John R. Zalcberg

E14119 Background: PDGFR inhibition by reducing tumoral interstitial fluid pressure may increase chemotherapy penetration and efficacy. Imatinib (IM) has anti-PDGFR activity at standard doses. The aims of this phase I study were to assess the MTD of IM in combination with mFOLFOX-bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC), identify potential PK interactions, toxicities and efficacy. Methods: Eligible pts had measurable disease, 0-1 prior regimens, ECOG 0-1, adequate organ function. On day -14, pts commenced IM p.o daily + Bev (5mg/kg/2 weekly). On day 1, (14 days post), pts commenced mFOLFOX-Bev (oxaliplatin 85mg/m²/2hrs, leucovorin 200mg/m², 5FU bolus 400mg/m² day 1, 5FU CI 2.4g/m²/46hrs). Bloods were taken for IM steady state PK analysis from day -14 to day 14; and for oxaliplatin and 5FU PK in cycle 1, days 1 to 3. DLTs were defined, in the first 6 weeks, as: grade (Gr) 4 neutropenia >7 days, Gr4 thrombocytopenia/Gr3 with bleeding, febrile neutropenia, drug-related Gr3/4 non-haematological toxicity, delay in the start of next cycle >2 weeks. Dose escalation was standard with 3 pt cohorts. IM planned dose levels (DL): DL1; 400mg, DL2; 600mg, DL3; 800mg po daily. Pts restaged on day 1 cycles 1 and 2 and then every 8 weeks. Results: 10 pts enrolled, M:F = 7:3, 1 pt had prior chemotherapy. DL1; 3 pts, DL2; 7 pts (1 replaced due to early progression). DLTs observed in 3 of 6 pts in DL2 (600mg): febrile neutropenia (2); Gr3 infection and Gr4 neutropenia (1). Worst drug-related AEs: DL1 (3); Gr3 thromboembolism (1), Gr3 hypertension (1), Gr4 neutropenia (1). DL2 (7); febrile neutropenia (2), Gr4 dehydration (1), Gr3 (4) and Gr4 (1) neutropenia. Median number of cycles: DL1 = 12, DL2 = 6 (range 1-12). Overall response rate: DL1 = 1/3 (SD 2/3), DL2 = 0/6 (SD 5/7). Steady state PK parameters for IM were not impacted by mFOLFOX-Bev. Oxaliplatin and 5FU PK parameters were not impacted by IM exposure. Conclusions: 400mg p.o. daily of IM was the MTD with mFOLFOX-Bev. Dose escalation of IM an inhibitor of PDGFR, ABL and KIT was limited by neutropenia. Further study is warranted as IM can be delivered at levels that inhibit PDGFR.

2034 Background: Dosing nomograms based upon metabolic phenotype/genotypes may reduce the marked interpatient variability in the clearance (CL) of cytotoxics in cancer patients (pts). Irinotecan (Ir) is a relevant model drug, its active moiety (SN38), undergoes glucuronidation by uridine diphosphoglucuronyl transferase (UGT)-1A1, and with its metabolites is excreted via biliary membrane transporters P glycoprotein (Pgp) and MRP. The aim of this trial was to correlate functional imaging of biliary excretion, and significant polymorphisms in the genes coding for Pgp (exons 12, 21, 26) and UGT-1A1(*28) with Ir pharmacology. Methods: Eligible pts had colorectal cancer, adequate organ function, ECOG PS 0–2. Pre-therapy all pts had bloods taken for Pgp single nucleotide polymorphism (SNP) analysis and UGT 1A1*28 carriage and underwent hepatic ^99mTc-DIDA and -MIBI scans, measures of biliary MRP and Pgp function, respectively. DIDA and MIBI hepatic extraction fraction (HEF), CL, elimination half-time and % retention at 1-hr were calculated. Pts received Ir 125mg/m²/90-min, Leucovorin 20mg/m², 5FU 500mg/m² bolus, days 1 & 8, q 3weekly. Plasma was taken for Ir and metabolite analysis on day 1 of cycle 1, using a limited sampling model. Results: 21 pts accrued, M:F = 16:5, Mean age 61 yrs. Mean Ir CL = 14.1 L.hr^-1.m^-2(CV: 20%), SN38 AUC = 253.9 ng.hr.ml^-1 (CV: 56%) (n= 17). Ir CL failed to correlate with either hepatic imaging mode. SN38 AUC inversely correlated with DIDA hepatic clearance (R² = 0.36). Pts hetero- and homozygous for Pgp exon 21 and 26 SNPs demonstrated a trend to increased SN38 AUC and similarly for pts hetero- (n = 7) and homozygous (n = 2) for UGT 1A1*28. The frequency of delayed diarrhea in cycle 1 was, Grade 0/1: n = 13 pts, Grade 2: 4, Grade 3: 4. A trend to increased DIDA HEF and % retention at 1-hr and MIBI HEF in pts with grade 2/3 diarrhea was noted relative to pts with grade 0/1 diarrhea. Conclusions: Functional hepatic imaging together with Pgp and UGT polymorphisms have shown potentially useful correlates with Ir and SN38 pharmacology and with further appraisal may allow for individualised dosing of this and other relevant cytotoxics. No significant financial relationships to disclose.

Prostate Cancer and Prostatic Diseases, covering all aspects of prostatic diseases, in particular prostate cancer. The journal is of interest to surgeons, oncologists, clinicians, and researchers involved in disease of the prostate.

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expression by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P =.01) and Pgp function (P =.03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts (P <.05). A good correlation between increased Pgp expression and function was observed in Pgp-negative (r =.90, P =.0001) and Pgp-positive blasts (r =.77, P =.0002). This increase in Pgp expression and function was inhibited by the addition of 1 micromol/L PSC 833 to blast cells at the time of their exposure to these cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo at 4 and 16 hours after the administration of standard chemotherapy with DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harvested at the time of presentation. These data suggest that upregulation of the MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expression by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P = .01) and Pgp function (P = .03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts (P < .05). A good correlation between increased Pgp expression and function was observed in Pgp-negative (r = .90, P = .0001) and Pgp-positive blasts (r = .77,P = .0002). This increase in Pgp expression and function was inhibited by the addition of 1 μmol/L PSC 833 to blast cells at the time of their exposure to these cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo at 4 and 16 hours after the administration of standard chemotherapy with DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harvested at the time of presentation. These data suggest that upregulation of the MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expression by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P = .01) and Pgp function (P = .03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts (P < .05). A good correlation between increased Pgp expression and function was observed in Pgp-negative (r = .90, P = .0001) and Pgp-positive blasts (r = .77,P = .0002). This increase in Pgp expression and function was inhibited by the addition of 1 μmol/L PSC 833 to blast cells at the time of their exposure to these cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo at 4 and 16 hours after the administration of standard chemotherapy with DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harvested at the time of presentation. These data suggest that upregulation of the MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.

The multidrug resistance (MDR1) gene product, P-glycoprotein (Pgp), is a 170-kDa ATP-dependent pump that expels a variety of anticancer drugs out of malignant cells, reducing drug accumulation and ...