ALBERT

Description: Introduction PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK). Methods This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3. PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUCinf (area under the plasma concentration versus time curve from time zero to infinity) and Cmax (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUCinf and Cmax for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Results PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUCinf of 2.40 (90% CI: 2.15 -2.68) and for Cmax of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, Cmax occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUCinf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for Cmax was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 Cmax occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related. Conclusions PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUCinf and 1.40-fold for Cmax) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful. Disclosures: Shaik: Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.

Description: Abstract 2159 Background: Acute myeloid leukemia (AML) is a heterogeneous and intrinsically resistant disease group of malignant hematopoietic disorders that accounts for approximately 80% of all adult leukemias. Heat shock proteins (HSPs) are often overexpressed in AML are their expression is associated with poor-prognosis and resistance to chemotherapy. Among HSPs, HSP90 is the main chaperone required for the stabilization of multiple oncogenic kinases, which contribute to AML pathogenesis, providing a rationale for the use of HSP90 inhibitors in the treatment of AML. Hypothesis: To identify patients with AML who will benefit from HSP90 inhibitor therapy there is a need to discover molecules and pathways in AML cells that confer sensitivity and lead to significant apoptosis upon HSP90 inhibition. Study design and Results: To evaluate the spectrum of sensitivities of AML cells to HSP90 inhibitors, and to investigate a possible relationship between their genetic background and apoptotic sensitivity to HSP90 inhibition, we investigated the effects of HSP90 inhibitors in a set of genetically characterized human AML cells. Addition of several HSP90 inhibitors to each of these cell lines potently inhibited cell growth, with a potency reflective of their affinity for HSP90. Normal peripheral blood leukocytes were unaffected at similar concentrations. HSP90 inhibition was associated with destabilization and subsequent degradation of Akt and c-Raf in all tested cells, as well as of several cell-specific onco-proteins such as mutant Flt3 in MOLM-13, TEL-TRKC in M0-91, AML1-ETO and mutant cKit in Kasumi-1 and SKNO-1, and mutant Jak2 in HEL cells, respectively. Notably, the proclivity for these cells to undergo apoptosis upon HSP90 inhibition varied considerably. The most sensitive cell lines were MOLM-13, MV-4-11 and M0-91 cells, and for each these cell lines we observed near 100% killing of the initial cell population after 48–72 h of HSP90 inhibitor treatment. In contrast, only 20% death was seen in HEL and HL-60 cells under these conditions. We next made use of specific inhibitors of known oncogenic signaling pathways known to be dysregulated in AML to demonstrate that apoptotic sensitivity of AML cells to HSP90 inhibition correlated with PI3K-Akt and STAT5 activation, but not with activation of the Raf-MAPK pathway. Importantly, similar results were observed in cells lines, xenograft models and isogenic cell line systems. We also found that dual activation of these two pathways, especially in the context of Bcl-xL overexpression, lowers the apoptotic threshold of AML when HSP90 is inhibited. Conclusions: We found that activation of oncogenic signaling pathways and expression of leukemogenic anti-apoptotic molecules, most importantly p-Akt, predicts for AML sensitivity to HSP90 inhibitors. Importantly, 50– 70% of patients with AML display phosphorylation of both Thr308 and Ser4 Akt. This molecule contributes to proliferation, survival and drug resistance in AML, and is associated with adverse outcome. Taken together, our findings suggest that AML patients with activation of Akt and STAT5 signaling are most likely to benefit from HSP90 inhibitor therapy, and clinical trials should aim to enroll patients with specific activation of these important signaling pathways. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3105 Background: EATL is a rare subtype of peripheral T-cell lymphomas characterized by primarily intestinal localization and a frequent association with celiac disease. The prognosis is considered to be poor with conventional chemotherapy. Limited data is available on the efficacy of ASCT in this lymphoma subtype. Primary objective was to study the outcome of ASCT as a consolidation or salvage strategy for EATL. The primary endpoint was overall survival (OS) and progression-free survival (PFS). Eligible patients were 〉 18 years who had received ASCT between 2000–2010 for EATL that was confirmed by review of written histopathology reports, and had sufficient information on disease history and follow-up available. The search strategy used the EBMT database to identify patients potentially fulfilling the eligibility criteria. An additional questionnaire was sent to individual transplant centres to confirm histological diagnosis (histopathology report or pathology review) as well as updated follow-up data. Patients and transplant characteristics were compared between groups using X2 test or Fisher's exact test for categorical variables and t-test or Mann-Whiney U-test for continuous variables. OS and PFS were estimated using the Kaplan-Meier product-limit estimate and compared by the log-rank test. Estimates for non-relapse mortality (NRM) and relapse or progression were calculated using cumulative incidence rates to accommodate competing risk and compared to Gray's test. Results: Altogether 138 patients were identified. Updated follow-up data was received from 74 patients (54 %) and histology report from 54 patients (39 %). In ten patients the diagnosis of EATL could not be adequately verified. Thus the final analysis included 44. There were 24 males and 20 females with a median age of 56 (35–72) years at the time of transplant. Twenty-five patients (57 %) had a history of celiac disease. Disease stage was I in nine patients (21 %), II in 14 patients (33 %) and IV in 19 patients (45 %). Twenty-four patients (55 %) were in the first CR or PR at the time of transplant. BEAM was used as a high-dose regimen in 36 patients (82 %) and all patients received peripheral blood grafts. The median follow-up for survivors was 46 (2–108) months from ASCT. Three patients died early from transplant-related reasons translating into a 2-year non-relapse mortality of 7 %. Relapse incidence at 4 years after ASCT was 39 %, with no events occurring beyond 2.5 years after ASCT. PFS and OS were 54 % and 59 % at four years, respectively. There was a trend for better OS in patients transplanted in the first CR or PR compared to more advanced disease status (70 % vs. 43 %, p=0.053). Of note, patients with a history of celiac disease had superior PFS (70 % vs. 35 %, p=0.02) and OS (70 % vs. 45 %, p=0.052) whilst age, gender, disease stage, B-symptoms at diagnosis or high-dose regimen were not associated with OS or PFS. Conclusions: This study shows for the first time in a larger patient sample that ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. Patients transplanted in first CR or PR appear to do better than those transplanted later. ASCT should be considered in EATL patients responding to initial therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points ASCT provides long-term remission in the majority of EATL patients transplanted in first complete or partial remission. ASCT should be considered in transplant-eligible EATL patients.

Description: As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P 〈 .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P 〈 .0001) and favorable interphase fluorescence in situ hybridization profile (P 〈 .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

Description: Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P 〈 .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P 〈 .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

Description: Abstract 3642 Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a rare disease accounting for 1–2% of all non-Hodgkin's lymphomas. It characteristically has an aggressive course with poor prognosis and a median overall survival (OS) in the order of 3 years. The median age at presentation is 65–70 years and most patients present with advanced stage disease. Due to its low incidence, few prospective clinical trials have been performed and the optimal treatment is not known. There is evidence that purine analogues are efficacious in AITL and the combination of fludarabine and cyclophosphamide (FluCy) has a high level of efficacy in other lymphoproliferative disorders. There are also good theoretical reasons and preliminary evidence to support the use of thalidomide in AITL. This multi-centre, phase II trial was designed to assess the efficacy and tolerability of FluCy chemotherapy and incremental response to consolidation with 6 months of thalidomide treatment. Methods: Using a Bayesian 2-stage design, it was planned to recruit 15 patients with a further 22 patients recruited to a second stage if a complete remission (CR) rate of 〉33% was achieved. Inclusion criteria were previously untreated AITL with measurable disease, performance status 18 years, and valid consent. The primary endpoint was response rate to FluCy. Secondary endpoints were response rate to thalidomide, toxicity, progression free survival (PFS), and OS. Treatment consisted of fludarabine 40mg/m2 and cyclophosphamide 250mg/m2 orally on days 1–3 of each 28 day cycle. Four cycles of FluCy were given prior to restaging. Patients progressing on FluCy came off study. Those with stable disease or responses had the option of 2 further cycles of FluCy prior to commencing thalidomide maintenance. Thalidomide 100mg once daily was given as continuous therapy starting 4 weeks after the final cycle of FluCy, with dose increases every 4 weeks to 300mg if tolerated. Results: 15 patients were recruited from 6 centres over 3 years from February 2009 to March 2012. The median age was 68 years (range 52–91) with more female than male patients (67% vs. 33%). 87% of patients had advanced stage disease. Four or more cycles of FluCy were administered in 53% of patients. Responses (CR, CRu, PR) were achieved in 9 patients (60%) with CR in 5 (33%). Reasons for early cessation of treatment were hematological toxicity (n=2), death (n=2) and failure to respond (n=3). Grade 3 or 4 hematological toxicity occurred in 8 (53%) patients, grade 3 or 4 non-hematological toxicity was experienced in 9 (60%) patients. Grade 1–2 peripheral neuropathy was reported in 2 patients. Guillain-Barré syndrome was reported in 2 patients in the thalidomide maintenance phase but resolved in both cases. Of the 9 patients with at least stable disease after FluCy, 7 received thalidomide, 2 patients did not receive thalidomide due to hematological toxicity and progression respectively. Remission status did not improve in any patients receiving thalidomide maintenance (6 patients progressed or have died and remission status was unchanged in the remaining patient). At a median follow-up of 14.9 months, 8 patients (53%) are alive. The estimated median OS is 18.2 months and median PFS is 7.9 months. Of the patients still alive, 4 have progressed, 2 (13%) are alive without progression, and 2 are not assessable for response due to early termination of treatment. The causes of death in the 7 deceased patients were lymphoma (5), infection (1), and Crohn's disease (1). Discussion: AITL is an aggressive lymphoma with poor outcome. The overall response rate in this trial of 60% (CR rate of 33%) was promising but remissions were short lived with a PFS of only 7.9 months. Only 2 patients are alive without progression at a median follow-up of 14.9 months. Thalidomide maintenance did not consolidate remission in any patients. The trial did not proceed to the 2nd stage of recruitment and demonstrates the difficulties in conducting prospective clinical trials in rare disorders such as AITL. The CR rate and duration of remission observed with FluCy are inferior to those reported with CHOP-type regimens. On the basis of these results, we recommend considering FluCy as first line treatment for AITL only when CHOP is contraindicated. Also, we found no evidence to support the use of thalidomide in this disease. Disclosures: Off Label Use: Thalidomide is used off licence in the trial for the treatment of AITL.