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Updated: Jan 2, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or
Cornelis M van Tilburg1,2,3, Till Milde1,2,3, Ruth Witt1,3
1KiTZ Clinical Trial Unit, Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
Background:
Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies.
Results:
A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome.
Conclusion:
An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker.
Trial Registration:
ClinicalTrials.gov, NCT01422499. Registered 24 August 2011.
Insights
This study determined a safe dose recommendation (SDR) of 130 mg/m²/day for vorinostat in pediatric patients with refractory cancers. Higher doses correlated with better outcomes and manageable toxicity, suggesting baseline cytokines may predict response.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Previous trials with histone deacetylase (HDAC) inhibitors like vorinostat in solid tumors showed limited efficacy in adults and children.
- Preclinical data suggest higher concentrations than currently achievable may be needed for significant activity.
- This study focused on pediatric patients with relapsed or refractory malignancies.
Purpose of the Study:
- To determine a safe dose recommendation (SDR) for single-agent vorinostat using an intra-patient dose escalation design.
- To conduct pharmacokinetic (PK) analyses and evaluate anti-cancer activity in pediatric patients.
- To identify potential predictive biomarkers for treatment response.
Main Methods:
- A Phase I intra-patient dose escalation/de-escalation study was conducted until the maximum tolerated dose (MTD) was reached.
- Patients (3-18 years) with relapsed/refractory malignancies received escalating doses of vorinostat.
- Pharmacokinetics, plasma cytokine profiles, and disease assessments were performed. A Phase II component followed MTD determination.
Main Results:
- A safe dose recommendation (SDR) of 130 mg/m²/day was established, with a maximum dose of 580 mg/m²/day.
- Most patients (92%) experienced reversible adverse events; 12% had serious adverse events, with no treatment-related deaths.
- Five patients achieved prolonged disease control (>12 months), associated with higher Cmax and MTDs. The overall response rate in Phase II was 22%.
Conclusions:
- The determined SDR of 130 mg/m²/day allows for safe dose escalation in pediatric patients.
- Higher vorinostat exposure correlated with improved response and disease stabilization, despite manageable toxicity.
- Low baseline plasma cytokine levels emerged as a promising predictive biomarker for favorable outcomes and better tolerability.
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