Table 2.

Treatment-related toxicity

QD (mg)4on/3off (mg)7on/7off (mg)
0.81.21.82.25a2.72.74.0a,b2.7a4.05.0
n = 3n = 3n = 7n = 6n = 3n = 7n = 6n = 6n = 6n = 2
Dose-limiting toxicities
Grade III transaminitis (n = 1)0010000000
Grade III CPK elevation (n = 3)0001100010
Grade III capillary leak syndrome (n = 1)0000000100
Grade III febrile neutropenia (n = 1)0000000010
SRD associated with grade III blurred vision (n = 1)0000000001
Grade III blurred vision (n = 3)0000101001
Most common adverse events (>10% patients)All gradesGrade ≥3 adverse events only
n(pt)%
Rash-relatedc4994.2%1243303120
Blood CPK increased2955.8%0011100030
Diarrhea2751.9%0000000000
Blurred vision2242.3%0000101001
Edema peripheral1630.8%0000010000
Stomatitis1325.0%0000000000
Asthenia1121.2%0000000000
Hypoalbuminemia1121.2%0010000000
Paronychia1121.2%0001001000
Nausea1019.2%0000000000
Serous retinal detachment1019.2%0000000000
Eyelid edema917.3%0000000001
Mucosal inflammation815.4%0000000000
Macular edema713.5%0000000000
Myalgia713.5%0000000000
Serious Adverse eventsAll gradesSerious adverse events (all grades)
n(ev)%
Rash47.7%01012f00000
Blood CPK increased35.8%00011g00010
Pulmonary embolism11.9%001d0000000
Diarrhea11.9%00001g00000
Left ventricular dysfunction11.9%00001g00000
Myopathy11.9%0001e000000
Capillary leak syndrome11.9%0000000100
Troponin increased11.9%0000001h000
Blurred vision11.9%00001f00000
Retinal detachment11.9%0000000001
Febrile neutropenia11.9%0000000010
Confusional state11.9%0000000001
  • NOTE: No treatment-related toxicities were seen with daily dosing of ≤0.4 mg (n = 3 patients). Only the most severe intensity was counted for multiple occurrences of the same adverse events/serious adverse events in one individual. Grade 3 adverse events not listed in this table: increased alanine aminotransferase, increased aspartate aminotransferase, decreased blood albumin, capillary leak syndrome, febrile neutropenia, increased gamma-glutamyltransferase, genital erythema, myopathy, palmar-plantar erythrodysaesthesia syndrome, increased transaminases, increased troponin and fatigue (all n = 1). In addition, Grade 4 pulmonary embolism occurred in one patient. Serious adverse events were defined as any adverse events that 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. CPK, creatine phosphokinase; SRD, serous retinal detachment; QD, daily; 4 days on/3 days off; 7 days on/7 days off. n(pt), represents patient number; n(ev), represents event number

  • aMaximum tolerated dose (MTD) for the regimen.

  • bNo further escalation was conducted on the 4on/3off regimen due to two early onset (8 hours after run-in dose) DLTs observed in the 7on/7off regimen at 5.0 mg.

  • cIncludes dermatitis acneiform, rash, folliculitis, rash pustular, eczema, erythema, psoriasis, rash erythematous, rash follicular, rash papular, and rash vesicular.

  • dGrade 4 serious adverse event.

  • eGrade 3 myopathy with muscular deficit of the scapula and pelvic belt.

  • f3 serious adverse events reported in the same patient.

  • gtwo serious adverse events reported in the same patient.

  • hNo associated symptoms, adverse event not due to pulmonary embolus, pericarditis, myocarditis, or rheumatoid arthritis. Coronary angiography, cardiac echography and MRI were normal.