Clinical trial NCT01860638: A Comparison of Continuous Bevacizumab (Avastin) Treatment or Placebo in Addition to Lomustine Followed by Standard of Care After Disease Progression in Participants With Glioblastoma
Official title: A Double-Blind, Placebo-Controlled, Randomised, Phase II Study Evaluating the Efficacy and Safety of Addition of Continuous Multiple Line Bevacizumab Treatment to Lomustine in Second (2nd)-Line Followed by Standard of Care (SOC) in Third (3rd)-Line and Beyond Compared to Addition of Placebo, Following First Progression of Disease (PD1) in Patients With Glioblastoma (GBM) After First (1st)-Line Treatment With Radiotherapy, Temozolomide and Bevacizumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-05-23
Enrollment: 296
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: This multicenter, double-blind, placebo-controlled, randomized study will evaluate the efficacy and safety of the addition of bevacizumab treatment to lomustine (in 2nd-line \[2L\] treatment) and SOC (in 3rd-line \[3L\] and subsequent lines of treatment) following first-line disease progression (PD1) in participants with newly diagnosed glioblastoma. All enrolled participants will receive 1L treatment with radiotherapy, temozolomide, and bevacizumab. At PD1, eligible participants will be randomized (1:1) to receive 2L treatment with either bevacizumab plus lomustine or placebo plus lomustine. After second-line disease progression (PD2), participants will receive 3L treatment and will continue blinded bevacizumab or placebo with the addition of an SOC agent. Following third-line disease progression (PD3), participants will receive subsequent lines of treatment and will either continue blinded bevacizumab or placebo (at the discretion of the investigator), or switch to open-label bevacizumab (at the choice of the participant).


Eligibility criteria: Inclusion Criteria at Enrollment (before PD1):

* Newly diagnosed, histologically confirmed glioblastoma not previously treated with chemotherapy or radiotherapy
* If female and not postmenopausal (less than \[\<\] 12 months of amenorrhea) or surgically sterile, must agree to use a highly effective contraceptive method during the treatment period and for at least 6 months after the last dose of study drug
* Karnofsky performance status (KPS) greater than or equal to (\>/=) 60
* Mandatory tissue collection during pre-study surgery or biopsy for confirmation of the diagnosis and pathology
* Craniotomy or intracranial biopsy site must be adequately healed. Study treatment should be initiated \> 28 days following the last surgical procedure

Inclusion Criteria at Randomization (following PD1):

* Documented PD1 according to RANO criteria
* Eligibility for second-line treatment with lomustine and bevacizumab as investigational medicinal products
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Bevacizumab well tolerated and not interrupted for longer than 60 days during first-line treatment
* Tissue submission among participants for whom operation/re-operation is indicated before second-line treatment starts; operation/re-operation performed \>/=28 days after last bevacizumab administration and second-line treatment initiated \>/=28 days after surgical wound healed
* Randomization within 28 days after PD1 among participants for whom operation/re-operation is not necessary
* First administration of second-line treatment no later than 2 days from randomization

Exclusion Criteria at Enrollment (before PD1):

* Any prior chemotherapy for glioblastoma and low-grade astrocytomas
* Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field
* Prior or current anti-angiogenic treatment
* Treatment with any other investigational drug within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment
* Inadequate hematological, renal, or liver function
* Inadequately controlled hypertension
* Prior history of gastrointestinal perforation or abscess
* Clinically significant cardiovascular disease
* History or evidence of central nervous system disease unrelated to cancer unless adequately treated with standard medical therapy
* History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
* Serious non-healing wound, active ulcer, or untreated bone fracture
* Known hypersensitivity to any component of bevacizumab/placebo or any of the study drugs
* Active infection requiring IV antibiotics at start of study treatment
* Other malignancy within 5 years prior to study enrollment, except for carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ treated with curative intent
* Pregnant or lactating women
* Participation in any other study

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)
Secondary outcomes:
measure: Percentage of Participants Alive at 6, 12, and 18 Months from Randomization
timeFrame: At 6, 12, and 18 months after randomization/PD1 (overall up to approximately 35 months)
measure: Progression-Free Survival (PFS) on 2L Treatment According to Modified Response Assessment in Neuro-Oncology (RANO) Criteria
timeFrame: From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months)
measure: PFS on 3L Treatment According to Modified RANO Criteria
timeFrame: From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months)
measure: Restricted PFS on 3L Treatment According to Modified RANO Criteria
timeFrame: From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months)
measure: Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) According to Modified RANO Criteria
timeFrame: From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurs first (approximately 18 months overall)
measure: Percentage of Participants with 3L Objective Response of CR or PR According to Modified RANO Criteria
timeFrame: From PD2 until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of study treatment, whichever occurs first (approximately 26 months overall)
measure: Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease According to Modified RANO Criteria
timeFrame: From randomization/PD1 until PD2, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 2L-treatment, whichever occurs first (approximately 18 months overall)
measure: Percentage of Participants with 3L Disease Control as CR, PR, or SD According to Modified RANO Criteria
timeFrame: From PD2/start of 3L-treatment until PD3, death, subsequent anticancer therapy, operation/re-operation for glioblastoma, or 13 weeks after last administration of 3L-treatment, whichever occurs first (approximately 26 months overall)
measure: Duration of 2L Objective Response Assessed According to Modified RANO Criteria
timeFrame: From first occurrence of CR/PR after randomization/PD1 until PD2, death from any cause, subsequent anticancer therapy, whichever occurs first (approximately 18 months overall)
measure: Duration of 3L Objective Response According to Modified RANO Criteria
timeFrame: From first occurrence of CR/PR after PD2 until PD3, subsequent anticancer therapy, or death from any cause, whichever occurs first (approximately 26 months overall)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: From baseline up to 30 days after last dose (up to 41 months overall)
measure: 1L Treatment: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Global Health Status/Global QoL Scale Score
timeFrame: Baseline;Week(Wk)3,5;end of Wk6;Maintenance:Day(D)1 (Visit[V]1), D15 (V2) Cycles(C)1-6 Q4W;Monotherapy:V1-V44 Q3W;Safety Follow-up(FU) (30 days after last 1L dose);PD FUs(8 Wk after Safety FU [PD FU1],then every 12 Wk until PD1) (up to 41 months overall)
measure: 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score
timeFrame: 2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
measure: 1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score
timeFrame: Baseline; Wk 3, 5; end of Wk6; Maintenance: D1(V1), D15(V2) of C1-6 (Q4W); Monotherapy: V1-V44 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
measure: 2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score
timeFrame: 2L Baseline (2L treatment V1); 2L treatment: V2-V41 (Q2W) until PD2; 3L treatment: V1-V61 (Q2W) until PD3; Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
measure: Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27
timeFrame: Baseline and 2L Baseline
measure: 1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) z-score
timeFrame: Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
measure: 2L and 3L Treatment: Change From 2L Baseline in HVLT-R z-score
timeFrame: 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
measure: 1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score
timeFrame: Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
measure: 2L and 3L Treatment: Change From 2L Baseline in COWA z-score
timeFrame: 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
measure: 1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A and B z-score
timeFrame: Baseline; Maintenance: D1(V1) Cycles 1, 3, 5 (Q4W); Monotherapy: every 3rd visit starting from V1 to V43 (Q3W); Safety FU (30 days after last 1L dose); PD FUs (8 Wk after Safety FU [PD FU1], then every 12 Wk until PD1) (up to 41 months overall)
measure: 2L and 3L Treatment: Change From 2L Baseline in TMT Part A and Part B z-score
timeFrame: 2L Baseline; 2L treatment: every 6th visit starting from V7 to V43 (Q2W); 3L treatment: every 6th visit starting from V1 to V37, V49, V61 (Q2W); Safety FU (30 days after last 3L dose); PD FU1 (8 Wk after Safety FU); end of study (up to 41 months overall)
measure: Number of Participants with Hospitalizations According to Type of Hospitalizations
timeFrame: From Baseline up to death or study withdrawal/study end (up to 41 months overall)
measure: Duration of Hospitalizations According to Type of Hospitalizations
timeFrame: From Baseline up to death or study withdrawal/study end (up to 41 months overall)
measure: EuroQol Five-Dimension Questionnaire (EQ-5D) Score
timeFrame: From Baseline up to death or study withdrawal/study end (up to 41 months overall)
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medizinische Universität Graz; Universitätsklinik für Neurologie
city: Innsbruck
country: Austria
facility: Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie
city: Linz
country: Austria
facility: Kepler Universitätsklinikum GmbH - Neuromed Campus; Innere Medizin mit Neuroonkologie
city: Salzburg
country: Austria
facility: Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.
city: Wien
country: Austria
facility: Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie
city: Wien
country: Austria
facility: Kaiser-Franz-Josef-Spital; Neurologische Abteilung
city: Sofia
country: Bulgaria
facility: MBAL Serdika EOOD
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre; Dept of Medicine
state: Alberta
city: Montreal
country: Canada
facility: McGill University; Montreal Neurological Institute; Oncology
state: Quebec
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Zagreb
city: Tartu
country: Estonia
facility: Tartu University Hospital; Clinic of Hematology and Oncology
city: Besancon
country: France
facility: HOPITAL JEAN MINJOZ; Oncologie
city: Bobigny
country: France
facility: Hopital Avicenne; Neurologie
city: Bordeaux
country: France
facility: Hopital Saint Andre; Département de Radiothérapie Et D'Oncologie Médicale
city: Bron
country: France
facility: Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie
city: Caen
country: France
facility: Hopital Cote De Nacre; Unite Neurologie Generale
city: Dijon
country: France
facility: Centre Georges Francois Leclerc; Oncologie 3
city: Lille
country: France
facility: Hopital Roger Salengro; Service de Neurologie
city: Marseille
country: France
facility: Hopital de La Timone - CHU de Marseille; Service de neuro-oncologie - Hôpital Adultes - 12ème étage
city: Nancy
country: France
facility: Hôpital Central; Departement de Neuro-Oncologie
city: Paris
country: France
facility: Hopital Pitié Salpétrière - CHU; Service de neurologie 2 - Mazarin
city: Toulouse Cedex 9
country: France
facility: Hopital Purpan
city: Kifisia
country: Greece
facility: Agioi Anargyroi Anticancer Hospital; Radiotherapeutic Clinic
city: Marousi
country: Greece
facility: Hygeia Hospital
city: Thessaloniki
country: Greece
facility: Papageorgiou General Hospital; Medical Oncology
city: Bologna
country: Italy
facility: Ospedale Bellaria; U.O. Oncologia Medica
state: Emilia-Romagna
city: Roma
country: Italy
facility: IFO - Istituto Regina Elena; Oncologia Medica
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico C. Besta; Neuro-oncologia Sperimentale e Terapia Genica
state: Lombardia
city: Torino
country: Italy
facility: Azienda Ospedaliera Le Molintte di Torino; Dipartimento Di Neurologia - Oncologia
state: Piemonte
city: Padova
country: Italy
facility: IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda
state: Veneto
city: Riga
country: Latvia
facility: Riga East Clinical University hospital, Clinic Gailezers, Dept of Neurosurgery
city: Coimbra
country: Portugal
facility: IPO de Coimbra; Servico de Oncologia Medica
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria; Servico de Oncologia Medica
city: Porto
country: Portugal
facility: Hospital de Sao Joao; Servico de Oncologia
city: Bucuresti
country: Romania
facility: Institutul Oncologic Prof. Dr. Al. Trestioreanu Bucuresti
city: Cluj-napoca
country: Romania
facility: Institut Oncologic Ion Chiricuta; Departament Radioterapie
city: Targu Mures
country: Romania
facility: Spital Clinic Judetean Mures; Oncologie
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
state: Barcelona
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia; Servicio de Oncologia
state: Cordoba
city: San Sebastian
country: Spain
facility: IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia
state: Guipuzcoa
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases; Servicio de Oncologia
state: Islas Baleares
city: Bilbao
country: Spain
facility: Hospital de Cruces; Servicio de Oncologia
state: Vizcaya
city: Badajoz
country: Spain
facility: Hospital Universitario Infanta Cristina; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals; Oncologia
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hosp. Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz; Servicio de Oncologia
city: Madrid
country: Spain
facility: HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia
city: Malaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya; Servicio de Oncologia
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca; Servicio de Oncologia
city: Linkoeping
country: Sweden
facility: Universitetssjukhuset; Onkologkliniken
city: Umea
country: Sweden
facility: Norrlands Universitetssjukhus; Cancer Centrum
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset, Onkologkliniken
city: Adana
country: Turkey
facility: Adana City Hospital, Medical Oncology
city: Ankara
country: Turkey
facility: Baskent Universitesi Tıp Fakultesi; Ic Hastalıkları Anabilim Dalı Tıbbi Onkoloji Bilim Dalı
city: Izmir
country: Turkey
facility: Dokuz Eylul Uni ; Medical Oncology
city: Izmit
country: Turkey
facility: Kocaeli University Faculty of Medicine; Medical oncology
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital; Dept of Oncology
city: London
country: United Kingdom
facility: University College Hospital; Department of Oncology
city: Manchester
country: United Kingdom
facility: Christie Hospital Nhs Trust; Medical Oncology
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital; Dept of Medical Oncology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Brandes AA, Gil-Gil M, Saran F, Carpentier AF, Nowak AK, Mason W, Zagonel V, Dubois F, Finocchiaro G, Fountzilas G, Cernea DM, Chinot O, Anghel R, Ghiringhelli F, Beauchesne P, Lombardi G, Franceschi E, Makrutzki M, Mpofu C, Urban HJ, Pichler J. A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. Oncologist. 2019 Apr;24(4):521-528. doi: 10.1634/theoncologist.2018-0290. Epub 2018 Sep 28.
citation: Brandes AA, Mason W, Pichler J, Nowak AK, Gil M, Saran F, Revil C, Lutiger B, Carpentier AF. Can bevacizumab prolong survival for glioblastoma patients through multiple lines of therapy? Future Oncol. 2014 May;10(7):1137-45. doi: 10.2217/fon.14.75.