Vorinostat demonstrates consistent safety

Berlin, Germany—Vorinostat demonstrates safety and tolerability alone and in combination with other systemic treatments for a wide range of solid and hematologic malignancies, according to a study of collated data from the vorinostat clinical trial program.

Investigators presented the safety data in a poster at the ECCO 15 - 34th ESMO Multidisciplinary Congress. The data suggest that a supratherapeutic single dose (800 mg) of this orally active histone deacetylase inhibitor does not prolong ventricular repolarization to a significant degree. This is reassuring, since cardiac rhythm and EEG changes are thought to be a class effect of HDACs.

Lead author David Siegel, MD, from Hackensack University Medical Center, Hackensack, New Jersey, and his fellow researchers observed that the study data support the overall safety profile of vorinostat use in cancer patients.

They based their analysis on 18 phase 1 and phase 2 vorinostat trials that included 498 patients, 341 who received the agent as monotherapy and 157 treated with the drug in combination with other therapies.

Vorinostat is approved by the US Food and Drug Administration to treat relapsed or refractory cutaneous T-cell lymphoma and was dosed at the approved level of 400 mg/day for 156 of the 341 patients in the monotherapy cohort. In the combination group, vorinostat was given on weekly or 2-weekly schedules instead of continuous dosing. 

In the monotherapy group, the most commonly reported treatment-related adverse events were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), and anorexia (48.1%). The most common grade 3/4 adverse events were fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.0%), decreased platelet count (5.3%), and anorexia (5.0%).

Seventy-one (20.8%) patients required dose modifications for toxicity and 38 (11.1%) discontinued study medication due to drug-related adverse events. Three drug-related adverse events led to death.

In the combination treatment cohort, nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%) were the most commonly reported adverse events. The most common grade 3/4 adverse events were fatigue (13.4%), thrombocytopenia (9.6%), neutropenia (8.3%), diarrhea (5.7%), and nausea. 

Dose modifications were required in 27 patients (17.2%). Discontinuation due to adverse events was necessary in 31 patients (19.7%), and 1 death was attributed to vorinostat combination treatment.

The QTc phase 1 substudy was randomized, partially blind, and placebo-controlled. None of the 22 evaluable patients included in the analysis experienced a QtcF change greater than 30 msec from their baseline scores.

Berlin, Germany—Vorinostat demonstrates safety and tolerability alone and in combination with other systemic treatments for a wide range of solid and hematologic malignancies, according to a study of collated data from the vorinostat clinical trial program.

Investigators presented the safety data in a poster at the ECCO 15 - 34th ESMO Multidisciplinary Congress. The data suggest that a supratherapeutic single dose (800 mg) of this orally active histone deacetylase inhibitor does not prolong ventricular repolarization to a significant degree. This is reassuring, since cardiac rhythm and EEG changes are thought to be a class effect of HDACs.

Lead author David Siegel, MD, from Hackensack University Medical Center, Hackensack, New Jersey, and his fellow researchers observed that the study data support the overall safety profile of vorinostat use in cancer patients.

They based their analysis on 18 phase 1 and phase 2 vorinostat trials that included 498 patients, 341 who received the agent as monotherapy and 157 treated with the drug in combination with other therapies.

Vorinostat is approved by the US Food and Drug Administration to treat relapsed or refractory cutaneous T-cell lymphoma and was dosed at the approved level of 400 mg/day for 156 of the 341 patients in the monotherapy cohort. In the combination group, vorinostat was given on weekly or 2-weekly schedules instead of continuous dosing. 

In the monotherapy group, the most commonly reported treatment-related adverse events were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), and anorexia (48.1%). The most common grade 3/4 adverse events were fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.0%), decreased platelet count (5.3%), and anorexia (5.0%).

Seventy-one (20.8%) patients required dose modifications for toxicity and 38 (11.1%) discontinued study medication due to drug-related adverse events. Three drug-related adverse events led to death.

In the combination treatment cohort, nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%) were the most commonly reported adverse events. The most common grade 3/4 adverse events were fatigue (13.4%), thrombocytopenia (9.6%), neutropenia (8.3%), diarrhea (5.7%), and nausea. 

Dose modifications were required in 27 patients (17.2%). Discontinuation due to adverse events was necessary in 31 patients (19.7%), and 1 death was attributed to vorinostat combination treatment.

The QTc phase 1 substudy was randomized, partially blind, and placebo-controlled. None of the 22 evaluable patients included in the analysis experienced a QtcF change greater than 30 msec from their baseline scores.

Berlin, Germany—Vorinostat demonstrates safety and tolerability alone and in combination with other systemic treatments for a wide range of solid and hematologic malignancies, according to a study of collated data from the vorinostat clinical trial program.

Investigators presented the safety data in a poster at the ECCO 15 - 34th ESMO Multidisciplinary Congress. The data suggest that a supratherapeutic single dose (800 mg) of this orally active histone deacetylase inhibitor does not prolong ventricular repolarization to a significant degree. This is reassuring, since cardiac rhythm and EEG changes are thought to be a class effect of HDACs.

Lead author David Siegel, MD, from Hackensack University Medical Center, Hackensack, New Jersey, and his fellow researchers observed that the study data support the overall safety profile of vorinostat use in cancer patients.

They based their analysis on 18 phase 1 and phase 2 vorinostat trials that included 498 patients, 341 who received the agent as monotherapy and 157 treated with the drug in combination with other therapies.

Vorinostat is approved by the US Food and Drug Administration to treat relapsed or refractory cutaneous T-cell lymphoma and was dosed at the approved level of 400 mg/day for 156 of the 341 patients in the monotherapy cohort. In the combination group, vorinostat was given on weekly or 2-weekly schedules instead of continuous dosing. 

In the monotherapy group, the most commonly reported treatment-related adverse events were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), and anorexia (48.1%). The most common grade 3/4 adverse events were fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.0%), decreased platelet count (5.3%), and anorexia (5.0%).

Seventy-one (20.8%) patients required dose modifications for toxicity and 38 (11.1%) discontinued study medication due to drug-related adverse events. Three drug-related adverse events led to death.

In the combination treatment cohort, nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%) were the most commonly reported adverse events. The most common grade 3/4 adverse events were fatigue (13.4%), thrombocytopenia (9.6%), neutropenia (8.3%), diarrhea (5.7%), and nausea. 

Dose modifications were required in 27 patients (17.2%). Discontinuation due to adverse events was necessary in 31 patients (19.7%), and 1 death was attributed to vorinostat combination treatment.

The QTc phase 1 substudy was randomized, partially blind, and placebo-controlled. None of the 22 evaluable patients included in the analysis experienced a QtcF change greater than 30 msec from their baseline scores.