Table 2.

Treatment-related toxicity

Total daily dose (mg)
Number of patientsOnce-daily dosingaTwice-daily dosingb
(n)1.5 (n = 4)3 (n = 3)4 (n = 3)5.5 (n = 4)7.5 (n = 4)10 (n = 4)13 (n = 4)17 (n = 9)21 (n = 4)
DLTs
 Grade III blurred vision (n = 1)1
 Grade III elevated CPK (n = 2)1c1
 Grade IV elevated CPK (n = 1)1
Treatment-related AEsAEs (all grades)AEs (grade III–IV only)
n%
Rash relatedd4591.81122
Diarrhea1632.7
Eye relatede1326.511
Elevated CPK918.4132
Fatigue816.3
Dry skin714.3
Nausea714.3
Skin fissures612.2
Vomiting612.2
Stomatitis510.2
Pruritus36.11
Asthenia36.11
Neutropenia36.111
Anemia24.11
Decreased appetite24.11
Depression12.01
Decreased Ejection Fraction12.01
Treatment-related SAEs (all grades)n%SAEs (all grades)
Depression12.01
Anemiaf12.01
Retinal vein occlusion12.01
Asthenia12.01
Decreased appetite12.01
Chorioretinopathy12.01
Elevated CPK12.01
Blurred vision12.01

NOTE: Data cutoff: January 28th 2011. Only the most severe intensity was counted for multiple occurrences of the same AE in one individual. Adverse events occurring in >10% of patients are shown above the dotted line.

  • aOnly one grade III toxicity (neutropenia) was reported in only one dosing-cohort in the once-daily regimen (1.5 mg once daily).

  • bThe most common AEs were reported at grade III or IV severity in the twice-daily dosing cohorts. Two grade IV AEs occurred, both elevated CPK (8.5 and 10.5 mg, twice daily). No grade V AEs occurred. Nausea/vomiting, skin rash, and/or diarrhea were only considered a DLT if they reached grade ≥III severity despite adequate supportive care measures. SAEs were defined as any AE, which was fatal; life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was medically significant or required intervention to prevent one or other of the outcomes listed above. No SAEs occurred in once-daily dosing cohorts.

  • cNo further DLTs were observed when the 17.0 mg (twice daily) cohort was expanded to 9 patients.

  • dIncludes dermatitis acneiform, rash, dermatitis, papular rash, folliculitis, and genital rash.

  • eIncludes blurred vision, photopsia, corneal erosion, dry eyes, periorbital edema, chorioretinopathy, punctate keratitis, and retinal vein occlusion.

  • fNo signs of chronic or acute gastrointestinal bleeding were observed and no hemoglobinuria was recorded.