A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

Martin H. Voss, A. Hussain, N. Vogelzang, J. L. Lee, B. Keam, SunYoung Rha, U. Vaishampayan, W. B. Harris, S. Richey, J. M. Randall, D. Shaffer, A. Cohn, T. Crowell, J. Li, A. Senderowicz, E. Stone, R. Figlin, R. J. Motzer, N. B. Haas, T. Hutson

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: Patients with mRCC and 2-3 prior lines of therapy were randomized 1: 1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 patients were randomized and received ≥ 1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0 .831). The objective response rate by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.

Original languageEnglish
Pages (from-to)2754-2760
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number11
DOIs
Publication statusPublished - 2017 Jan 1

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Standard of Care
Renal Cell Carcinoma
Disease-Free Survival
Pharmaceutical Preparations
Nanoparticles
Confidence Intervals
Topoisomerase I Inhibitors
Safety
IT-101
Bevacizumab
Hypoxia-Inducible Factor 1
Camptothecin
Proxy
Neoplasms
Research Personnel
Survival

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Voss, Martin H. ; Hussain, A. ; Vogelzang, N. ; Lee, J. L. ; Keam, B. ; Rha, SunYoung ; Vaishampayan, U. ; Harris, W. B. ; Richey, S. ; Randall, J. M. ; Shaffer, D. ; Cohn, A. ; Crowell, T. ; Li, J. ; Senderowicz, A. ; Stone, E. ; Figlin, R. ; Motzer, R. J. ; Haas, N. B. ; Hutson, T. / A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma. In: Annals of Oncology. 2017 ; Vol. 28, No. 11. pp. 2754-2760.
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title = "A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma",
abstract = "Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: Patients with mRCC and 2-3 prior lines of therapy were randomized 1: 1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 patients were randomized and received ≥ 1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95{\%} confidence interval, 2.0-4.3) and 3.9 months (95{\%} confidence interval 2.2-5.4), respectively (stratified log-rank P = 0 .831). The objective response rate by IRR was 5{\%} with CRLX101+bevacizumab versus 14{\%} with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.",
author = "Voss, {Martin H.} and A. Hussain and N. Vogelzang and Lee, {J. L.} and B. Keam and SunYoung Rha and U. Vaishampayan and Harris, {W. B.} and S. Richey and Randall, {J. M.} and D. Shaffer and A. Cohn and T. Crowell and J. Li and A. Senderowicz and E. Stone and R. Figlin and Motzer, {R. J.} and Haas, {N. B.} and T. Hutson",
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Voss, MH, Hussain, A, Vogelzang, N, Lee, JL, Keam, B, Rha, S, Vaishampayan, U, Harris, WB, Richey, S, Randall, JM, Shaffer, D, Cohn, A, Crowell, T, Li, J, Senderowicz, A, Stone, E, Figlin, R, Motzer, RJ, Haas, NB & Hutson, T 2017, 'A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma', Annals of Oncology, vol. 28, no. 11, pp. 2754-2760. https://doi.org/10.1093/annonc/mdx493

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma. / Voss, Martin H.; Hussain, A.; Vogelzang, N.; Lee, J. L.; Keam, B.; Rha, SunYoung; Vaishampayan, U.; Harris, W. B.; Richey, S.; Randall, J. M.; Shaffer, D.; Cohn, A.; Crowell, T.; Li, J.; Senderowicz, A.; Stone, E.; Figlin, R.; Motzer, R. J.; Haas, N. B.; Hutson, T.

In: Annals of Oncology, Vol. 28, No. 11, 01.01.2017, p. 2754-2760.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

AU - Voss, Martin H.

AU - Hussain, A.

AU - Vogelzang, N.

AU - Lee, J. L.

AU - Keam, B.

AU - Rha, SunYoung

AU - Vaishampayan, U.

AU - Harris, W. B.

AU - Richey, S.

AU - Randall, J. M.

AU - Shaffer, D.

AU - Cohn, A.

AU - Crowell, T.

AU - Li, J.

AU - Senderowicz, A.

AU - Stone, E.

AU - Figlin, R.

AU - Motzer, R. J.

AU - Haas, N. B.

AU - Hutson, T.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: Patients with mRCC and 2-3 prior lines of therapy were randomized 1: 1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 patients were randomized and received ≥ 1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0 .831). The objective response rate by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.

AB - Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. Patients and methods: Patients with mRCC and 2-3 prior lines of therapy were randomized 1: 1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. Results: In total, 111 patients were randomized and received ≥ 1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0 .831). The objective response rate by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. Conclusions: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.

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JO - Annals of Oncology

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