A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Eric S. Schafer, Rachel E. Rau, Stacey Berg, Xiaowei Liu, Charles G. Minard, David D'Adamo, Rachael Scott, Larisa Reyderman, Gresel Martinez, Sandhya Devarajan, Joel M Reid, Elizabeth Fox, Brenda J. Weigel, Susan M. Blaney

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2/dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2/dose, respectively. One subject at the 1.4 mg/m2/dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2/dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2/dose on days 1 and 8 of a 21-day cycle.

Original languageEnglish (US)
JournalPediatric Blood and Cancer
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

eribulin
Microtubules
Pharmacokinetics
Neutropenia
Neoplasms
Central Nervous System Neoplasms
Lymphopenia
Ewing's Sarcoma
Hypokalemia
Anorexia
Peripheral Nervous System Diseases
Tubulin
Antineoplastic Agents
Nausea
Fatigue
Half-Life

Keywords

  • Children
  • Eribulin
  • Pharmacokinetics
  • Phase 1

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors : A Children's Oncology Group Phase 1 Consortium study (ADVL1314). / Schafer, Eric S.; Rau, Rachel E.; Berg, Stacey; Liu, Xiaowei; Minard, Charles G.; D'Adamo, David; Scott, Rachael; Reyderman, Larisa; Martinez, Gresel; Devarajan, Sandhya; Reid, Joel M; Fox, Elizabeth; Weigel, Brenda J.; Blaney, Susan M.

In: Pediatric Blood and Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Schafer, Eric S. ; Rau, Rachel E. ; Berg, Stacey ; Liu, Xiaowei ; Minard, Charles G. ; D'Adamo, David ; Scott, Rachael ; Reyderman, Larisa ; Martinez, Gresel ; Devarajan, Sandhya ; Reid, Joel M ; Fox, Elizabeth ; Weigel, Brenda J. ; Blaney, Susan M. / A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors : A Children's Oncology Group Phase 1 Consortium study (ADVL1314). In: Pediatric Blood and Cancer. 2018.
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abstract = "Background: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2/dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2/dose, respectively. One subject at the 1.4 mg/m2/dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2/dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2/dose on days 1 and 8 of a 21-day cycle.",
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author = "Schafer, {Eric S.} and Rau, {Rachel E.} and Stacey Berg and Xiaowei Liu and Minard, {Charles G.} and David D'Adamo and Rachael Scott and Larisa Reyderman and Gresel Martinez and Sandhya Devarajan and Reid, {Joel M} and Elizabeth Fox and Weigel, {Brenda J.} and Blaney, {Susan M.}",
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T1 - A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors

T2 - A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

AU - Schafer, Eric S.

AU - Rau, Rachel E.

AU - Berg, Stacey

AU - Liu, Xiaowei

AU - Minard, Charles G.

AU - D'Adamo, David

AU - Scott, Rachael

AU - Reyderman, Larisa

AU - Martinez, Gresel

AU - Devarajan, Sandhya

AU - Reid, Joel M

AU - Fox, Elizabeth

AU - Weigel, Brenda J.

AU - Blaney, Susan M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2/dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2/dose, respectively. One subject at the 1.4 mg/m2/dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2/dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2/dose on days 1 and 8 of a 21-day cycle.

AB - Background: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2/dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2/dose, respectively. One subject at the 1.4 mg/m2/dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2/dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2/dose on days 1 and 8 of a 21-day cycle.

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KW - Pharmacokinetics

KW - Phase 1

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