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/m 2 /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/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /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/m 2 /dose on days 1 and 8 of a 21-day cycle.

Original languageEnglish (US)
Article numbere27066
JournalPediatric Blood and Cancer
Volume65
Issue number8
DOIs
StatePublished - Aug 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

  • Phase 1
  • children
  • eribulin
  • pharmacokinetics

PubMed: MeSH publication types

  • Clinical Trial, Phase I
  • Journal Article

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, Vol. 65, No. 8, e27066, 01.08.2018.

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 ; Vol. 65, No. 8.
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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/m 2 /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/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /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/m 2 /dose on days 1 and 8 of a 21-day cycle.",
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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 - 2018/8/1

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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/m 2 /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/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /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/m 2 /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/m 2 /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/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /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/m 2 /dose on days 1 and 8 of a 21-day cycle.

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