Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors Journal Article
| Authors: | Camacho, L. H.; Olson, J.; Tong, W. P.; Young, C. W.; Spriggs, D. R.; Malkin, M. G. |
| Article Title: | Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors |
| Abstract: | Background: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. Methods: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Results: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA ≥1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Conclusions: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended. © 2006 Springer Science+Business Media, LLC. |
| Keywords: | adult; clinical article; controlled study; human tissue; treatment outcome; aged; middle aged; unclassified drug; clinical trial; constipation; fatigue; neutropenia; advanced cancer; cancer growth; drug withdrawal; side effect; solid tumor; antineoplastic agents; methodology; neoplasms; controlled clinical trial; lung toxicity; lung non small cell cancer; nausea; thrombocytopenia; sedation; cell differentiation; dose-response relationship, drug; dizziness; drug dose escalation; drug fever; flushing; pancreas carcinoma; sarcoma; cancer inhibition; chemotherapy induced emesis; confusion; drug induced headache; drug mechanism; histone; disease progression; glioblastoma; ovary carcinoma; peripheral edema; drug infusion; drug metabolism; drug blood level; maximum tolerated dose; phase 1 clinical trial; hemangiopericytoma; colon carcinoma; bladder carcinoma; infusions, intravenous; amnesia; metabolic disorder; musculoskeletal disease; diuretic agent; arylbutyric acid derivative; dysgeusia; biotransformation; phase i; phenylacetic acid derivative; catabolism; disorientation; drug acetylation; phenylacetic acid; cellular differentiation; histone acetylation; phenylbutyrate; phenylacetylglutamine; phenylbutyrate sodium; central nervous system depression; rectum hemangiopericytoma; sodium load; somatosensory disorder; phenylbutyrates |
| Journal Title: | Investigational New Drugs |
| Volume: | 25 |
| Issue: | 2 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2007-04-01 |
| Start Page: | 131 |
| End Page: | 138 |
| Language: | English |
| DOI: | 10.1007/s10637-006-9017-4 |
| PUBMED: | 17053987 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 25" - "Export Date: 17 November 2011" - "CODEN: INNDD" - "Source: Scopus" |
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