Clinical trial NCT02755597: A Study Evaluating Venetoclax (ABT-199) in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy
Official title: A Phase 3, Multicenter, Randomized, Double Blind Study of Bortezomib and Dexamethasone in Combination With Either Venetoclax or Placebo in Subjects With Relapsed or Refractory Multiple Myeloma Who Are Sensitive or Naïve to Proteasome Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Relapsed/refractory multiple myeloma
Relapsed multiple myeloma
Refractory multiple myeloma
Multiple myeloma
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2016-04-29
Enrollment: 291
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a Phase 3, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of venetoclax plus bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2
* Participant has documented relapsed or progressive multiple myeloma on or after any regimen or who are refractory to the most recent line of therapy. Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet the criteria for refractory myeloma. Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease \[PD\]) while on primary or salvage therapy, or progresses within 60 days of last therapy.
* Participant must have received prior treatment with at least one, but no more than three, prior lines of therapy for multiple myeloma. A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens.
* Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided ALL of the following criteria are met: Disease is NOT refractory to any proteasome inhibitor, defined as no disease progression (i.e., PD, per International Myeloma Working Group \[IMWG\] or European Society for Blood and Marrow Transplantation \[EBMT\] criteria) while receiving proteasome inhibitor therapy or within 60 days after the last dose, AND best response achieved with any proteasome inhibitor therapy (alone or in combination) was at least a Partial Response (PR), AND participant did not discontinue any proteasome inhibitor due to intolerance or ≥ Grade 3 related toxicity.
* Participant has measurable disease at Screening, defined as at least one of the following: Serum M-protein ≥ 0.5 g/dL, OR Urine M-protein ≥ 200 mg in 24-hours, OR serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is abnormal.

Exclusion Criteria:

* Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
* Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
* Participant has any of the following conditions:

Non-secretory multiple myeloma, active plasma cell leukemia i.e., either 20% of peripheral white blood cells or greater than 2.0 X 10\^9/liter (L) circulating plasma cells by standard differential, Waldenstrom's macroglobulinemia, amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), known Human Immunodeficiency Viral (HIV) infection, active hepatitis B or C infection based on blood screen tests, significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6 months of randomization, or congestive heart failure New York Heart Association (NYHA) Class ≥ 3, major surgery within 4 weeks prior to randomization, acute infections requiring parenteral therapy (antibiotic, antifungal, or antiviral) within 14 days prior to randomization, peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to randomization, uncontrolled diabetes or uncontrolled hypertension within 14 days prior to randomization, any other medical condition that, in the opinion of the Investigator, would adversely affect the participant's participation in the study

* Participant has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions: Adequately treated in situ carcinoma of the cervix uteri or the breast, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment, previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study
* If participant had prior allogeneic stem cell transplant (SCT), participant has evidence of ongoing graft-versus-host disease (GvHD)

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Median duration of follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary outcomes:
measure: Very Good Partial Response (VGPR) or Better Response Rate
timeFrame: Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
measure: Progression-Free Survival (PFS) in Participants With High B-cell Lymphoma 2 (BCL-2) Expression
timeFrame: Median duration of follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
measure: Duration of Response (DOR)
timeFrame: Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
measure: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain
timeFrame: Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
measure: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
measure: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
measure: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score
timeFrame: Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
measure: Overall Survival (OS).
timeFrame: Median duration of follow-up was 45.6 months for the venetoclax group and 45.6 months for the placebo group
measure: Time to Progression (TTP)
timeFrame: Median time on follow-up up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
measure: Overall Response Rate (ORR)
timeFrame: Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
measure: Minimal Residual Disease (MRD) Negativity Rate
timeFrame: Assessed at Screening; to confirm a stringent Complete Response (sCR) or Complete Response (CR); at 6 months and 12 months post-confirmed CR/sCR
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center/Eastern Colorado Health Care System /ID# 156524
state: Colorado
city: Aurora
country: United States
facility: Univ of Colorado Cancer Center /ID# 149130
state: Colorado
city: Durham
country: United States
facility: Duke Cancer Center /ID# 149099
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research /ID# 149098
state: Ohio
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital /ID# 149108
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital /ID# 149106
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital /ID# 149110
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital /ID# 149105
state: Queensland
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital /ID# 149104
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital /ID# 149111
state: Tasmania
city: Box Hill
country: Australia
facility: Box Hill Hospital /ID# 149112
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Ctr /ID# 149107
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health /ID# 150085
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital /ID# 148967
state: Western Australia
city: Nedlands
country: Australia
facility: Perth Blood Institute Ltd /ID# 148966
state: Western Australia
city: Goiania
country: Brazil
facility: Hospital das Clinicas da Universidade Federal de Goiás /ID# 149290
state: Goias
city: Natal
country: Brazil
facility: Liga Norte Riograndense Contra o Câncer /ID# 149023
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas da PUCRS /ID# 149027
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Clinica Sao Germano /ID# 149851
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA) /ID# 149020
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo /ID# 149025
city: London
country: Canada
facility: Victoria Hospital /ID# 149846
state: Ontario
city: Greenfield Park
country: Canada
facility: CISSS de la Monteregie /ID# 149844
state: Quebec
city: Limoges CEDEX 1
country: France
facility: CHU Limoges - Dupuytren 1 /ID# 149292
state: Franche-Comte
city: Nantes
country: France
facility: CHU de Nantes, Hotel Dieu -HME /ID# 149294
state: Pays-de-la-Loire
city: Pierre Benite CEDEX
country: France
facility: Duplicate_Centre Hospitalier Lyon Sud /ID# 149300
state: Rhone
city: Brest
country: France
facility: CHRU de Brest - Hopital Morvan /ID# 149299
city: La Tronche
country: France
facility: CHU Grenoble - Hopital Michallon /ID# 149301
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus Mitte /ID# 148949
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 148948
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona /ID# 150116
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont /ID# 152517
state: Hajdu-Bihar
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz /ID# 152516
state: Somogy
city: Budapest
country: Hungary
facility: Semmelweis Egyetem /ID# 152519
city: Budapest
country: Hungary
facility: Semmelweis Egyetem /ID# 152520
city: Budapest
country: Hungary
facility: Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 152518
city: Galway
country: Ireland
facility: University Hospital Galway /ID# 149061
city: Rome
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 148939
state: Lazio
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona /ID# 148942
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 148936
city: Rome
country: Italy
facility: Ospedale S.Eugenio /ID# 148938
city: Turin
country: Italy
facility: A.O.U. Città della Salute e della Scienza di Torino/Ospedale Molinette /ID# 148943
city: Nagoya shi
country: Japan
facility: Nagoya City University Hospital /ID# 150943
state: Aichi
city: Fukuoka-shi
country: Japan
facility: Kyushu University Hospital /ID# 150896
state: Fukuoka
city: Ogaki-shi
country: Japan
facility: Ogaki Municipal Hospital /ID# 150783
state: Gifu
city: Maebashi-shi
country: Japan
facility: Gunma University Hospital /ID# 150275
state: Gunma
city: Shibukawa-shi
country: Japan
facility: National Hospital Organization Shibukawa Medical Center /ID# 150281
state: Gunma
city: Hiroshima-shi
country: Japan
facility: Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital /ID# 150242
state: Hiroshima
city: Kobe-shi
country: Japan
facility: Kobe City Medical Center General Hospital /ID# 150944
state: Hyogo
city: Higashi Ibaraki-gun
country: Japan
facility: National Hospital Organization Mito Medical Center /ID# 151051
state: Ibaraki
city: Kyoto-shi
country: Japan
facility: Duplicate_Kyoto Prefectural University of Medicine /ID# 150719
state: Kyoto
city: Kyoto-shi
country: Japan
facility: JCHO Kyoto Kuramaguchi Medical /ID# 150781
state: Kyoto
city: Sendai-shi
country: Japan
facility: Tohoku University Hospital /ID# 150945
state: Miyagi
city: Okayama-shi
country: Japan
facility: Okayama Medical Center /ID# 150717
state: Okayama
city: Osaka-shi
country: Japan
facility: Japanese Red Cross Osaka Hospital /ID# 150716
state: Osaka
city: Kawagoe-shi
country: Japan
facility: Saitama Medical Center /ID# 151044
state: Saitama
city: Utsunomiya-shi
country: Japan
facility: Tochigi Cancer Center /ID# 150192
state: Tochigi
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital /ID# 151039
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital Of JFCR /ID# 150780
state: Tokyo
city: Shibuya-ku
country: Japan
facility: Japanese Red Cross Medical Center /ID# 149902
state: Tokyo
city: Tachikawa-shi
country: Japan
facility: National Hospital Organization Disaster Medical Center /ID# 150784
state: Tokyo
city: Goyang
country: Korea, Republic of
facility: National Cancer Center /ID# 150889
state: Gyeonggido
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital /ID# 150888
state: Gyeonggido
city: Seoul
country: Korea, Republic of
facility: Duplicate_Yonsei University Health System, Severance hospital. /ID# 150891
state: Seoul Teugbyeolsi
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital /ID# 150894
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center /ID# 150893
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital /ID# 150890
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center /ID# 150892
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital /ID# 150895
city: Kemerovo
country: Russian Federation
facility: Kuzbass Regional Clinical Hospital /ID# 148955
state: Kemerovskaya Oblast
city: Ryazan
country: Russian Federation
facility: State Institution of Health of the Ryazan Regional Clinical Hospital /ID# 148956
state: Ryazanskaya Oblast
city: Pyatigorsk
country: Russian Federation
facility: LLC Novaya Klinika /ID# 148974
state: Stavropol Skiy Kray
city: Moscow
country: Russian Federation
facility: Central Clinical Hospital RZHD Medicine /ID# 148954
city: Omsk
country: Russian Federation
facility: Clinical Oncology Dispensary of Omsk /ID# 148953
city: Samara
country: Russian Federation
facility: Samara State Medical University /ID# 148952
city: Ufa
country: Russian Federation
facility: Bashkir State Medical University /ID# 151206
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals /ID# 148989
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa /ID# 148980
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre /ID# 148981
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset /ID# 148986
city: Changhua City, Changhua County
country: Taiwan
facility: Changhua Christian Hospital /ID# 154447
city: Taichung City
country: Taiwan
facility: China Medical University Hospital /ID# 154446
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital /ID# 154444
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hosp /ID# 154445
city: Cherkasy
country: Ukraine
facility: Communal Nonprofit Enterprise Cherkasy Regional Oncology Dispensary /ID# 152414
city: Dnipro
country: Ukraine
facility: Municipal Non-Profit Enterprise City Clinical Hospital 4 of Dnipro City Council /ID# 152411
city: Kyiv
country: Ukraine
facility: National Cancer Institute /ID# 152413
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary /ID# 149057
state: England
city: London
country: United Kingdom
facility: Barts Health NHS Trust /ID# 149050
state: London, City Of
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust /ID# 149047
state: Nottinghamshire
city: Blackpool
country: United Kingdom
facility: Blackpool Teaching Hospitals NHS Foundation Trust /ID# 149058
city: Canterbury
country: United Kingdom
facility: East Kent Hospitals University NHS Foundation Trust /ID# 149059
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust /ID# 149044
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust /ID# 149045
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust /ID# 149046
city: Romford
country: United Kingdom
facility: Barking, Havering and Redbridge University Hospitals NHS Trust /ID# 149055
city: Wolverhampton
country: United Kingdom
facility: The Royal Wolverhampton NHS Trust /ID# 149043
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, Hungria V, Salwender H, Suzuki K, Kim I, Punnoose EA, Hong WJ, Freise KJ, Yang X, Sood A, Jalaluddin M, Ross JA, Ward JE, Maciag PC, Moreau P. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1630-1642. doi: 10.1016/S1470-2045(20)30525-8. Epub 2020 Oct 29.