Patient-controlled analgesia (PCA) represents a drug-delivery system in which patients self-administer predetermined doses of opiate analgesics. We have taken advantage of recent advances in pump technology and developed a system in which patients with severe pain received a continuous narcotic infusion, along with the capability of PCA bolus for breakthrough pain. All patients were experiencing chronic pain related to cancer and were unable to obtain adequate pain control with either intermittent parenteral, oral, or rectal narcotics. Sixty-nine percent of patients were treated in the home setting, and the majority received morphine sulfate subcutaneously (SQ). Admixture stability studies using high-pressure liquid chromatography (HPLC) showed that dexamethasone, metoclopramide, and haloperidol could be added to the morphine solutions and remain stable for 1 week at room temperature. Of 117 patients entered, 95% received excellent pain control, and side effects were rare, consisting of subcutaneous needle site infection and respiratory depression. Progressive pain due to either advancing disease or development of drug tolerance could be controlled by increasing opiate infusion rates. We conclude that (1) continuous infusion opiate with PCA bolus capability can be initiated and administered safely in the home setting; (2) patients with pain related to malignancy can be managed well with this system; and (3) pain control programs can be designed, implemented, and evaluated in the private practice setting.

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13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination. [Table: see text] [Table: see text]

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Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of AML1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the translocation t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 to the novel partner gene Friend of GATA-2 (FOG2). The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses transcription from the promoter of a hematopoietic target of AML1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and both proteins associate in a protein complex. These results suggest a role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATA developmental programs in the pathogenesis of myelodysplasia.