A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma

Sumanta Pal, Arun Azad, Shailender Bhatia, Harry A Drabkin, Brian John Costello, John Sarantopoulos, Ravindran Kanesvaran, Richard Lauer, Alexander Starodub, Ralph Hauke, Christopher J Sweeney, Noah Hahn, Guru Sonpavde, Stephen Richey, Timothy Breen, Gabriel Kremmidiotis, Annabell F Leske, Elizabeth Doolin, David Bibby, Jose Iglesias & 1 others Thomas E Hutson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including >/= 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82 vs. arm B: 30.30 , P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation
Original languageEnglish
Pages (from-to)3420-3427
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number15
DOIs
Publication statusPublished - 2015
Externally publishedYes

Cite this

Pal, S., Azad, A., Bhatia, S., Drabkin, H. A., Costello, B. J., Sarantopoulos, J., ... Hutson, T. E. (2015). A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma. Clinical Cancer Research, 21(15), 3420-3427. https://doi.org/10.1158/1078-0432.CCR-14-3370
Pal, Sumanta ; Azad, Arun ; Bhatia, Shailender ; Drabkin, Harry A ; Costello, Brian John ; Sarantopoulos, John ; Kanesvaran, Ravindran ; Lauer, Richard ; Starodub, Alexander ; Hauke, Ralph ; Sweeney, Christopher J ; Hahn, Noah ; Sonpavde, Guru ; Richey, Stephen ; Breen, Timothy ; Kremmidiotis, Gabriel ; Leske, Annabell F ; Doolin, Elizabeth ; Bibby, David ; Iglesias, Jose ; Hutson, Thomas E. / A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 15. pp. 3420-3427.
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title = "A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma",
abstract = "PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including >/= 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82 vs. arm B: 30.30 , P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation",
author = "Sumanta Pal and Arun Azad and Shailender Bhatia and Drabkin, {Harry A} and Costello, {Brian John} and John Sarantopoulos and Ravindran Kanesvaran and Richard Lauer and Alexander Starodub and Ralph Hauke and Sweeney, {Christopher J} and Noah Hahn and Guru Sonpavde and Stephen Richey and Timothy Breen and Gabriel Kremmidiotis and Leske, {Annabell F} and Elizabeth Doolin and David Bibby and Jose Iglesias and Hutson, {Thomas E}",
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Pal, S, Azad, A, Bhatia, S, Drabkin, HA, Costello, BJ, Sarantopoulos, J, Kanesvaran, R, Lauer, R, Starodub, A, Hauke, R, Sweeney, CJ, Hahn, N, Sonpavde, G, Richey, S, Breen, T, Kremmidiotis, G, Leske, AF, Doolin, E, Bibby, D, Iglesias, J & Hutson, TE 2015, 'A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma' Clinical Cancer Research, vol. 21, no. 15, pp. 3420-3427. https://doi.org/10.1158/1078-0432.CCR-14-3370

A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma. / Pal, Sumanta; Azad, Arun; Bhatia, Shailender; Drabkin, Harry A; Costello, Brian John; Sarantopoulos, John; Kanesvaran, Ravindran; Lauer, Richard; Starodub, Alexander; Hauke, Ralph; Sweeney, Christopher J; Hahn, Noah; Sonpavde, Guru; Richey, Stephen; Breen, Timothy; Kremmidiotis, Gabriel; Leske, Annabell F; Doolin, Elizabeth; Bibby, David; Iglesias, Jose; Hutson, Thomas E.

In: Clinical Cancer Research, Vol. 21, No. 15, 2015, p. 3420-3427.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma

AU - Pal, Sumanta

AU - Azad, Arun

AU - Bhatia, Shailender

AU - Drabkin, Harry A

AU - Costello, Brian John

AU - Sarantopoulos, John

AU - Kanesvaran, Ravindran

AU - Lauer, Richard

AU - Starodub, Alexander

AU - Hauke, Ralph

AU - Sweeney, Christopher J

AU - Hahn, Noah

AU - Sonpavde, Guru

AU - Richey, Stephen

AU - Breen, Timothy

AU - Kremmidiotis, Gabriel

AU - Leske, Annabell F

AU - Doolin, Elizabeth

AU - Bibby, David

AU - Iglesias, Jose

AU - Hutson, Thomas E

PY - 2015

Y1 - 2015

N2 - PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including >/= 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82 vs. arm B: 30.30 , P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation

AB - PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including >/= 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82 vs. arm B: 30.30 , P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation

U2 - 10.1158/1078-0432.CCR-14-3370

DO - 10.1158/1078-0432.CCR-14-3370

M3 - Article

VL - 21

SP - 3420

EP - 3427

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 15

ER -