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

Glioblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01860638
• Other study ID #: MO28347
• Secondary ID: 2012-003138-17
• Status: Completed
• Phase: Phase 2
• Start date: August 19, 2013
• Est. completion date: May 5, 2017

Study information

• Verified date: April 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 296
• Est. completion date: May 5, 2017
• Est. primary completion date: January 13, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• Bevacizumab
Bevacizumab will be administered at a dose of 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks (Q2W) throughout the study, with the exception of bevacizumab monotherapy prior to PD1, which will be given as 15 mg/kg IV every 3 weeks (Q3W).
• Lomustine
Lomustine will be administered at a dose of 90 milligrams per square meter (mg/m^2) orally (PO) every 6 weeks (Q6W), with a cap of 160 milligrams (mg) per dose. In the absence of hematologic toxicity following the first dose, the second and subsequent doses may be increased to 110 mg/m^2 PO Q6W, with a cap of 200 mg per dose.
• Placebo
Placebo will be administered via IV infusion, in a formulation matched to bevacizumab, Q2W after randomization.

Radiation:
• Radiotherapy
Radiotherapy will be administered for a total dose of 60 Gray (Gy), administered in 2-Gy fractions, 5 days per week for 6 weeks during first-line treatment.

Drug:
• Temozolomide
Temozolomide will be administered orally (PO) as 75 mg/m^2 per day for the first 6 weeks of first-line treatment (concurrent treatment), followed by 6 cycles (28 days each) as follows: 150 mg/m^2 per day for the first 5 days of Cycle 1, then 200 mg/m^2 per day (if permitted by the participant's hematological and non-hematological toxicity profile) for the first 5 days of Cycles 2-6.
• SOC Agent
The choice of SOC agent will be at the discretion of investigator. The SOC agent will be administered during third-line treatment and subsequent lines, as per standard practice.

Locations

Country	Name	City	State
Austria	Medizinische Universität Graz; Universitätsklinik für Neurologie	Graz
Austria	Uniklinik fuer Neurologie, Medizinische Universitaet Innsbruck; Department fuer Neurologie	Innsbruck
Austria	Kepler Universitätsklinikum GmbH - Neuromed Campus; Innere Medizin mit Neuroonkologie	Linz
Austria	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg
Austria	Kaiser-Franz-Josef-Spital; Neurologische Abteilung	Wien
Austria	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie	Wien
Bulgaria	MBAL Serdika EOOD	Sofia
Canada	Tom Baker Cancer Centre; Dept of Medicine	Calgary	Alberta
Canada	McGill University; Montreal Neurological Institute; Oncology	Montreal	Quebec
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Estonia	Tartu University Hospital; Clinic of Hematology and Oncology	Tartu
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Hopital Avicenne; Neurologie	Bobigny
France	Hopital Saint Andre; Département de Radiothérapie Et D'Oncologie Médicale	Bordeaux
France	Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie	Bron
France	Hopital Cote De Nacre; Unite Neurologie Generale	Caen
France	Centre Georges Francois Leclerc; Oncologie 3	Dijon
France	Hopital Roger Salengro; Service de Neurologie	Lille
France	Hopital de La Timone - CHU de Marseille; Service de neuro-oncologie - Hôpital Adultes - 12ème étage	Marseille
France	Hôpital Central; Departement de Neuro-Oncologie	Nancy
France	Hopital Pitié Salpétrière - CHU; Service de neurologie 2 - Mazarin	Paris
France	Hopital Purpan	Toulouse Cedex 9
Greece	Agioi Anargyroi Anticancer Hospital; Radiotherapeutic Clinic	Kifisia
Greece	Hygeia Hospital	Marousi
Greece	Papageorgiou General Hospital; Medical Oncology	Thessaloniki
Italy	Ospedale Bellaria; U.O. Oncologia Medica	Bologna	Emilia-Romagna
Italy	Fondazione IRCCS Istituto Neurologico C. Besta; Neuro-oncologia Sperimentale e Terapia Genica	Milano	Lombardia
Italy	IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda	Padova	Veneto
Italy	IFO - Istituto Regina Elena; Oncologia Medica	Roma	Lazio
Italy	Azienda Ospedaliera Le Molintte di Torino; Dipartimento Di Neurologia - Oncologia	Torino	Piemonte
Latvia	Riga East Clinical University hospital, Clinic Gailezers, Dept of Neurosurgery	Riga
Portugal	IPO de Coimbra; Servico de Oncologia Medica	Coimbra
Portugal	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa
Portugal	Hospital de Sao Joao; Servico de Oncologia	Porto
Romania	Institutul Oncologic Prof. Dr. Al. Trestioreanu Bucuresti	Bucuresti
Romania	Institut Oncologic Ion Chiricuta; Departament Radioterapie	Cluj-napoca
Romania	Spital Clinic Judetean Mures; Oncologie	Targu Mures
Spain	Hospital Universitario Infanta Cristina; Servicio de Oncologia	Badajoz
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Duran i Reynals; Oncologia	Barcelona
Spain	Hospital de Cruces; Servicio de Oncologia	Bilbao	Vizcaya
Spain	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba
Spain	Hosp. Clinico San Carlos	Madrid
Spain	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia	Madrid
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Regional Universitario Carlos Haya; Servicio de Oncologia	Malaga
Spain	Hospital Universitario Son Espases; Servicio de Oncologia	Palma De Mallorca	Islas Baleares
Spain	Hospital Clinico Universitario de Salamanca; Servicio de Oncologia	Salamanca
Spain	IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia	San Sebastian	Guipuzcoa
Sweden	Universitetssjukhuset; Onkologkliniken	Linkoeping
Sweden	Norrlands Universitetssjukhus; Cancer Centrum	Umea
Sweden	Akademiska sjukhuset, Onkologkliniken	Uppsala
Turkey	Adana City Hospital, Medical Oncology	Adana
Turkey	Baskent Universitesi Tip Fakultesi; Ic Hastaliklari Anabilim Dali Tibbi Onkoloji Bilim Dali	Ankara
Turkey	Dokuz Eylul Uni ; Medical Oncology	Izmir
Turkey	Kocaeli University Faculty of Medicine; Medical oncology	Izmit
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Addenbrookes Hospital; Dept of Oncology	Cambridge
United Kingdom	University College Hospital; Department of Oncology	London
United Kingdom	Christie Hospital Nhs Trust; Medical Oncology	Manchester
United Kingdom	Royal Marsden Hospital; Dept of Medical Oncology	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Austria,  Bulgaria,  Canada,  Croatia,  Estonia,  France,  Greece,  Italy,  Latvia,  Portugal,  Romania,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)		From randomization at PD1 until death from any cause or end of study (overall approximately 35 months)
Secondary	Percentage of Participants Alive at 6, 12, and 18 Months from Randomization		At 6, 12, and 18 months after randomization/PD1 (overall up to approximately 35 months)
Secondary	Progression-Free Survival (PFS) on 2L Treatment According to Modified Response Assessment in Neuro-Oncology (RANO) Criteria		From first administration of randomized treatment until PD2 or death from any cause (overall approximately 18 months)
Secondary	PFS on 3L Treatment According to Modified RANO Criteria		From first administration of randomized treatment until PD3 or death from any cause (overall approximately 35 months)
Secondary	Restricted PFS on 3L Treatment According to Modified RANO Criteria		From first administration of treatment after PD2 until PD3 or death from any cause (overall approximately 26 months)
Secondary	Percentage of Participants with 2L Objective Response of Complete Response (CR) or Partial Response (PR) According to Modified RANO Criteria		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)
Secondary	Percentage of Participants with 3L Objective Response of CR or PR According to Modified RANO Criteria		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)
Secondary	Percentage of Participants with 2L Disease Control as CR, PR, or Stable Disease According to Modified RANO Criteria		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)
Secondary	Percentage of Participants with 3L Disease Control as CR, PR, or SD According to Modified RANO Criteria		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)
Secondary	Duration of 2L Objective Response Assessed According to Modified RANO Criteria		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)
Secondary	Duration of 3L Objective Response According to Modified RANO Criteria		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)
Secondary	Percentage of Participants with Adverse Events (AEs)		From baseline up to 30 days after last dose (up to 41 months overall)
Secondary	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		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)
Secondary	2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ C30 Global Health Status/Global QoL Scale Score		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)
Secondary	1L Treatment: Change From Baseline in EORTC QLQ Brain Cancer Module 20 (BN20) Multiple Item Score		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)
Secondary	2L and 3L Treatment: Change From 2L Baseline in EORTC QLQ BN20 Multiple Item Score		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)
Secondary	Percentage of Participants with Mini Mental Status Examination (MMSE) Score <27 or >/=27		Baseline and 2L Baseline
Secondary	1L Treatment: Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) z-score		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)
Secondary	2L and 3L Treatment: Change From 2L Baseline in HVLT-R z-score		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)
Secondary	1L Treatment: Change From Baseline in Controlled Oral Word Association (COWA) z-score		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)
Secondary	2L and 3L Treatment: Change From 2L Baseline in COWA z-score		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)
Secondary	1L Treatment: Change From Baseline in Trail-Making Test (TMT) Part A and B z-score		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)
Secondary	2L and 3L Treatment: Change From 2L Baseline in TMT Part A and Part B z-score		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)
Secondary	Number of Participants with Hospitalizations According to Type of Hospitalizations		From Baseline up to death or study withdrawal/study end (up to 41 months overall)
Secondary	Duration of Hospitalizations According to Type of Hospitalizations		From Baseline up to death or study withdrawal/study end (up to 41 months overall)
Secondary	EuroQol Five-Dimension Questionnaire (EQ-5D) Score		From Baseline up to death or study withdrawal/study end (up to 41 months overall)