Table 1.

Clinical experience with DON in humans

Early Studies (1957ā€“1962) at low daily dosing
Patients enrolled Disease typeDosing regimen(s)ToxicitiesOutcomesReference
63 patientsRefractory tumors: majority breast/lungMajority dosed at 0.2ā€“1.1 mg/kg daily IV, IM, or POMucositis (83%)Diarrhea (48%)Nausea/vomiting (30%)7/63 patients with partial response(37)
10 patients in DON cohort10 to 15 mg daily in combination (with 6-MP or an alkylator)Not reported1/10 patients with decreased urine tumor markers(39)
Metastatic testicular cancer
41 patientsHodgkins lymphoma, lymphosarcoma, bronchogenic carcinoma, melanoma0.2 mg/kg PO daily x 30 daysStomatitisDiarrheaVomiting47% Hodgkin's lymphoma lesions decreased by ā‰„20%(38)
71 pediatric patientsUntreated acute leukemia0.25 mg/kg DON PO daily + 2.5 mg/kg 6MP daily for 28 daysMucositis (85%)GI symptoms (28%)Leukopenia (60%)30/71 patients with complete remission(40)
Phase II Studies (1980sā€“2000s) at high intermittent dosing
23 patients160 mg/m2/dose IVNausea/vomitingNo responses(48)
Diarrhea
Advanced lung cancerThree consecutive days every 3 weeksLeukopenia/Thrombocytopenia
23 patients (14 evaluable)Advanced colorectal carcinoma200 mg/m2/dose IVTwice weekly for four doses every 3 weeksNausea/vomiting ThrombocytopeniaProgressive disease: 11/14 patients(50)
30 patientsAdvanced colorectal carcinoma160 mg/m2/dose IVThree consecutive days every 3 weeksNausea/vomitingRare CNS toxicity (diplopia/ataxia/visual hallucinations)HyperbilirubinemiaProgressive disease: 13/30Stable disease: 16/30(51)
98 patients, 41 treated with DONAdvanced sarcomas50 mg/m2/dose IVFive consecutive days every 4 weeksNausea/vomitingDiarrheaMyelosuppressionNo objective responses(49)
55 patientsAdvanced refractory solid tumors140 mg/m2/dose IVTwice weekly every 3 weeks + once weekly 120 IU/m2PEGylated glutaminaseFatigueNausea and vomitingDiarrheaProgression free at 5 months: 5/17Partial response: 1/17(52)