Search

7030Background: B cell acute lymphoblastic leukemia with overexpression of CRLF2 (CRLF2 B-ALL) is a Ph-like leukemia with poor outcome in children, as well as in adults. Activation of the CRLF2 rec...

4575 Background: The efficacy of therapies for prostate cancer following failure of androgen deprivation and docetaxel is limited. SRC dysregulation may be important in prostate cancer progression....

8134 Background: PLD and bortezomib (BORT) are FDA-approved for MM patients who have received one prior therapy. We have previously demonstrated in laboratory studies that lower doses of PLD administered more frequently are better tolerated than higher doses given less often. The combination of BORT and dexamethasone (DEX) is effective for previously untreated MM patients. Prior studies by our group have shown that intravenous administration of DEX 40 mg, BORT 1.0 mg/m2 and PLD 5 mg/m2 (DVD) on days 1, 4, 8, and 11 of a 28-day cycle is effective for relapsed/refractory MM patients and well tolerated. Methods: We conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the DVD regimen. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Thirty-five patients were enrolled with a median age of 65 years (range, 42-82 years). Thirty and 33 patients are currently ...

e16053 Background: We conducted a single arm, phase II trial of single-agent bortezomib, a proteasome inhibitor, in patients with prostate cancer with biochemical recurrence (PSA relapse) after definitive local therapy. Eligible patients had previous radical prostatectomy and/or radiation therapy (including brachytherapy), and a rising PSA over 1 ng/mL without bone scan evidence of metastasis. The primary goal of this study was to determine the PSA response to single agent bortezomib. Secondary goal was to identify the time to PSA relapse after bortezomib therapy defined as time from nadir to PSA >1ng/ml. Methods: Treatment was composed of bortezomib 1.3mg/m2 IV on days 1,4,8,11 then 10 days off for the first two cycles. The third cycle was comprised of weekly bortezomib therapy for three out of four weeks. Sixteen patients were enrolled and treated at 4 sites with13 evaluable patients. Results: Median baseline PSA was 12.0 ng/ml. 3 of 13 patients (23%) achieved complete responses and 1 a partial response (PR) for a response rate of 30% (95% CI: 0.09 –0.61). Median time to PSA relapse in these 3 patients was 6.0 months. Linear longitudinal modeling was used to compare the rate of increase in PSA prior to treatment versus during treatment with bortezomib and found that treatment significantly decreased the slope of log PSA during treatment, slowing PSA rise (p = 0.003). The major toxicity associated with bortezomib therapy was peripheral neuropathy (7 pts, grade 3 in 3 pts) requiring dose reductions in 3 cases and discontinuation of therapy in 4 patients. Other toxicities included non-neutropenic infections (shingles in 2 pts), 1 small bowel ileus (grade 3), and 1 case of thrombocytopenia (grade 3). Conclusions: In a small number of patients there was a 30% PSA response rate to single agent bortezomib therapy. Further investigations using bortezomib as a single-agent or in combination are warranted in this patient population. No significant financial relationships to disclose.

14535 Background: ABT-869, an orally administered, potent small molecule inhibitor of VEGF receptors 1–3 and platelet derived growth factor, is active in solid malignancies. Consistent with similar...

13064 Background: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor are identified in 20–25% of adult AML patients associated with poor prognosis. ABT-869 is active in FLT3-AML and is currently under clinical investigaton. We hypothesize that the combination of ABT-869 with chemotherapy can improve the therapeutic index in FLT3-AML. Methods: Using Calcusyn software, the additive, synergistic or antagonistic effect of ABT-869 with concurrent or sequential cytosine arabinoside (Ara-C) or doxorubicin (Dox) was measured in MV4–11 and MOLM-14 cells. The synergistic combination sequence was further tested in a MV4–11 xenograft model in four groups (10 mice/group) including control, Ara-C, ABT-869, and combination (Ara-C first for 4 days, then daily ABT-869). Cell cycle analysis and apoptosis and signal pathway assays were performed in vitro and in vivo. Results: ABT-869 induced dose- and time-dependent apoptosis on FLT3-AML cells resulting in down regulation of p-FLT3, p-STAT5, Bcl-XL and up regulation of p53 and BID. ABT-869 caused G1-phase arrest and the removal of cells in the S- and G2/M-phase mediated by reduction of cyclins D and E. We observed significant synergistic effect with Ara-C or Dox first, followed by ABT-869, as well as in concurrent treatment with ABT-869 and Dox. Simultaneous treatment with ABT-869 and Ara-C only achieved additive effect. Conversely, we found an antagonistic effect in the sequence of pretreatment of ABT-869 followed by chemotherapy. In a MV4–11 xenograft model, all mice succumbed to leukemia in the control and Ara-C groups (median survival = 53 and 55.5 days respectively). Combination therapy gave a faster reduction of tumor volume compared to ABT-869 treatment alone (p=0.03) without recurrence of leukemia in either group by day 67. In vivo immunohistochemistry (IHC) analysis revealed ABT-869 potently inhibited VEGF and phosphor-ERK. Conclusions: ABT-869 can be given after Ara-C or Dox to act synergistically. Our study suggests that combinations of RTKIs with chemotherapy should be carefully tested prior to clinical protocol development. A clinical trial of such combination therapy in FLT3-AML is warranted. No significant financial relationships to disclose.