Carcinogenicity studies have not been performed with vorinostat.

Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).

Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.

No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. [See Warnings and Precautions (5.7).]

Cutaneous T-cell Lymphoma

In two open-label clinical studies, patients with refractory CTCL have been eva luated to determine their response rate to oral ZOLINZA. One study was a single-arm clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity.

Study 1

In an open-label, single‑arm, multicenter non-randomized study, 74 patients with advanced CTCL were treated with ZOLINZA at a dose of 400 mg once daily. The primary endpoint was response rate to oral ZOLINZA in the treatment of skin disease in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following two systemic therapies. Enrolled patients should have received, been intolerant to or not a candidate for bexarotene. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (%TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient’s palm as a “ruler”. The total %TBSA for each lesion type was multiplied by a severity weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was measured as either a Complete Clinical Response (CCR) defined as no evidence of disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin assessment score compared to baseline. Both CCR and PR had to be maintained for at least 4 weeks.

Secondary efficacy endpoints included response duration, time to progression, and time to objective response.

The population had been exposed to a median of three prior therapies (range 1 to 12).

Table 2 summarizes the demographic and disease characteristics of the Study 1 population.

The overall objective response rate was 29.7% (22/74, 95% CI [19.7 to 41.5%]) in all patients treated with ZOLINZA. In patients with Stage IIB and higher CTCL, the overall objective response rate was 29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median times to response were 55 and 56 days (range 28 to