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Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial.

Abstract

PURPOSE

The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.

METHODS

Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat.

RESULTS

Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer.

CONCLUSIONS

The combination of belinostat 2000 mg/m2 days 1-5 and 13-cRA 100 mg/m2 days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.

Authors+Show Affiliations

Department of Medical Oncology, City of Hope, Duarte, USA.Department of Biostatistics, City of Hope, Duarte, USA.UPMC Hillman Cancer Center, Pittsburgh, USA.Department of Medical Oncology, City of Hope, Duarte, USA.Department of Medical Oncology, City of Hope, Duarte, USA.UPMC Hillman Cancer Center, Pittsburgh, USA.University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA.University of California Davis Cancer Center, Sacramento, CA, 95817, USA.UPMC Hillman Cancer Center, Pittsburgh, USA.Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Dr., MSC 9739, Bethesda, MD, 20892, USA.Beckman Research Institute City of Hope, Duarte, CA, 91010, USA. enewman@coh.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31522242

Citation

Luu, Thehang, et al. "Phase I Trial of Belinostat in Combination With 13-cis-retinoic Acid in Advanced Solid Tumor Malignancies: a California Cancer Consortium NCI/CTEP Sponsored Trial." Cancer Chemotherapy and Pharmacology, 2019.
Luu T, Frankel P, Beumer JH, et al. Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. Cancer Chemother Pharmacol. 2019.
Luu, T., Frankel, P., Beumer, J. H., Lim, D., Cristea, M., Appleman, L. J., ... Newman, E. M. (2019). Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. Cancer Chemotherapy and Pharmacology, doi:10.1007/s00280-019-03955-7.
Luu T, et al. Phase I Trial of Belinostat in Combination With 13-cis-retinoic Acid in Advanced Solid Tumor Malignancies: a California Cancer Consortium NCI/CTEP Sponsored Trial. Cancer Chemother Pharmacol. 2019 Sep 14; PubMed PMID: 31522242.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. AU - Luu,Thehang, AU - Frankel,Paul, AU - Beumer,Jan H, AU - Lim,Dean, AU - Cristea,Mihaela, AU - Appleman,Leonard J, AU - Lenz,Heinz J, AU - Gandara,David R, AU - Kiesel,Brian F, AU - Piekarz,Richard L, AU - Newman,Edward M, Y1 - 2019/09/14/ PY - 2019/08/14/received PY - 2019/08/21/accepted PY - 2019/9/16/entrez PY - 2019/9/16/pubmed PY - 2019/9/16/medline KW - Histone deacetylase (HDAC) inhibitors KW - Pharmacokinetics KW - Phase I clinical trial KW - Retinoids JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. N2 - PURPOSE: The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. METHODS: Belinostat was administered days 1-5 and 13-cRA days 1-14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat. RESULTS: Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. CONCLUSIONS: The combination of belinostat 2000 mg/m2 days 1-5 and 13-cRA 100 mg/m2 days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/31522242/Phase_I_trial_of_belinostat_in_combination_with_13-cis-retinoic_acid_in_advanced_solid_tumor_malignancies:_a_California_Cancer_Consortium_NCI/CTEP_sponsored_trial L2 - https://dx.doi.org/10.1007/s00280-019-03955-7 DB - PRIME DP - Unbound Medicine ER -