`
`v.
`0. Pl MTAIIY7‘21R1M
`vvvl
`:19”.-
`ations hi.p of vitamin metaboliIte
`profile, drug exposure, andothre patient
`characteristics to toxicity
`
`C. Niyikiza, S. Baker, R. johnson, J. Wailing, D. Seitz, R. Ailen. Liliy Research
`Laboratories, Indiana, USA; Cancer Treatment and Research Center, Texas,
`
`USA; Univ of Colorado Heaith Sciences Center, Colorado, USA
`
`Introduction: MTA is a novei multitargeted antifolate with inhibitory activity
`against multipie enzymes. Phase ifil studies have shown activity in a variety
`of tumors. Historical data on other antifolates have suggested that a patient's
`nuiriiionat status may play a role in the likelihood of experiencing severe toxicity.
`The purpose of this study was to assess the relationship of vitamin metabolites,
`drug exposure, and other prespecified baseline patient characteristics to toxicity
`following treatment with MTA.
`u-Wgu
`“UV...
`Methngjg- Hnmnmicztmnn {Hgvs‘i mictmthinnine and methxrlmninmr‘ smirl were
`measured in 139 phase li patients with tumors of the colon, breast pancreas,
`and esophagus at baseline and once each cycle thereafter. Stepwise regres-
`sion modeling, muitivariate anaiysis of variance, and discriminant analysis
`were implemented to determine which predictors might correlate with severe
`toxicity after one course of MTA. Prognostic factors considered were age, gen~
`
`Annals ol Oncoiogy
`Year:19‘?£ Volume
`
`E
`
`Page {QC-.43 7
`
`ACCORD EX 1006
`
`ACCORD EX 1006
`
`
`
`der. prior treatment, baseline albumin, liver enzymes, ANC, platelets, vitamin
`metabolites, and AUC.
`
`Results: Statistically significant predictors of Grade 4 neutropenia (n221
`pts) were albumin (p = 0.0006) and Hcys (p = 0.0012), while Grade 4
`thrombocytopenia (n=8) was highly predicted by Hcys (p < 0.0001) and
`pretreatment AST (p = 0.0012). Hcys 3 10m predicted Grade 4 neutropenia
`in cycle one 75% of the time. Grade 4 neutropenia was predicted by Hcys
`alone in 70% of cases. Hcys and albumin levels did not appear to change
`from baseline during treatment with MTA. While AUC was not found to be a
`predictor of toxicity,
`little variability was observed in AUC. Maximum values
`were still below AUC values related to hematologic toxicity in phase I studies.
`Conclusions: Taxicities resulting from treatment with MTA appear to be
`predictable from pretreatment homocysteine levels. Elevated baseline h0-
`mocysteine levels (2 mall/t) highly correlate with severe hematologic and
`nonhematologic toxicities following treatment with MTA. Homocysteirle was
`found to be better than albumin at predicting toxicity. These results apply to
`the tumor types studied. Further studies are underway in patients with renal
`impairment or patients who received prior oispiatin.
`
`.
`Annals of Oncology
`Year: [54 9 Volumei Page 53%;.“ '7
`
`
`
`
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