Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors

Leo Mascarenhas; Chitose Ogawa; Theodore W. Laetsch; Brenda J. Weigel; Michael W. Bishop; Julie Krystal; Scott C. Borinstein; Emily K. Slotkin; Jodi A. Muscal; Pooja Hingorani; Donna E. Levy; Gary Mo; Ashwin Shahir; Jennifer Wright; Steven G. DuBois

doi:10.1002/cam4.3658

Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors

Leo Mascarenhas, Chitose Ogawa, Theodore W. Laetsch, Brenda J. Weigel, Michael W. Bishop, Julie Krystal, Scott C. Borinstein, Emily K. Slotkin, Jodi A. Muscal, Pooja Hingorani, Donna E. Levy, Gary Mo, Ashwin Shahir, Jennifer Wright, Steven G. DuBois

Pediatrics - Hematology

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

1 Scopus citations

Abstract

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

Original language	English (US)
Pages (from-to)	843-856
Number of pages	14
Journal	Cancer medicine
Volume	10
Issue number	3
DOIs	https://doi.org/10.1002/cam4.3658
State	Published - Feb 2021

Bibliographical note

Funding Information:
L. Mascarenhas reports speaking fees from Bayer and travel expenses from Salarius and Thermo Fisher Scientific. C. Ogawa has no potential conflicts to disclose. T.W. Laetsch reports consulting for Eli Lilly and Company, Loxo Oncology, Bayer, Pfizer, and Novartis, and research funding from Bayer, Pfizer, and Novartis. B.J. Weigel has no potential conflicts to disclose. M.W. Bishop reports research funding from Pfizer. J. Krystal has no potential conflicts to disclose. S.C. Borinstein reports no potential conflicts in the past 12 months and has served on the Advisory Board with Bayer within 2 years. E.K. Slotkin has no potential conflicts to disclose. J.A. Muscal medical advisory board fees from Bayer Pharmaceuticals. P. Hingorani has no potential conflicts to disclose. D.E. Levy has no potential conflicts to disclose. Gary Mo is an employee and stockholder of Eli Lilly and Company and is an inventor on a pending patent application entitled Dosing Regimen. A. Shahir is an employee and stockholder of Eli Lilly and Company. J. Wright is an employee and stockholder of Eli Lilly and Company. S.G. DuBois reports consulting fees and travel expenses from Loxo Oncology prior to acquisition by Eli Lilly and Company, as well as travel expenses from Roche and Salarius.

Funding Information:
The authors would like to acknowledge Rodney L. Decker of Eli Lilly and Company for support in pharmacokinetics analyses. Medical writing and editorial support were provided by Prudence Stanford, Andrea Metti, Dana Schamberger, and Antonia Baldo of Syneos Health and funded by Eli Lilly and Company. This study was supported by Eli Lilly and Company, Alex’s Lemonade Stand Center of Excellence award (SGD), and Eugene P. Frenkel, M.D. Scholarship in Clinical Medicine (TWL).

Publisher Copyright:
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Keywords

chemotherapy
olaratumab
pediatric cancer
platelet-derived growth factor receptor

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Mascarenhas, L., Ogawa, C., Laetsch, T. W., Weigel, B. J., Bishop, M. W., Krystal, J., Borinstein, S. C., Slotkin, E. K., Muscal, J. A., Hingorani, P., Levy, D. E., Mo, G., Shahir, A., Wright, J., & DuBois, S. G. (2021). Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors. Cancer medicine, 10(3), 843-856. https://doi.org/10.1002/cam4.3658

Mascarenhas, L, Ogawa, C, Laetsch, TW, Weigel, BJ, Bishop, MW, Krystal, J, Borinstein, SC, Slotkin, EK, Muscal, JA, Hingorani, P, Levy, DE, Mo, G, Shahir, A, Wright, J & DuBois, SG 2021, 'Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors', Cancer medicine, vol. 10, no. 3, pp. 843-856. https://doi.org/10.1002/cam4.3658

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abstract = "Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.",

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author = "Leo Mascarenhas and Chitose Ogawa and Laetsch, {Theodore W.} and Weigel, {Brenda J.} and Bishop, {Michael W.} and Julie Krystal and Borinstein, {Scott C.} and Slotkin, {Emily K.} and Muscal, {Jodi A.} and Pooja Hingorani and Levy, {Donna E.} and Gary Mo and Ashwin Shahir and Jennifer Wright and DuBois, {Steven G.}",

note = "Funding Information: L. Mascarenhas reports speaking fees from Bayer and travel expenses from Salarius and Thermo Fisher Scientific. C. Ogawa has no potential conflicts to disclose. T.W. Laetsch reports consulting for Eli Lilly and Company, Loxo Oncology, Bayer, Pfizer, and Novartis, and research funding from Bayer, Pfizer, and Novartis. B.J. Weigel has no potential conflicts to disclose. M.W. Bishop reports research funding from Pfizer. J. Krystal has no potential conflicts to disclose. S.C. Borinstein reports no potential conflicts in the past 12 months and has served on the Advisory Board with Bayer within 2 years. E.K. Slotkin has no potential conflicts to disclose. J.A. Muscal medical advisory board fees from Bayer Pharmaceuticals. P. Hingorani has no potential conflicts to disclose. D.E. Levy has no potential conflicts to disclose. Gary Mo is an employee and stockholder of Eli Lilly and Company and is an inventor on a pending patent application entitled Dosing Regimen. A. Shahir is an employee and stockholder of Eli Lilly and Company. J. Wright is an employee and stockholder of Eli Lilly and Company. S.G. DuBois reports consulting fees and travel expenses from Loxo Oncology prior to acquisition by Eli Lilly and Company, as well as travel expenses from Roche and Salarius. Funding Information: The authors would like to acknowledge Rodney L. Decker of Eli Lilly and Company for support in pharmacokinetics analyses. Medical writing and editorial support were provided by Prudence Stanford, Andrea Metti, Dana Schamberger, and Antonia Baldo of Syneos Health and funded by Eli Lilly and Company. This study was supported by Eli Lilly and Company, Alex{\textquoteright}s Lemonade Stand Center of Excellence award (SGD), and Eugene P. Frenkel, M.D. Scholarship in Clinical Medicine (TWL). Publisher Copyright: {\textcopyright} 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

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month = feb,

doi = "10.1002/cam4.3658",

language = "English (US)",

volume = "10",

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T1 - Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors

AU - Mascarenhas, Leo

AU - Ogawa, Chitose

AU - Laetsch, Theodore W.

AU - Weigel, Brenda J.

AU - Bishop, Michael W.

AU - Krystal, Julie

AU - Borinstein, Scott C.

AU - Slotkin, Emily K.

AU - Muscal, Jodi A.

AU - Hingorani, Pooja

AU - Levy, Donna E.

AU - Mo, Gary

AU - Shahir, Ashwin

AU - Wright, Jennifer

AU - DuBois, Steven G.

N1 - Funding Information: L. Mascarenhas reports speaking fees from Bayer and travel expenses from Salarius and Thermo Fisher Scientific. C. Ogawa has no potential conflicts to disclose. T.W. Laetsch reports consulting for Eli Lilly and Company, Loxo Oncology, Bayer, Pfizer, and Novartis, and research funding from Bayer, Pfizer, and Novartis. B.J. Weigel has no potential conflicts to disclose. M.W. Bishop reports research funding from Pfizer. J. Krystal has no potential conflicts to disclose. S.C. Borinstein reports no potential conflicts in the past 12 months and has served on the Advisory Board with Bayer within 2 years. E.K. Slotkin has no potential conflicts to disclose. J.A. Muscal medical advisory board fees from Bayer Pharmaceuticals. P. Hingorani has no potential conflicts to disclose. D.E. Levy has no potential conflicts to disclose. Gary Mo is an employee and stockholder of Eli Lilly and Company and is an inventor on a pending patent application entitled Dosing Regimen. A. Shahir is an employee and stockholder of Eli Lilly and Company. J. Wright is an employee and stockholder of Eli Lilly and Company. S.G. DuBois reports consulting fees and travel expenses from Loxo Oncology prior to acquisition by Eli Lilly and Company, as well as travel expenses from Roche and Salarius. Funding Information: The authors would like to acknowledge Rodney L. Decker of Eli Lilly and Company for support in pharmacokinetics analyses. Medical writing and editorial support were provided by Prudence Stanford, Andrea Metti, Dana Schamberger, and Antonia Baldo of Syneos Health and funded by Eli Lilly and Company. This study was supported by Eli Lilly and Company, Alex’s Lemonade Stand Center of Excellence award (SGD), and Eugene P. Frenkel, M.D. Scholarship in Clinical Medicine (TWL). Publisher Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

PY - 2021/2

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N2 - Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

AB - Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

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KW - olaratumab

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Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors

Abstract

Bibliographical note

Keywords

UN SDGs

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