Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial

William D Tap; Zsuzsanna Papai; Brian A Van Tine; Steven Attia; Kristen N Ganjoo; Robin L Jones; Scott Schuetze; Damon Reed; Sant P Chawla; Richard F Riedel; Anders Krarup-Hansen; Maud Toulmonde; Isabelle Ray-Coquard; Peter Hohenberger; Giovanni Grignani; Lee D Cranmer; Scott Okuno; Mark Agulnik; William Read; Christopher W Ryan; Thierry Alcindor; Xavier F Garcia Del Muro; G Thomas Budd; Hussein Tawbi; Tillman Pearce; Stew Kroll; Denise K Reinke; Patrick Schöffski

doi:10.1016/S1470-2045(17)30381-9

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial

William D Tap, Zsuzsanna Papai, Brian A Van Tine, Steven Attia, Kristen N Ganjoo, Robin L Jones, Scott Schuetze, Damon Reed, Sant P Chawla, Richard F Riedel, Anders Krarup-Hansen, Maud Toulmonde, Isabelle Ray-Coquard, Peter Hohenberger, Giovanni Grignani, Lee D Cranmer, Scott Okuno, Mark Agulnik, William Read, Christopher W RyanThierry Alcindor, Xavier F Garcia Del Muro, G Thomas Budd, Hussein Tawbi, Tillman Pearce, Stew Kroll, Denise K Reinke, Patrick Schöffski

Department of Clinical Medicine

103 Citations (Scopus)

Abstract

Background Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. Methods We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m² via bolus injection administered over 5–20 min or continuous intravenous infusion for 6–96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m² intravenously for 30–60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Findings Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88–1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6–22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2–22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3–4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3–4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). Interpretation The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. Funding Threshold Pharmaceuticals.

Original language	English
Journal	Lancet Oncology
Volume	18
Issue number	8
Pages (from-to)	1089-1103
Number of pages	15
ISSN	1470-2045
DOIs	https://doi.org/10.1016/S1470-2045(17)30381-9
Publication status	Published - Aug 2017

Keywords

Aged
Antibiotics, Antineoplastic/adverse effects
Antineoplastic Combined Chemotherapy Protocols/adverse effects
Disease-Free Survival
Doxorubicin/administration & dosage
Drug Eruptions/etiology
Exanthema/chemically induced
Female
Hematologic Diseases/chemically induced
Humans
Male
Middle Aged
Nitroimidazoles/administration & dosage
Phosphoramide Mustards/administration & dosage
Sarcoma/drug therapy
Soft Tissue Neoplasms/drug therapy
Stomatitis/chemically induced
Survival Rate

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Tap, W. D., Papai, Z., Van Tine, B. A., Attia, S., Ganjoo, K. N., Jones, R. L., Schuetze, S., Reed, D., Chawla, S. P., Riedel, R. F., Krarup-Hansen, A., Toulmonde, M., Ray-Coquard, I., Hohenberger, P., Grignani, G., Cranmer, L. D., Okuno, S., Agulnik, M., Read, W., ... Schöffski, P. (2017). Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncology, 18(8), 1089-1103. https://doi.org/10.1016/S1470-2045(17)30381-9

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021) : an international, multicentre, open-label, randomised phase 3 trial. / Tap, William D; Papai, Zsuzsanna; Van Tine, Brian A et al.

In: Lancet Oncology, Vol. 18, No. 8, 08.2017, p. 1089-1103.

Research output: Contribution to journal › Journal article › Research › peer-review

Tap, WD, Papai, Z, Van Tine, BA, Attia, S, Ganjoo, KN, Jones, RL, Schuetze, S, Reed, D, Chawla, SP, Riedel, RF, Krarup-Hansen, A, Toulmonde, M, Ray-Coquard, I, Hohenberger, P, Grignani, G, Cranmer, LD, Okuno, S, Agulnik, M, Read, W, Ryan, CW, Alcindor, T, Del Muro, XFG, Budd, GT, Tawbi, H, Pearce, T, Kroll, S, Reinke, DK & Schöffski, P 2017, 'Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial', Lancet Oncology, vol. 18, no. 8, pp. 1089-1103. https://doi.org/10.1016/S1470-2045(17)30381-9

@article{299c5b5aa3224467ab0b4a19a78890f9,

title = "Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial",

abstract = "Background Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. Methods We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5–20 min or continuous intravenous infusion for 6–96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30–60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Findings Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88–1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6–22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2–22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3–4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3–4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). Interpretation The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. Funding Threshold Pharmaceuticals.",

keywords = "Aged, Antibiotics, Antineoplastic/adverse effects, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Disease-Free Survival, Doxorubicin/administration & dosage, Drug Eruptions/etiology, Exanthema/chemically induced, Female, Hematologic Diseases/chemically induced, Humans, Male, Middle Aged, Nitroimidazoles/administration & dosage, Phosphoramide Mustards/administration & dosage, Sarcoma/drug therapy, Soft Tissue Neoplasms/drug therapy, Stomatitis/chemically induced, Survival Rate",

author = "Tap, {William D} and Zsuzsanna Papai and {Van Tine}, {Brian A} and Steven Attia and Ganjoo, {Kristen N} and Jones, {Robin L} and Scott Schuetze and Damon Reed and Chawla, {Sant P} and Riedel, {Richard F} and Anders Krarup-Hansen and Maud Toulmonde and Isabelle Ray-Coquard and Peter Hohenberger and Giovanni Grignani and Cranmer, {Lee D} and Scott Okuno and Mark Agulnik and William Read and Ryan, {Christopher W} and Thierry Alcindor and {Del Muro}, {Xavier F Garcia} and Budd, {G Thomas} and Hussein Tawbi and Tillman Pearce and Stew Kroll and Reinke, {Denise K} and Patrick Sch{\"o}ffski",

year = "2017",

month = aug,

doi = "10.1016/S1470-2045(17)30381-9",

language = "English",

volume = "18",

pages = "1089--1103",

journal = "The Lancet Oncology",

issn = "1470-2045",

publisher = "TheLancet Publishing Group",

number = "8",

}

TY - JOUR

T1 - Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021)

T2 - an international, multicentre, open-label, randomised phase 3 trial

AU - Tap, William D

AU - Papai, Zsuzsanna

AU - Van Tine, Brian A

AU - Attia, Steven

AU - Ganjoo, Kristen N

AU - Jones, Robin L

AU - Schuetze, Scott

AU - Reed, Damon

AU - Chawla, Sant P

AU - Riedel, Richard F

AU - Krarup-Hansen, Anders

AU - Toulmonde, Maud

AU - Ray-Coquard, Isabelle

AU - Hohenberger, Peter

AU - Grignani, Giovanni

AU - Cranmer, Lee D

AU - Okuno, Scott

AU - Agulnik, Mark

AU - Read, William

AU - Ryan, Christopher W

AU - Alcindor, Thierry

AU - Del Muro, Xavier F Garcia

AU - Budd, G Thomas

AU - Tawbi, Hussein

AU - Pearce, Tillman

AU - Kroll, Stew

AU - Reinke, Denise K

AU - Schöffski, Patrick

PY - 2017/8

Y1 - 2017/8

N2 - Background Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. Methods We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5–20 min or continuous intravenous infusion for 6–96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30–60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Findings Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88–1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6–22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2–22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3–4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3–4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). Interpretation The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. Funding Threshold Pharmaceuticals.

AB - Background Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. Methods We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5–20 min or continuous intravenous infusion for 6–96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30–60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Findings Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88–1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6–22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2–22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3–4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3–4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). Interpretation The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. Funding Threshold Pharmaceuticals.

KW - Aged

KW - Antibiotics, Antineoplastic/adverse effects

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Disease-Free Survival

KW - Doxorubicin/administration & dosage

KW - Drug Eruptions/etiology

KW - Exanthema/chemically induced

KW - Female

KW - Hematologic Diseases/chemically induced

KW - Humans

KW - Male

KW - Middle Aged

KW - Nitroimidazoles/administration & dosage

KW - Phosphoramide Mustards/administration & dosage

KW - Sarcoma/drug therapy

KW - Soft Tissue Neoplasms/drug therapy

KW - Stomatitis/chemically induced

KW - Survival Rate

U2 - 10.1016/S1470-2045(17)30381-9

DO - 10.1016/S1470-2045(17)30381-9

M3 - Journal article

C2 - 28651927

SN - 1470-2045

VL - 18

SP - 1089

EP - 1103

JO - The Lancet Oncology

JF - The Lancet Oncology

IS - 8

ER -