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 language | English |
|---|---|
| Pages (from-to) | 2754-2760 |
| Number of pages | 7 |
| Journal | Annals of Oncology |
| Volume | 28 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2017 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Hematology
- Oncology
Cite this
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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 journal › Article
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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U2 - 10.1093/annonc/mdx493
DO - 10.1093/annonc/mdx493
M3 - Article
C2 - 28950297
AN - SCOPUS:85034025597
VL - 28
SP - 2754
EP - 2760
JO - Annals of Oncology
JF - Annals of Oncology
SN - 0923-7534
IS - 11
ER -