BRIM-P

A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma

Julia C Chisholm, Jozef Suvada, Ira J Dunkel, Michela Casanova, Weijiang Zhang, Natasha Ritchie, YounJeong Choi, Jane Park, Meghna Das Thakur, Stephen Simko, Nga Wan Rachel Tam, Andrea Ferrari

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323).

PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated.

RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively.

CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

Original languageEnglish
Pages (from-to)e26947
JournalPediatric Blood and Cancer
Volume65
Issue number5
DOIs
Publication statusPublished - May 2018

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Melanoma
Pediatrics
Mutation
Maximum Tolerated Dose
Disease Progression
Neoplasms
Proto-Oncogene Proteins B-raf
Confidence Intervals
PLX4032
Exanthema
Nausea
Disease-Free Survival
Fatigue
Headache
Diarrhea
Pharmacokinetics
Safety
Skin
Survival
Therapeutics

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BRIM-P : A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma. / Chisholm, Julia C; Suvada, Jozef; Dunkel, Ira J; Casanova, Michela; Zhang, Weijiang; Ritchie, Natasha; Choi, YounJeong; Park, Jane; Das Thakur, Meghna; Simko, Stephen; Wan Rachel Tam, Nga; Ferrari, Andrea.

In: Pediatric Blood and Cancer, Vol. 65, No. 5, 05.2018, p. e26947.

Research output: Contribution to journalArticle

Chisholm, Julia C ; Suvada, Jozef ; Dunkel, Ira J ; Casanova, Michela ; Zhang, Weijiang ; Ritchie, Natasha ; Choi, YounJeong ; Park, Jane ; Das Thakur, Meghna ; Simko, Stephen ; Wan Rachel Tam, Nga ; Ferrari, Andrea. / BRIM-P : A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma. In: Pediatric Blood and Cancer. 2018 ; Vol. 65, No. 5. pp. e26947.
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abstract = "BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323).PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated.RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95{\%} confidence interval [CI] = 2.7-5.2) and 8.1 months (95{\%} CI = 5.1-12.0), respectively.CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.",
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T2 - A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma

AU - Chisholm, Julia C

AU - Suvada, Jozef

AU - Dunkel, Ira J

AU - Casanova, Michela

AU - Zhang, Weijiang

AU - Ritchie, Natasha

AU - Choi, YounJeong

AU - Park, Jane

AU - Das Thakur, Meghna

AU - Simko, Stephen

AU - Wan Rachel Tam, Nga

AU - Ferrari, Andrea

N1 - © 2018 Wiley Periodicals, Inc.

PY - 2018/5

Y1 - 2018/5

N2 - BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323).PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated.RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively.CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

AB - BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323).PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated.RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively.CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

U2 - 10.1002/pbc.26947

DO - 10.1002/pbc.26947

M3 - Article

VL - 65

SP - e26947

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 5

ER -