A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Alba A. Brandes, Miguel Gil-Gil, Frank Saran, Antoine F. Carpentier, Anna K. Nowak, Warren Mason, Vittorina Zagonel, François Dubois, Gaetano Finocchiaro, George Fountzilas, Dana Michaela Cernea, Oliver Chinot, Rodica Anghel, Francois Ghiringhelli, Patrick Beauchesne, Giuseppe Lombardi, Enrico Franceschi, Martina Makrutzki, Chiedzo Mpofu, Hans Joerg Urban & 1 others Josef Pichler

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Abstract

Background: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

Original languageEnglish
Pages (from-to)521-528
Number of pages8
JournalONCOLOGIST
Volume24
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

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Glioblastoma
Lomustine
Safety
temozolomide
Placebos
Random Allocation
Therapeutics
Confidence Intervals
Bevacizumab
Radiotherapy
Survival
Disease Progression
Multicenter Studies
Disease-Free Survival

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Brandes, Alba A. ; Gil-Gil, Miguel ; Saran, Frank ; Carpentier, Antoine F. ; Nowak, Anna K. ; Mason, Warren ; Zagonel, Vittorina ; Dubois, François ; Finocchiaro, Gaetano ; Fountzilas, George ; Cernea, Dana Michaela ; Chinot, Oliver ; Anghel, Rodica ; Ghiringhelli, Francois ; Beauchesne, Patrick ; Lombardi, Giuseppe ; Franceschi, Enrico ; Makrutzki, Martina ; Mpofu, Chiedzo ; Urban, Hans Joerg ; Pichler, Josef. / A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. In: ONCOLOGIST. 2019 ; Vol. 24, No. 4. pp. 521-528.
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title = "A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma",
abstract = "Background: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33{\%}, placebo 31{\%}). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95{\%} confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95{\%} CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95{\%} CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95{\%} CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19{\%} (CCNU + BEV) versus 15{\%} (CCNU + placebo). Conclusion: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.",
keywords = "Clinical trial, Continuous bevacizumab, Overall survival, Recurrent glioblastoma",
author = "Brandes, {Alba A.} and Miguel Gil-Gil and Frank Saran and Carpentier, {Antoine F.} and Nowak, {Anna K.} and Warren Mason and Vittorina Zagonel and Fran{\cc}ois Dubois and Gaetano Finocchiaro and George Fountzilas and Cernea, {Dana Michaela} and Oliver Chinot and Rodica Anghel and Francois Ghiringhelli and Patrick Beauchesne and Giuseppe Lombardi and Enrico Franceschi and Martina Makrutzki and Chiedzo Mpofu and Urban, {Hans Joerg} and Josef Pichler",
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doi = "10.1634/theoncologist.2018-0290",
language = "English",
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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 2019, 'A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma' ONCOLOGIST, vol. 24, no. 4, pp. 521-528. https://doi.org/10.1634/theoncologist.2018-0290

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. / Brandes, Alba A.; Gil-Gil, Miguel; Saran, Frank; Carpentier, Antoine F.; Nowak, Anna K.; Mason, Warren; Zagonel, Vittorina; Dubois, François; Finocchiaro, Gaetano; Fountzilas, George; Cernea, Dana Michaela; Chinot, Oliver; Anghel, Rodica; Ghiringhelli, Francois; Beauchesne, Patrick; Lombardi, Giuseppe; Franceschi, Enrico; Makrutzki, Martina; Mpofu, Chiedzo; Urban, Hans Joerg; Pichler, Josef.

In: ONCOLOGIST, Vol. 24, No. 4, 01.04.2019, p. 521-528.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

AU - Brandes, Alba A.

AU - Gil-Gil, Miguel

AU - Saran, Frank

AU - Carpentier, Antoine F.

AU - Nowak, Anna K.

AU - Mason, Warren

AU - Zagonel, Vittorina

AU - Dubois, François

AU - Finocchiaro, Gaetano

AU - Fountzilas, George

AU - Cernea, Dana Michaela

AU - Chinot, Oliver

AU - Anghel, Rodica

AU - Ghiringhelli, Francois

AU - Beauchesne, Patrick

AU - Lombardi, Giuseppe

AU - Franceschi, Enrico

AU - Makrutzki, Martina

AU - Mpofu, Chiedzo

AU - Urban, Hans Joerg

AU - Pichler, Josef

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

AB - Background: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

KW - Clinical trial

KW - Continuous bevacizumab

KW - Overall survival

KW - Recurrent glioblastoma

UR - http://www.scopus.com/inward/record.url?scp=85054883848&partnerID=8YFLogxK

U2 - 10.1634/theoncologist.2018-0290

DO - 10.1634/theoncologist.2018-0290

M3 - Article

VL - 24

SP - 521

EP - 528

JO - ONCOLOGIST

JF - ONCOLOGIST

SN - 1083-7159

IS - 4

ER -