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Pediatr Blood Cancer. 2018 Jul;65(7):e27023. doi: 10.1002/pbc.27023. Epub 2018 Mar 30.

Phase I study of vorinostat in combination with isotretinoin in patients with refractory/recurrent neuroblastoma: A new approaches to Neuroblastoma Therapy (NANT) trial.

Author information

1
Seattle Children's Hospital, University of Washington, Seattle, Washington.
2
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.
3
Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California.
4
Global Clinical Development-Oncology, Merck Research Laboratories, North Wales, Pennsylvania.
5
Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, New York City, New York.
6
Department of Preventative Medicine, University of Southern California, Los Angeles, California.
7
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
8
Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
9
Cancer Center and Cell Biology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
10
Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
11
Pediatric Hematology/Oncology/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
12
UCSF Benioff Children's Hospital, University of California, San Francisco, California.
13
UCSF School of Medicine, University of California, San Francisco, California.

Abstract

BACKGROUND:

Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.

METHODS:

Isotretinoin (cis-13-retinoic acid) 80 mg/m2 /dose was administered by mouth twice daily on days 1-14 in combination with escalating doses of daily vorinostat up to 430 mg/m2 /dose (days 1-4; 8-11) in each 28-day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.

RESULTS:

Twenty-nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1-15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose-limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2 /day, days 1-4; 8-11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.

CONCLUSIONS:

Increased dose vorinostat (430 mg/m2 /day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

KEYWORDS:

histone acetylation; neuroblastoma; pharmacokinetics; phase I clinical trial

PMID:
29603591
PMCID:
PMC6040651
DOI:
10.1002/pbc.27023
[Indexed for MEDLINE]
Free PMC Article

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