunofixation but not on electrophoresis. Complete response= >5% plasma cells in myelogram with absence of paraprotein in serum and urine according to immunofixation.	Up to 27 months
Secondary	Time to Progression (TTP)	TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria.	From randomization until PD or death (up to 52 months)
Secondary	Progression Free Survival 2 (PFS2)	PFS2 is defined as the time from the date of randomization to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurred first.	From the date of randomization to every 12 weeks until second PD or death (up to 88 months)
Secondary	Time to Next Line Therapy (TTNT)	TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy.	From randomization until PD or death (up to 52 months)
Secondary	Time to End of the Next-line of Therapy After Study Treatment	Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment.	From randomization until PD or death (up to 52 months)
Secondary	Duration of Next-line Therapy	Duration of next-line therapy is defined as the time from the date of the first dose of the next line of antineoplastic therapy coming after study treatment to the date of the last dose.	From randomization until PD or death (up to 52 months)
Secondary	Percentage of Participants Who Develop a New Primary Malignancy		From randomization until PD or death (up to 52 months)
Secondary	Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative	Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry. MRD negativity was defined as absence of MRD and MRD positivity was defined as presence of MRD. MRD was assessed by 8-color flow cytometry with the IMWG recommended sensitivity of 10^-5.	Up to 52 months
Secondary	Correlation of MRD Status With PFS and OS	PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 52 months in this outcome measure. OS was measured as the time from the date of randomization to the date of death, assessed for up to 52 months in this outcome measure. Participants with various types of known MRD status were pooled together for analysis of overall survival in this outcome measure.	From randomization up to 52 months
Secondary	OS in a High-risk Population	High-risk population included but not be limited to participants carrying cytogenetic deletion (del)17, translocation [t](4;14), t(14;16). OS was measured as the time from the date of randomization to the date of death.	From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)
Secondary	PFS in a High-risk Population	High-risk population included but not be limited to participants carrying del17, t(4;14), t(14;16). PFS was defined as the time from the date of randomization to the date of first documentation of PD or death from any cause.	From randomization until PD or death (up to 52 months)
Secondary	Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status	ECOG performance status assesses a participant's performance status on a 6-point scale ranging from 0=fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. Lower grades indicate improvement.	Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26, progression free survival follow-up (PFSFU)- Visit 37 and progressive disease follow-up (PDFU)- Visit 26 (cycle length=28 days)
Secondary	Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. TEAEs were defined as events that occurred after administration of the first dose of ixazomib or placebo through 30 days after the last dose of ixazomib or placebo. A SAE means any untoward medical occurrence that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was considered medically significant.	First dose of study drug through 30 days after last dose of study drug (up to 88 months)
Secondary	Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) as Measured by the Global Health Status (GHS)	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. The change from baseline in GHS (EORTC QLQ-C30) score is presented. Participant responses to the question "How would you rate your overall health during the past week?" are scored on a 7-point scale (1=very poor to 7=excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall GHS.	Baseline, Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26 (cycle length=28 days)
Secondary	Correlation Between Frailty Status and PFS and OS	Participant's frailty status is classified as fit, unfit or frail on the bases of 4 components: age, the Charlson comorbidity scoring system without age weighting, the Katz index of independence in activities of daily living, and the Lawton instrumental activities of daily living scale. The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first, assessed for up to 52 months in this outcome measure. OS will be measured as the time from the date of randomization to the date of death, assessed for up to 52 months in this outcome measure.	From randomization up to 52 months
Secondary	Pharmacokinetic Parameter: Plasma Concentration of Ixazomib	Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) were measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay.	Cycle 1 (1 and 4 hours post-dose Day 1, Days 8 and 15 pre-dose); Cycle 2 and 5 (Days 1 and 8 pre-dose) and Cycles 3, 4, 6 to 10 (Day 1 pre-dose) (cycle length=28 days)
Secondary	Time to Resolution of Peripheral Neuropathy (PN) Events	PN is defined as the event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the medical dictionary for regulatory activities (MedDRA). A PN event was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution was defined as the time from the initial onset date (inclusive) to the resolution date for resolved events.	Up to 52 months
Secondary	Time to Improvement of PN Events	PN is defined as the event in the high-level term of peripheral neuropathies NEC according to the MedDRA. A PN event was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the improvement date or the day before and after. Time to improvement was defined as the time from the initial onset date (inclusive) to the improvement of event.	Up to 52 months