Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

G. E. Konecny; A. E.Wahner Hendrickson; T. M. Davidson; B. J. Winterhoff; S. Ma; S. Mahner; J. Sehouli; P. A. Fasching; G. Feisel-Schwickardi; M. Poelcher; L. D. Roman; A. Rody; B. Y. Karlan; S. A. Mullany; H. Chen; I. L. Ray-Coquard; D. M. Provencher; A. Yachnin; P. H. Cottu; J. A. Glaspy; P. Haluska; D. J. Slamon

doi:10.1016/j.ygyno.2021.09.025

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

G. E. Konecny, A. E.Wahner Hendrickson, T. M. Davidson, B. J. Winterhoff, S. Ma, S. Mahner, J. Sehouli, P. A. Fasching, G. Feisel-Schwickardi, M. Poelcher, L. D. Roman, A. Rody, B. Y. Karlan, S. A. Mullany, H. Chen, I. L. Ray-Coquard, D. M. Provencher, A. Yachnin, P. H. Cottu, J. A. GlaspyP. Haluska, D. J. Slamon

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. Results: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). Conclusion: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Original language	English (US)
Pages (from-to)	465-472
Number of pages	8
Journal	Gynecologic oncology
Volume	163
Issue number	3
Early online date	Oct 9 2021
DOIs	https://doi.org/10.1016/j.ygyno.2021.09.025
State	Published - Dec 2021

Bibliographical note

Funding Information:
Study was designed by academic investigators as an investigator-initiated study. Translational Research In Oncology (TRIO) an academically led international clinical trial network conducted the trial which was supported by Amgen, Inc. This was a multicenter, randomized, double-blind phase 2 clinical trial assessing the safety and efficacy of ganitumab in combination with carboplatin and paclitaxel. Patients were randomized through an Interactive Web Response System (IWRS), after central review of eligibility. Patients were stratified according to stage (III versus IV) and type of histology (papillary serous versus non-papillary serous) and randomized 1:1 to receive carboplatin AUC6 and 175 mg/m2 paclitaxel plus 18 mg/kg of ganitumab IV on day 1 of every 3 week cycle or carboplatin AUC6 and 175 mg/m2 paclitaxel plus placebo IV on day 1 of every 3 week cycle. After completion of 6 cycles of carboplatin/paclitaxel plus ganitumab or placebo, an additional 6 cycles of ganitumab/placebo as single agent at 18 mg/kg IV on day 1 of each 21-day cycle were administered. Based on phase I studies the recommended phase II dose of ganitumab was 18 mg/kg [16,17]. There was no unblinding in the maintenance treatment and cross over was not allowed. Neoadjuvant chemotherapy was not allowed. The study was conducted according to the Declaration of Helsinki and approved by the institutional review boards of each participating institution. All patients were provided written informed consent. The study is registered with ClinicalTrials.gov under the identifier NCT00718523.This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494.

Funding Information:
This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494 .

Publisher Copyright:
© 2021 The Authors

Keywords

Ganitumab
IGFR1 inhibitor
Insulin-like growth factor
Ovarian cancer
Targeted therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ygyno.2021.09.025

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Konecny, G. E., Hendrickson, A. E. W., Davidson, T. M., Winterhoff, B. J., Ma, S., Mahner, S., Sehouli, J., Fasching, P. A., Feisel-Schwickardi, G., Poelcher, M., Roman, L. D., Rody, A., Karlan, B. Y., Mullany, S. A., Chen, H., Ray-Coquard, I. L., Provencher, D. M., Yachnin, A., Cottu, P. H., ... Slamon, D. J. (2021). Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer. Gynecologic oncology, 163(3), 465-472. https://doi.org/10.1016/j.ygyno.2021.09.025

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer. / Konecny, G. E.; Hendrickson, A. E.Wahner; Davidson, T. M. et al.
In: Gynecologic oncology, Vol. 163, No. 3, 12.2021, p. 465-472.

Research output: Contribution to journal › Article › peer-review

Konecny, GE, Hendrickson, AEW, Davidson, TM, Winterhoff, BJ, Ma, S, Mahner, S, Sehouli, J, Fasching, PA, Feisel-Schwickardi, G, Poelcher, M, Roman, LD, Rody, A, Karlan, BY, Mullany, SA, Chen, H, Ray-Coquard, IL, Provencher, DM, Yachnin, A, Cottu, PH, Glaspy, JA, Haluska, P & Slamon, DJ 2021, 'Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer', Gynecologic oncology, vol. 163, no. 3, pp. 465-472. https://doi.org/10.1016/j.ygyno.2021.09.025

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title = "Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer",

abstract = "Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. Results: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). Conclusion: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.",

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author = "Konecny, {G. E.} and Hendrickson, {A. E.Wahner} and Davidson, {T. M.} and Winterhoff, {B. J.} and S. Ma and S. Mahner and J. Sehouli and Fasching, {P. A.} and G. Feisel-Schwickardi and M. Poelcher and Roman, {L. D.} and A. Rody and Karlan, {B. Y.} and Mullany, {S. A.} and H. Chen and Ray-Coquard, {I. L.} and Provencher, {D. M.} and A. Yachnin and Cottu, {P. H.} and Glaspy, {J. A.} and P. Haluska and Slamon, {D. J.}",

note = "Funding Information: Study was designed by academic investigators as an investigator-initiated study. Translational Research In Oncology (TRIO) an academically led international clinical trial network conducted the trial which was supported by Amgen, Inc. This was a multicenter, randomized, double-blind phase 2 clinical trial assessing the safety and efficacy of ganitumab in combination with carboplatin and paclitaxel. Patients were randomized through an Interactive Web Response System (IWRS), after central review of eligibility. Patients were stratified according to stage (III versus IV) and type of histology (papillary serous versus non-papillary serous) and randomized 1:1 to receive carboplatin AUC6 and 175 mg/m2 paclitaxel plus 18 mg/kg of ganitumab IV on day 1 of every 3 week cycle or carboplatin AUC6 and 175 mg/m2 paclitaxel plus placebo IV on day 1 of every 3 week cycle. After completion of 6 cycles of carboplatin/paclitaxel plus ganitumab or placebo, an additional 6 cycles of ganitumab/placebo as single agent at 18 mg/kg IV on day 1 of each 21-day cycle were administered. Based on phase I studies the recommended phase II dose of ganitumab was 18 mg/kg [16,17]. There was no unblinding in the maintenance treatment and cross over was not allowed. Neoadjuvant chemotherapy was not allowed. The study was conducted according to the Declaration of Helsinki and approved by the institutional review boards of each participating institution. All patients were provided written informed consent. The study is registered with ClinicalTrials.gov under the identifier NCT00718523.This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494. Funding Information: This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494 . Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

doi = "10.1016/j.ygyno.2021.09.025",

language = "English (US)",

volume = "163",

pages = "465--472",

journal = "Gynecologic oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

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TY - JOUR

T1 - Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

AU - Konecny, G. E.

AU - Hendrickson, A. E.Wahner

AU - Davidson, T. M.

AU - Winterhoff, B. J.

AU - Ma, S.

AU - Mahner, S.

AU - Sehouli, J.

AU - Fasching, P. A.

AU - Feisel-Schwickardi, G.

AU - Poelcher, M.

AU - Roman, L. D.

AU - Rody, A.

AU - Karlan, B. Y.

AU - Mullany, S. A.

AU - Chen, H.

AU - Ray-Coquard, I. L.

AU - Provencher, D. M.

AU - Yachnin, A.

AU - Cottu, P. H.

AU - Glaspy, J. A.

AU - Haluska, P.

AU - Slamon, D. J.

N1 - Funding Information: Study was designed by academic investigators as an investigator-initiated study. Translational Research In Oncology (TRIO) an academically led international clinical trial network conducted the trial which was supported by Amgen, Inc. This was a multicenter, randomized, double-blind phase 2 clinical trial assessing the safety and efficacy of ganitumab in combination with carboplatin and paclitaxel. Patients were randomized through an Interactive Web Response System (IWRS), after central review of eligibility. Patients were stratified according to stage (III versus IV) and type of histology (papillary serous versus non-papillary serous) and randomized 1:1 to receive carboplatin AUC6 and 175 mg/m2 paclitaxel plus 18 mg/kg of ganitumab IV on day 1 of every 3 week cycle or carboplatin AUC6 and 175 mg/m2 paclitaxel plus placebo IV on day 1 of every 3 week cycle. After completion of 6 cycles of carboplatin/paclitaxel plus ganitumab or placebo, an additional 6 cycles of ganitumab/placebo as single agent at 18 mg/kg IV on day 1 of each 21-day cycle were administered. Based on phase I studies the recommended phase II dose of ganitumab was 18 mg/kg [16,17]. There was no unblinding in the maintenance treatment and cross over was not allowed. Neoadjuvant chemotherapy was not allowed. The study was conducted according to the Declaration of Helsinki and approved by the institutional review boards of each participating institution. All patients were provided written informed consent. The study is registered with ClinicalTrials.gov under the identifier NCT00718523.This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494. Funding Information: This work was supported in part by Amgen Inc. Thousand Oaks, CA, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Thelma L. Culverson Endowed Cancer Research Fund, and the Stranahan Foundation for Translational Cancer Research and Advanced Clinical Cancer Research. Sisi Ma was supported by the CTSI grant UL1TR002494 . Publisher Copyright: © 2021 The Authors

PY - 2021/12

Y1 - 2021/12

N2 - Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. Results: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). Conclusion: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

AB - Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. Results: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). Conclusion: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

KW - Ganitumab

KW - IGFR1 inhibitor

KW - Insulin-like growth factor

KW - Ovarian cancer

KW - Targeted therapy

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Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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