Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial

TRINOVA-3/ENGOT-ov2/GOG-3001 investigators

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen.

Original languageEnglish (US)
Pages (from-to)862-876
Number of pages15
JournalThe Lancet Oncology
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2019

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Carboplatin
Paclitaxel
Ovarian Neoplasms
Placebos
Disease-Free Survival
Therapeutics
Angiopoietin-2
Angiopoietin-1
trebananib
Fallopian Tube Neoplasms
Safety
Cancer Care Facilities
Phase III Clinical Trials
Fallopian Tubes
Leukopenia
Receptor Protein-Tyrosine Kinases
Colitis
Neutropenia
Gynecology
Platelet Count

ASJC Scopus subject areas

  • Oncology

Cite this

Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001) : a randomised, double-blind, phase 3 trial. / TRINOVA-3/ENGOT-ov2/GOG-3001 investigators.

In: The Lancet Oncology, Vol. 20, No. 6, 01.06.2019, p. 862-876.

Research output: Contribution to journalArticle

@article{665d6cf9a54c4552aa5c52b6ca1099a9,
title = "Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial",
abstract = "Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60{\%}]of 678 in the trebananib group and 221 [66{\%}]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95{\%} CI 0·79–1·09]; p=0·36). 512 (76{\%})of 675 patients in the trebananib group and 237 (71{\%})of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35{\%}]vs placebo 126 [38{\%}])anaemia (76 [11{\%}]vs 40 [12{\%}]), and leucopenia (81 [12{\%}]vs 35 [10{\%}]). 269 (40{\%})patients in the trebananib group and 104 (31{\%})in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen.",
author = "{TRINOVA-3/ENGOT-ov2/GOG-3001 investigators} and Ignace Vergote and Giovanni Scambia and O'Malley, {David M.} and {Van Calster}, Ben and Park, {Sang Yoon} and {del Campo}, {Josep M.} and Werner Meier and Aristotelis Bamias and Nicoletta Colombo and Wenham, {Robert M.} and Al Covens and Christian Marth and {Raza Mirza}, Mansoor and Kroep, {Judith R.} and Haijun Ma and Pickett, {Cheryl A.} and Monk, {Bradley J.} and Park, {Sang Yoon} and Song, {Yong Sang} and Yulia Makarova and Joshua Trinidad and Ngan, {Hextan Yuen Sheung} and Gerasimos Aravantinos and Nam, {Joo Hyun} and Vera Gorbunova and Ludmila Krikunova and Bae, {Duk Soo} and Arija, {Jose Angel Arranz} and Mirza, {Mansoor Raza} and Claudio Zamagni and Christos Papandreou and Francesco Raspagliesi and Alla Lisyanskaya and Benzaquen, {Ana Oaknin} and Germana Tognon and Eugenia Ortega and Herraez, {Antonio Casado} and Joseph Buscema and Andrew Green and Robert Burger and Dina Sakaeva and Sanchez, {Andres Redondo} and Sharad Ghamande and Laurel King and Edgar Petru and Ulla Peen and Satoshi Takeuchi and Kimio Ushijima and Martin, {Antonio Gonzalez} and Jeanne Schilder",
year = "2019",
month = "6",
day = "1",
doi = "10.1016/S1470-2045(19)30178-0",
language = "English (US)",
volume = "20",
pages = "862--876",
journal = "The Lancet Oncology",
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TY - JOUR

T1 - Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001)

T2 - a randomised, double-blind, phase 3 trial

AU - TRINOVA-3/ENGOT-ov2/GOG-3001 investigators

AU - Vergote, Ignace

AU - Scambia, Giovanni

AU - O'Malley, David M.

AU - Van Calster, Ben

AU - Park, Sang Yoon

AU - del Campo, Josep M.

AU - Meier, Werner

AU - Bamias, Aristotelis

AU - Colombo, Nicoletta

AU - Wenham, Robert M.

AU - Covens, Al

AU - Marth, Christian

AU - Raza Mirza, Mansoor

AU - Kroep, Judith R.

AU - Ma, Haijun

AU - Pickett, Cheryl A.

AU - Monk, Bradley J.

AU - Park, Sang Yoon

AU - Song, Yong Sang

AU - Makarova, Yulia

AU - Trinidad, Joshua

AU - Ngan, Hextan Yuen Sheung

AU - Aravantinos, Gerasimos

AU - Nam, Joo Hyun

AU - Gorbunova, Vera

AU - Krikunova, Ludmila

AU - Bae, Duk Soo

AU - Arija, Jose Angel Arranz

AU - Mirza, Mansoor Raza

AU - Zamagni, Claudio

AU - Papandreou, Christos

AU - Raspagliesi, Francesco

AU - Lisyanskaya, Alla

AU - Benzaquen, Ana Oaknin

AU - Tognon, Germana

AU - Ortega, Eugenia

AU - Herraez, Antonio Casado

AU - Buscema, Joseph

AU - Green, Andrew

AU - Burger, Robert

AU - Sakaeva, Dina

AU - Sanchez, Andres Redondo

AU - Ghamande, Sharad

AU - King, Laurel

AU - Petru, Edgar

AU - Peen, Ulla

AU - Takeuchi, Satoshi

AU - Ushijima, Kimio

AU - Martin, Antonio Gonzalez

AU - Schilder, Jeanne

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen.

AB - Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen.

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