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

NCT ID: NCT01860638

Last Updated: 2018-04-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 296 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-19
• Study Completion Date: 2017-05-05

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).

Conditions

Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

First-Line Bevacizumab followed by Bevacizumab + Lomustine/SOC

Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to bevacizumab will receive bevacizumab plus lomustine until PD2. Following PD2, participants will continue with blinded bevacizumab with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Radiotherapy

Intervention Type: RADIATION

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.

Temozolomide

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

First-Line Bevacizumab followed by Placebo + Lomustine/SOC

Participants will receive first-line treatment with radiotherapy, temozolomide, and bevacizumab. All three treatments will be given concurrently for the first 6 weeks, followed by 6 cycles (28 days each) of temozolomide plus bevacizumab, followed by bevacizumab monotherapy until PD1 or unacceptable toxicity. At PD1, participants randomized to placebo will receive placebo plus lomustine until PD2. Following PD2, participants will continue with blinded placebo with the addition of appropriate SOC. Following PD3, for subsequent treatment lines blinded bevacizumab may continue or open-label bevacizumab may be given at the discretion of the investigator and the participant.

Group Type: PLACEBO_COMPARATOR

Bevacizumab

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

Placebo will be administered via IV infusion, in a formulation matched to bevacizumab, Q2W after randomization.

Radiotherapy

Intervention Type: RADIATION

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.

Temozolomide

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

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).

Intervention Type: DRUG

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.

Intervention Type: DRUG

Placebo

Placebo will be administered via IV infusion, in a formulation matched to bevacizumab, Q2W after randomization.

Intervention Type: DRUG

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.

Intervention Type: RADIATION

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

Avastin

Eligibility Criteria

Inclusion Criteria

• 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

• 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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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

Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie

Vienna, , Austria

Kaiser-Franz-Josef-Spital; Neurologische Abteilung

Vienna, , Austria

MBAL Serdika EOOD

Sofia, , Bulgaria

Tom Baker Cancer Centre; Dept of Medicine

Calgary, Alberta, Canada

McGill University; Montreal Neurological Institute; Oncology

Montreal, Quebec, Canada

Clinical Hospital Centre Zagreb

Zagreb, , Croatia

Tartu University Hospital; Clinic of Hematology and Oncology

Tartu, , Estonia

HOPITAL JEAN MINJOZ; Oncologie

Besançon, , 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, , France

Agioi Anargyroi Anticancer Hospital; Radiotherapeutic Clinic

Kifissia, , Greece

Hygeia Hospital

Marousi, , Greece

Papageorgiou General Hospital; Medical Oncology

Thessaloniki, , Greece

Ospedale Bellaria; U.O. Oncologia Medica

Bologna, Emilia-Romagna, Italy

IFO - Istituto Regina Elena; Oncologia Medica

Rome, Lazio, Italy

Fondazione IRCCS Istituto Neurologico C. Besta; Neuro-oncologia Sperimentale e Terapia Genica

Milan, Lombardy, Italy

Azienda Ospedaliera Le Molintte di Torino; Dipartimento Di Neurologia - Oncologia

Turin, Piedmont, Italy

IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda

Padua, Veneto, Italy

Riga East Clinical University hospital, Clinic Gailezers, Dept of Neurosurgery

Riga, , Latvia

IPO de Coimbra; Servico de Oncologia Medica

Coimbra, , Portugal

Hospital de Santa Maria; Servico de Oncologia Medica

Lisbon, , Portugal

Hospital de Sao Joao; Servico de Oncologia

Porto, , Portugal

Institutul Oncologic Prof. Dr. Al. Trestioreanu Bucuresti

Bucharest, , Romania

Institut Oncologic Ion Chiricuta; Departament Radioterapie

Cluj-Napoca, , Romania

Spital Clinic Judetean Mures; Oncologie

Târgu Mureş, , Romania

Hospital Universitario Son Espases; Servicio de Oncologia

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia

Badalona, Barcelona, Spain

Hospital Universitario Reina Sofia; Servicio de Oncologia

Córdoba, Cordoba, Spain

IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia

Donostia / San Sebastian, Guipuzcoa, Spain

Hospital de Cruces; Servicio de Oncologia

Bilbao, Vizcaya, Spain

Hospital Universitario Infanta Cristina; Servicio de Oncologia

Badajoz, , Spain

Hospital del Mar; Servicio de Oncologia

Barcelona, , Spain

Hospital Duran i Reynals; Oncologia

Barcelona, , Spain

Hospital Ramon y Cajal; Servicio de Oncologia

Madrid, , Spain

Hosp. Clinico San Carlos

Madrid, , Spain

Hospital Universitario 12 de Octubre; Servicio de Oncologia

Madrid, , Spain

Hospital Universitario La Paz; Servicio de Oncologia

Madrid, , Spain

HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia

Madrid, , Spain

Hospital Regional Universitario Carlos Haya; Servicio de Oncologia

Málaga, , Spain

Hospital Clinico Universitario de Salamanca; Servicio de Oncologia

Salamanca, , Spain

Universitetssjukhuset; Onkologkliniken

Linköping, , Sweden

Norrlands Universitetssjukhus; Cancer Centrum

Umeå, , Sweden

Akademiska sjukhuset, Onkologkliniken

Uppsala, , Sweden

Adana City Hospital, Medical Oncology

Adana, , Turkey (Türkiye)

Baskent Universitesi Tıp Fakultesi; Ic Hastalıkları Anabilim Dalı Tıbbi Onkoloji Bilim Dalı

Ankara, , Turkey (Türkiye)

Dokuz Eylul Uni ; Medical Oncology

Izmir, , Turkey (Türkiye)

Kocaeli University Faculty of Medicine; Medical oncology

İzmit, , Turkey (Türkiye)

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, , United Kingdom

Countries

Austria; Bulgaria; Canada; Croatia; Estonia; France; Greece; Italy; Latvia; Portugal; Romania; Spain; Sweden; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 30266892 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24947255 (View on PubMed)

Other Identifiers

2012-003138-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MO28347

Identifier Type: -

Identifier Source: org_study_id