First Cycle Of Therapy Research Articles

Parameterizing the Logistic Model of Tumor Growth by DW-MRI and DCE-MRI Data to Predict Treatment Response and Changes in Breast Cancer Cellularity during Neoadjuvant Chemotherapy

Diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) data of 28 patients were obtained pretreatment, after one cycle, and after completion of all cycles of neoadjuvant chemotherapy (NAC). For each patient at each time point, the tumor cell number was estimated using the apparent diffusion coefficient and the extravascular extracellular (ve) and plasma volume (vp) fractions. The proliferation/death rate was obtained using the number of tumor cells from the first two time points in conjunction with the logistic model of tumor growth, which was then used to predict tumor cellularity at the conclusion of NAC. The Pearson correlation coefficient between the predicted and the experimental number of tumor cells measured at the end of NAC was 0.81 (P = .0043). The proliferation rate estimated after the first cycle of therapy was able to separate patients who went on to achieve pathologic complete response from those who did not (P = .021) with a sensitivity and specificity of 82.4% and 72.7%, respectively. These data provide preliminary results indicating that incorporating readily available quantitative MRI data into a simple model of tumor growth can lead to potentially clinically relevant information for predicting an individual patient's response to NAC.

Pilot study of cisplatin, etoposide, bleomycin, and escalating dose cyclophosphamide therapy for children with high risk germ cell tumors: A report of the children's oncology group (COG)

To establish the maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide with cisplatin, etoposide, and bleomycin (C-PEB) in children with high-risk malignant germ cell tumors (HR-MGCT). Eligibility criteria included untreated patients ≤ 21 years of age with stage III/IV extragonadal, extra cranial MGCT. Patients received four cycles (repeated every 3 weeks) of cisplatin (20 mg/m(2) /day × 5 days), etoposide (100 mg/m(2) /day × 5 days), and bleomycin (15 mg/m(2) on Day 1) with escalating doses of cyclophosphamide on Day 1, assigned at the time of enrollment (1.2, 1.8, or 2.4 g/m(2)). Patients with complete response had therapy discontinued. Patients with residual disease underwent second-look surgery, those with pathologic evidence of residual MGCT or whose markers had not normalized received two more cycles. All other patients had protocol therapy stopped. Nineteen patients were enrolled between July 2004 and August 2007. Three patients were non-evaluable. Sixteen patients completed four cycles. Eleven had complete response, one had progressive disease and four had partial response. All four with partial response underwent second look surgery followed by two more cycles. Only one patient, on dose 1.8 g/m(2), experienced dose-limiting toxicity (DLT) during the first cycle of therapy (grade 3 hyperglycemia). The 4-year EFS and OS (± standard deviation) were 74 ± 7% and 89 ± 10%, respectively. The addition of cyclophosphamide to the standard PEB regimen (cisplatin, etoposide, and bleomycin) is feasible and well-tolerated at all dose levels used on this study.

Implications of rapidity of response to initial therapy in multiple myeloma.

8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (>= 1 g/dL), dFLC (>=10 mg/dl) or 24 hour urinary M protein excretion (UrM; >=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P<0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]

High‐dose cytarabine (24 g/m2) in combination with idarubicin (HiDAC‐3) results in high first‐cycle response with limited gastrointestinal toxicity in adult acute myeloid leukaemia

Although induction chemotherapy comprising high-dose cytarabine (HiDAC) in combination with idarubicin and etoposide or 'ICE' for adult acute myeloid leukaemia (AML) produces a complete remission rate of nearly 80%, gastrointestinal toxicity is significant. Omission of etoposide may produce similar clinical outcomes with potentially less gastrointestinal toxicity. Fifty-three consecutive patients aged 15-60 with newly diagnosed AML, receiving high-dose cytarabine induction at the Alfred Hospital, Melbourne, were retrospectively analysed. Regimens included HiDAC-3 (idarubicin 12 mg/m(2) day 1-3, cytarabine 3 gm/m(2) bd day 1,3,5,7) or ICE (idarubicin 9 mg/m(2) day 1-3, cytarabine 3 g/m(2) bd day 1,3,5,7, etoposide 75 mg/m(2) day 1-7). Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.03. Thirty-one patients received HIDAC-3 and 22 patients received ICE induction. HiDAC-3 was better tolerated than ICE in terms of lower frequency of grade 3-4 nausea (0% vs 41%; P < 0.01), grade 3-4 diarrhoea (26% vs 55%; P = 0.05), lower rates of radiologically evident enterocolitis (6% vs 32%; P = 0.03) and less cumulative days of total parenteral nutrition use (1.2 vs 7.3 days; P < 0.01). Times to haematological recovery were similar between the two regimens. Thirty-day mortality was 0% for HiDAC-3 and 9% for ICE. Eighty-four per cent of HiDAC-3-treated patients achieved complete remission after the first cycle of therapy, compared with 77% with ICE. No differences in survival were evident between the two regimens. HiDAC-3 is a clinically effective induction regimen for adult AML, producing a high rate of first-cycle complete remission with less treatment-related gastrointestinal toxicity than ICE.

Lenalidomide, Bortezomib, and Dexamethasone (RVD) in Combination with Vorinostat As Front-Line Therapy for Patients with Multiple Myeloma (MM): Results of a Phase 1 Study

Abstract 3034 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate. The goal of the current trial is to improve on the CR rate compared with RVD by adding a novel targeted agent. Preclinical studies have demonstrated that vorinostat (Vor), an HDAC inhibitor, is synergistic with bortezomib, immunomodulatory (IMiD®) compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study is to determine the tolerability and preliminary efficacy of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (Pts) received the current standard RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5-8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. DLT (≥ G3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of ANC to ≥1,000/μL or platelets to ≥50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified EBMT and Uniform criteria. Pts with PR or better could proceed to autologous transplant after ≥ 4 cycles. Results: Eleven pts (median age 54, 82% men, 54.5% ISS Stage II/III) have been enrolled to date with n=4 pts each in cohorts 1 (Vor 100mg) and 2 (Vor 200mg), and 3 pts in cohort 3 (Vor 300 mg). One patient has completed 8 cycles, 1 pt completed 4 cycles and proceeded to transplant, 6 pts remain on study treatment and 3 pts have discontinued therapy (1 for significant peripheral neuropathy {grade 3}, 1 for patient choice unrelated to toxicity and 1 for non adherence). Two DLTs have occurred: syncope (cohort 1) and asymptomatic grade 3 elevation of ALT (cohort 2) with none in cohort 3.The episode of syncope was not related to cardiac arrhythmia. One study related SAE has occurred (syncope). One other episode of grade 3 elevation of ALT occurred in a pt in cycle 3 in cohort 1. Both episodes of increased ALT resolved and patients remained on study with dose modification. One patient developed grade 3 diarrhea in cohort 1. No patients have developed a grade 4 toxicity. Treatment emergent peripheral neuropathy occurred in 6 patients (4 grade 1, 1 grade 2 and 1 grade 3). No episodes of study related grade 3 fatigue, nausea, or vomiting have occurred. The MTD has not been reached. Eight patients are evaluable for response. All have responded to study therapy with 3 CRs, 1 VGPR and 4 PRs. Three patients went on to stem cell collection after 4 cycles and all collected an adequate dose for transplant of >5 ×106 CD34+ cells/kg. Conclusion: The combination of RVD with vorinostat has been generally well tolerated to date. No unexpected toxicity has been noted with side effects commensurate with prior experience with each of the drugs and no additive toxicity seen to date. While asymptomatic elevation of ALT has been seen and will require ongoing monitoring, grade 3 ALT elevation was a DLT in the original RVD study and related to dexamethasone, so may not be related to the addition of vorinostat. Early efficacy data is promising with 50% of patients achieving a VGPR or higher. Accrual is ongoing to determine the MTD. Disclosures: Kaufman: Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Off Label Use: Use of lenalidomide as upfront therapy. Use of vorinostat as upfront therapy. Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding. Heffner: Millenium: Consultancy, Honoraria, Research Funding. Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Orlowski: Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Lonial: Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau.

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

AbstractAbstract 4082 Background:ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods:The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim.Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results:To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway.Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial.In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations.An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions:The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures:Shah:Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Combination of Sorafenib and 5-Azacytidine Has Significant Activity in Patients with Relapsed/Refractory or Untreated Acute Myeloid Leukemia and FLT3-ITD mutation

Abstract 1519▪▪This icon denotes a clinically relevant abstract Background:The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods:Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results:43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions:Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures:Ravandi:Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

A Phase I Clinical Trial Using Eltrombopag in Patients with Acute Myelogenous Leukemia

AbstractAbstract ▪3576▪This icon denotes a clinically relevant abstractEltrombopag, a non-peptide, small molecule, thrombopoietin receptor agonist, has been shown to increase platelet counts in patients with idiopathic thrombocytopenic purpura (ITP), hepatitis C associated thrombocytopenia and severe aplastic anemia. Pre-clinical studies show that eltrombopag stimulates megakaryopoiesis in bone marrow samples from patients with acute myelogenous leukemia (AML) and inhibits leukemic cell growth. The clinical use of eltrombopag in the AML patient population has not been previously explored. We report the results of an investigator-initiated, phase I dose escalation clinical trial to evaluate the safety and efficacy of eltrombopag monotherapy in older patients with AML.Eligible patients were ≥ 60 years old with non-M3 AML and a baseline platelet count ≤75,000/ul. A standard 3+3 design was used employing dose escalation in 4 sequential cohorts of 50mg, 100mg, 200mg and 300mg of eltrombopag daily. Subjects who did not complete at least one cycle of therapy (4 weeks) or experience a dose-limiting toxicity (DLT) were replaced. The primary endpoint was safety. Secondary endpoints included platelet and disease response. Bone marrow biopsies to evaluate for disease response and fibrosis were planned at one month, 3 months and 6 months.Twenty-three subjects were enrolled from June 2010 to February 2012 at the Hospital of the University of Pennsylvania and received at least one dose of study drug. The median patient age was 73 (range 60–86). Twenty-one of 23 subjects were relapsed or refractory after prior therapy. Two of 23 subjects (ages 85 and 86) were previously untreated. Nineteen subjects were platelet transfusion-dependent. Thirteen subjects had a history of antecedent myelodysplastic syndrome (MDS) and 6 were requiring hydroxyurea at time of study entry.Fourteen of 23 subjects completed the first cycle of therapy. Three remained on study for the entire 6-month study period. At the time of this report one subject remains on eltrombopag in an extension phase (8+ months of therapy). Indications for drug cessation included: possible DLT=1; progressive disease=5; death due to sepsis=5; lack of response=6, loss of response=1; and pursuit of hospice or alternative therapy=4. Overall eltrombopag was well tolerated at all doses studied and a maximally tolerated dose (MTD) was not reached. One subject at the 300mg dose level developed Grade 4 hepatic laboratory abnormalities possibly related to study drug, which met criteria for a DLT. The subject had concurrent polymicrobial sepsis and subsequently died. No other grade 3 or greater liver function abnormalities were observed. Asymptomatic skin discoloration with associated abnormal serum pigmentation was noted in subjects at the 200mg and 300mg dose levels.There were no platelet responses in the 50 mg or 100 mg cohorts (7 subjects total). Two of 7 subjects treated at the 200mg dose level and 2 of 9 subjects treated at the 300mg dose level achieved a platelet response (25% platelet response rate at these higher dose levels). All 4 of these subjects became platelet transfusion independent. The duration of platelet responses were 5 weeks, 12 weeks, 6 months and 8+ months (ongoing at time of this report).One subject with primary refractory AML, associated with monosomy 7, obtained a complete morphologic and cytogenetic response by 3 months of therapy at the 300mg dose level. This response was sustained at most recent bone marrow biopsy at 6 months of therapy and the patient remains on study drug. Increased reticulin fibrosis was also observed in this subject over time. No other subjects experienced a PR or CR. 6 patients had stable disease (SD) at one month, which was maintained at 3 months for 4 patients.Our study shows that eltrombopag is well tolerated in patients with AML at doses well above those typically used to treat ITP. At higher doses, we observed clinically meaningful platelet and antileukemic responses. Further exploration of eltrombopag as both a platelet agonist and disease-modifying agent in the treatment of AML is justified. Disclosures:Frey:GSK: Consultancy, Research Funding. Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Perl:Astellas: Consultancy. Carroll:GlaxoSmithKlein: Research Funding.

Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

AbstractAbstract 3661 Objective:We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods:A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results:A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions:Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures:Off Label Use: Temsirolimus for mantle cell lymphoma.

Phase 2 Study of Decitabine in Combination with Tretinoin in Myelodysplastic Syndromes and Acute Myelogenous Leukemia: Interim Results

AbstractAbstract 3815 Background:The activity of DNA methyltransferase inhibitor (DNMTI) monotherapy is suboptimal for most patients (pts) with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). DNMTI combinations studied to date have not convincingly produced higher response rates compared to DNMTI monotherapy, although time to response appears to be improved in some studies. We combined decitabine (DAC) with tretinoin (ATRA), an RAR ligand which can recruit histone acetyltransferases to gene regulatory regions, as a means to upregulate gene expression, and to induce apoptosis or differentiation, as is seen in in vitro studies of non-M3 AML. Our previous phase 1 study established 65 mg/m2/day of ATRA as the MTD (headache was DLT at 85 mg/m2/d) when given on days 10–19 following standard dose decitabine (20 mg/m2/d), given on days 1–5 of a 28-day cycle (Klimek VM, et al. Leuk Res, 2011;35:S70-S). Materials and Methods:MDS pts with any FAB or WHO subtype were enrolled if they had an IPSS score ≥ 0.5, were ineligible for allogeneic stem cell transplant (AlloSCT) at study entry, and had adequate hepatic and renal function. Prior DAC or 5-azacytidine (5-aza) responders who then progressed off treatment, and pts whose MDS progressed on 5-aza were eligible. Pts received up to 10 cycles of DAC (given on days 1–5) and tretinoin (65 mg/m2/d on days 10–19 of a 28-day cycle), allowing for delays due to infection or to allow count recovery as deemed necessary by the treating physician. Those with an ongoing response after 10 cycles continued DAC alone off-study. The primary endpoint is efficacy, assessed after even-numbered cycles using the 2006 Modified International Working Group MDS response criteria. Kaplan-Meier methodology was used to estimate duration of best response due to the censoring for patients undergoing AlloSCT. Results:36 eligible pts (27M, 9F; median age 66, range 45–84 yrs) were enrolled in the phase 2 cohort as of 6/2012. FAB/WHO subtypes included: RA/RCMD, n=3 (8%); RARS/RCMD-RARS, n=1 (3%); RAEB/RAEB-1 & 2, n= 24 (67%); RAEBt/AML, n= 6 (17%); CMML/CMML-1, n=2 (6%). IPSS risk categories included: Int-1, n=5 (14%); Int-2, n=16 (44%); High Risk, n=11 (31%), and pts with ≥ Int-1 (n=3) or ≥ Int-2 (n=1) risk disease who could not be definitively classified using the IPSS. Most pts (n=20) had IPSS poor risk cytogenetics (CG), 11 had IPSS good risk CG (all with normal karyotype), 3 had intermediate risk CG, and CG results were unknown in 2 pts. 15/36 (42%) had therapy-related disease (t-MDS/AML), all with IPSS poor risk CG and either IPSS Int-2 (n=9) or High Risk (n=6) disease. Marrow blasts were ≥ 5% in 26/36 pts: (5–10%, n=13; 11–20%, n=13; 21–30%, n=6). Prior MDS therapy included lenalidomide (n=2), thalidomide (n=1), 5-aza (n=3), DAC (n=1), and lintuzumab (n=1). Pts received a median of 4 cycles of therapy (range, 1–10), and started therapy 0.6–180 months (median, 1.42 months) from the time of diagnosis. Two pts were classified as treatment failures since they died during the first cycle of therapy. One pt with CMML-1 at baseline progressed to AML during the screening period, and was deemed ineligible. Two pts on study have not yet had a full response assessment. Best responses in the evaluable intent to treat cohort (n=33) include: CR, n=7 (21%); PR, n=1 (3%); mCR, n=3 (9%); mCR+HI, n=3 (9 %); HI alone, n=3 (9 %); Stable disease, n=10 (30%); Disease progression, n= 3 (9%). The composite CR rate (CR+mCR±HI) was 39% (13/33), and the overall response rate (CR+PR+mCR±HI+HI) is 51% (17/33). Median time from diagnosis to start of therapy for responders was 1.7 months (range, 0.8–180). The ORR for the 13 t-MDS/AML pts was 46% (6/13), including 5 pts with monosomy 17 and/or p53 loss by FISH. The median time to initial response and best response is 1.1 months and 2.3 months, respectively. The median response duration is 7.8 months, incorporating the 7 pts censored at the time they came off study to undergo AlloSCT. Conclusions:DAC/ATRA is active in IPSS Int-2 and High Risk MDS and in t-MDS/AML, which is characterized by poor risk cytogenetics and an increased frequency of p53 or chromosome 17p loss. Although our interim ORR appears similar to DAC and 5-aza monotherapy trials, our results were achieved in a higher risk cohort, and the CR rate is equal to or greater than some earlier monotherapy studies with a shorter median time to response. Ongoing and planned correlative studies may define pre-treatment biomarkers for response. Disclosures:Off Label Use: Tretinoin.

Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to Sunitinib in metastatic renal cancer

Background:Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC.Methods:Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels.Results:The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure.Conclusion:We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Intraperitoneal Recombinant Human Endostatin Combined with Chemotherapy for Refractory Malignant Ascites due to Gastrointestinal Cancer: A Pilot Study

To evaluate the efficacy, safety and consequent impact on quality of life of a combined-modality using intraperitoneal recombinant human endostatin, Endostar and chemotherapy in patients with refractory malignant ascites caused by gastrointestinal cancer. Patients received combined intraperitoneal therapy repeated 3 weeks, which consisted of 5-fluorouracil 600 mg/m2 and cisplatin 30 mg/m2 on day 1-3 followed by Endostar 60 mg on day 4. A total of 18 patients were treated. The overall response rate was 55.6%, with a complete remission rate of 22.2%. The malignant ascites controlled rate was 77.8%. The median time to progression and overall survival was 2.6 and 4.9 months, respectively. Therapy-associated toxicities were generally mild to moderate treatment-related deaths. The mean Karnofsky performance status score was significantly improved from 59.4±2.49 at enrollment to 69.4±3.18 at 2 weeks after the first cycle of therapy (p=0.001). The mean score for overall ascites-associated symptoms was improved from 5.3±0.35 to 4.0±0.23 (p=0.004). Significant improvements of 6 individual symptoms were also observed. The combined-modality using intraperitoneal Endostar and chemotherapy is effective and safe in selected patients with refractory malignant ascites due to gastrointestinal cancer and significantly improves patient's quality of life with encouraging survival, which merits further investigation.

Activity and safety of CPBev regimen (cisplatinum, pemetrexed, and bevacizumab) as first-line therapy for locally advanced or metastatic adenocarcinoma of the lung: Final results of a phase II study.

e18026 Background: During the past five years the paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs-regimen containing both these agents and cis-platinum, we conducted a multi-institutional phase II study started on november 2007. Methods: chemonaive patients with non-squamous non-small cell lung cancer were considered eligible We adopt the two-stage of Simon model as statistical design of the study; activity of the regime, expressed as overall response rate and safety were the main end-points. Administered doses were 75 and 500 mg/p.s.m for cis-platinum and pemetrexed respectively and 7.5 mg./kg for Bevacizumab, for 3 - 6 cycles. G-CSF were administered only after the first cycle of therapy, whereas vitamin supplementation started from day 1 of the first cycle. No maintenance therapy was allowed. Results: We registered 9 partial responses among the first 15 patients treated so, accordingly with the design of the study, we completed the enrollment up to 32 patients. Patients characteristics are: male/female: 20/12, median age (years): 59 (r. 36 - 77), ECOG-WHO/PS 0/1: 21/11. One hundred eighty-three cycles of CPBev were administered: we registered only 13 cases of grade 3 adverse events. No grade 4 toxicities were observed. One case of allergic reaction to cis-platinum were observed. In terms of response rate, we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). Results in terms of outcome parameters expressed by progression-free and overall survival will be presented at the meeting. Conclusions: On the basis of our data, CPBev have a good toxicity profile and seems to be extremely active in advanced non-squamous lung carcinomas.

Phase 1 dose‐escalation trial evaluating the combination of the selective MET (mesenchymal‐epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib

Amplification of the mesenchymal-epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR-MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose-limiting toxicity in the first cycle of therapy (21 days). Thirty-two patients received combination treatment. Tivantinib serum concentrations were not dose-proportional. The most common (≥ 20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment-related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer.

Abstract 2391: All patients with metastatic breast, colorectal and prostate carcinoma have circulating tumor cells

Abstract Background: Presence of EpCAM+ cytokeratin+ nucleated circulating tumor cells (CTC) in metastatic carcinoma patients is associated with poor survival and may be used to guide treatment. Assessment of treatment targets on these CTC holds the promise of a liquid biopsy. However the proportion of patients in which a sufficient number of CTC are detected in 7.5 mL of blood is not sufficient. In this study we estimate the number of CTC in blood of patients with metastatic disease, explore the relationship with survival and determine whether assay modifications and/or increases in sample volume are needed to achieve the required increase in number of CTC detected. Methods: EpCAM+CK+DNA+CD45- CTC enumeration was performed with the CellSearch® system in 7.5 mL of blood of 836 patients with metastatic breast, colorectal and prostate cancer patients (Cristofanilli, NEJM 2004, Cohen, JCO 2008, De Bono, CCR 2008). EpCAM+, CD45-, Nucleic acid+ CTC were enumerated in 100ul of NH4CL lysed blood from 140 metatatic cancer patients and compared to CTC as enumerated with the CellSearch system. Image analysis for automated CTC enumeration and modeling of CTC frequencies was performed in Matlab. Results: The median number of CTC in 7.5mL of blood metastatic breast, colorectal and prostate is 5 and in 39% of patients no CTC are detected. The best fit of the CTC frequency distribution was used to extrapolate the sample volume to 5 liters of blood and predicted that 99% (95% confidence interval, CI, 95-99.8%) of patients had at least 1 CTC before initiation of therapy, which decreased to 97% (95% CI 87-99.5%) after the first cycles of therapy. One hundred CTC per liter of blood are present in ∼80% of patients, 1 CTC per ml of blood in ∼40% of patients and 10 CTC per ml of blood in ∼20% of patients. The median survival of patients with CTC is reduced by 6.6 months for each tenfold CTC increase. CTC definitions that do not include a requirement for presence of DNA, EpCAM, cytokeratin 8,18,19 (CK) or absence of CD45 are less predictive of survival, than the strictest definition requiring a CTC to be EpCAM+CK+DNA+CD45-. Comparison of CTC detected by flow cytometry to the CellSearch CTC method on 140 patients shows that improvements in EpCAM recovery may increase the average number of detected CTC by 6.5 fold (95% CI 5.6-7.3), yet the fits predict that this will only reduce the number of patients with 0 CTC from 39% to 21% (95% CI 13-31%). Conclusions: EpCAM+CK+DNA+CD45- CTC are present in blood of all patients with metastatic breast, colorectal and prostate cancer. The predicted strong relation with survival suggests the importance of this phenotype for metastasis. To use CTC as a liquid biopsy for the majority of patients, the CTC yield needs to be improved 100-1000 fold. This requires a dramatic increase in sample volume which may be achieved by in vivo flow cytometry, or through processing an apheresis product. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2391. doi:1538-7445.AM2012-2391

Abstract 2762: Phase I study of pazopanib and ixabepilone in patients with solid tumors

Abstract Background: Pazopanib is a tyrosine kinase inhibitor targeting multiple receptors including vascular endothelial growth factor receptor, platelet derived growth factor receptor, and C-KIT and acts by inhibiting angiogenesis and tumor growth. Ixabepilone is a semi-synthetic analog of epothilone B and promotes microtubule stabilization inducing tumor cell apoptosis. The purpose of this study was to determine the optimal tolerated regimen (OTR) of combination pazopanib and ixabepilone during the first cycle of therapy for the treatment of advanced, previously treated solid tumor malignancies. Methods: Treatment was given until disease progression, unacceptable toxicity, or patient refusal. Ixabepilone was administered intravenously on day 1 of a 21-day cycle. Dose escalation started at 32 mg/m2 and increased to 40mg/m2. Pazopanib was administered orally once daily beginning on day 1 at a starting dose of 400mg and escalating at 200mg increments up to 800mg. Toxicity was assessed by using the Common Terminology Criteria for Adverse Events (version 3.0). Disease assessment was done every 2 cycles. Results: Twenty-eight patients (17 male and 11 female) with ECOG PS of 0 or 1 were enrolled from December 2009 to September 2011.The median age was 58 years (range 30-72). Primary tumor sites included lung (8), colon (9), skin (2), gallbladder (1), cholangiocarcinoma (1), neuroendocrine (1), head and neck (3), esophagus (1), small cell cancer (1), and leimyosarcoma (1). A total of 120 cycles of chemotherapy was administered with a median number of cycles per patient of 4 (range 1-13). Two dose-limiting toxicities (DLT) were seen including grade 4 neutropenia at dose level 2 (ixabepilone 40 mg/m2 and pazopanib 400 mg) and grade 4 thrombocytopenia with proteinuria at dose level 4 (ixabepilone 32 mg/m2 and pazopanib 800 mg). Dose level 2a was added to the study to confirm the safety of the proposed ixabepilone dose (32 mg/m2) before escalating the dose of pazopanib to levels 3 and 4. Dose level 3 was determined to be the optimal tolerated regimen (pazopanib 600 mg and ixabepilone 32 mg/m2). Grade 3-4 hematologic toxicities included neutropenia (14), febrile neutropenia (1), thrombocytopenia (2), and anemia (1). Grade 3-4 non-hematologic toxicities included weakness (1), dehydration (1), transaminitis (1), and fatigue (1). One patient withdrew from the study due to toxicity. Median time to progression during the study period was 3 months. Disease stabilization was seen in 11 patients and partial response in 5 patients. Conclusions: We were able to establish the OTR for combination of pazopanib and ixabepilone. Progression-free survival seen in patients with a variety of previously treated, advanced solid tumors warrants further investigation of this regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2762. doi:1538-7445.AM2012-2762

Circulating plasma cells predict the outcome of relapsed or refractory multiple myeloma

Pretreatment detection of peripheral blood malignant circulating plasma cells (CPCs) has been shown to be of negative prognostic value in multiple myeloma (MM). We hypothesized that the assessment of CPC kinetics in response to one therapy cycle using six-color flow cytometry could be helpful in the early detection of MM refractoriness to treatment. Forty-two patients with refractory or relapsed (RR) MM were enrolled. Median time to tumor progression (TTP) of 51 days and median overall survival (OS) of 308 days was shortest in patients whose CPCs with aberrant phentoype (aCPCs) did not decrease after one therapy cycle compared to patients with decreasing (median TTP 258 days and OS 856 days) or undetectable (median TTP 581 days and OS 1006 days) aCPCs (p < 0.001 and p = 0.007 for TTP and OS, respectively). Non-reduction of aCPCs in patients with RR MM after the first cycle of therapy may be useful in early identification of patients resistant to a given therapy.

124I-cG250 PET scan for early detection of response to sunitinib in patients (Pts) with metastatic clear cell renal cell carcinoma (MccRCC).

362 Background: Mutation and/or methylation of the von Hippel-Lindau gene leading to overexpression of hypoxia-inducible factor-1 alpha (HIF1α) has been implicated as a driving event in the pathogenesis of ccRCC. Downstream effectors of HIF1α such as VEGF have become key targets of novel therapies for MccRCC (eg, sunitinib (S)). Carbonic anhydrase-IX (CAIX) transcription is also regulated by HIF1α and is overexpressed in ~95% of ccRCC. Linkage of cG250 (Girentuximab), a chimeric antibody to CAIX, to radioactive iodine (124I), has resulted in a radiotracer specific for ccRCC; 124I-cG250 (124I-Girentuximab) PET/CT demonstrated a sensitivity of 86% and a specificity of 87% for detecting primary ccRCC (Uzzo AUA 2010). Since responses to targeted therapies likely occur on a molecular level before they are detectable with standard imaging, we hypothesize that 124I-cG250 PET/CT could allow earlier recognition of response or progression to S than CT in pts with MccRCC. Methods: This is a pilot study of 124I-cG250 PET/CT in 25 pts with MccRCC planned to begin treatment (Tx) with S. 124I-cG250 PET/CT will be assessed for its ability to predict Tx response during (days 25–28) and at completion (days 39-42) of the first cycle of therapy, in comparison to standard CT imaging at routine intervals. PET/CT and CT will each be interpreted by 1 nuclear medicine physician, who will be blinded to the results of the comparator imaging modality, but aware of the clinical history of the pts. Eligibility include age ≥18, ECOG PS &lt; 2, histologically confirmed MccRCC, Tx planned with S, and radiographic evidence of unidimensionally measurable disease with at least one lesion ≥2 cm in diameter on 16-slice multi-detector CT. Key exclusion criteria include uncontrolled/unstable hyperthyroidism or Grave’s Disease, unstable cardiac disease and uncontrolled seizure disorder or history of CVA or TIA within the past 12 months. Results: NA. Conclusions: This is the first clinical trial to prospectively evaluate the use of a histologically specific imaging modality to measure early changes in ccRCC CAIX protein expression as a predictor of response to biologically targeted Tx. Enrollment will commence in November 2011.

AC220, a Potent and Specific FLT3 Inhibitor, Enhances the Activity of Combined Cytarabine and Daunorubicin Chemotherapy in a FLT3-ITD Model of AML

Abstract 1538Acute myeloid leukemia patients harboring an activated FLT receptor have a poorer prognosis following standard chemotherapy treatment compared to patients with a wild type receptor. This suggests that the combination of FLT3 inhibitor with chemotherapy may improve clinical outcome in this patient population. AC220, a potent and selective FLT3 inhibitor, has a subnanomolar anti-proliferative EC50 against cells containing activated FLT3 receptor. Using the homozygous FLT3-ITD (internal tandem duplication) cell line MV4-11 we previously demonstrated that treatment of cells with AC220 concurrent with or the day following treatment with the individual chemotherapeutic agents generally provided additive to slightly synergistic effects in vitro, with no indications of drug antagonism or increased toxicity as measured by body weight changes and CBC analysis (ASH 2009).Because induction therapy in AML patients is typically comprised of Cytarabine (Ara-C) plus an anthracyline, we sought to more closely approximate this chemotherapeutic dosing regimen in a preclinical model. In the current study, we treated MV4-11 tumor bearing animals with two cycles of ‘5+3 therapy'; 5 days of Ara-C at 80mg/kg IP concurrent with 3 days of daunorubicin (DNR) at 1 mg/kg IV with cycles separated by 10 days. These doses were at or near the MTD for tumor bearing SCID mice. AC220 at 0.5 mg/kg PO was delivered either concurrently and continuously throughout the two cycles or was delivered episodically for 7 days immediately following the end of the DNR dosing period or the end of the Ara-C dosing period. Monotherapy with the chemotherapeutic agents alone or in a 5+3 combination dosing regimen provided measurable but statistically non-significant anti-tumor benefit with a tumor growth delay (TGD) of 7 days for the 5+3 cohort (endpoint =1500 mm3). AC220 alone delivered continuously at 0.5 mg/kg from the beginning of the dosing period did provide significant anti-tumor benefit, with a tumor growth delay (TGD) of 21 days and a tumor growth inhibition (TGI) of 17% when measured at the end of the first cycle (day 30). Continuous AC220 treatment initiated on day 1 in conjunction with 5+3 therapy led to a slightly increased TGD of 23 days and further reduced the TGI to 12%. AC220 alone delivered episodically for 7 days at 0.5 mg/kg starting on either day 4 or on day 6 (mimicking post-DNR or post-Ara-C treatment, respectively) provided a TGD of 11 days. Layering 7 day episodic dosing of AC220 immediately following treatment with DNR or Ara-C in a 5+3 regimen led to a TGD of 16 or 18 days, respectively. However, comparison of the TGI at the end of the first cycle of therapy suggests that episodic dosing of AC220 post-AraC is more efficacious (TGI 22%) than episodic dosing of AC220 post-DNR (TGI 35%). These results suggest that episodic dosing of AC220 post-5+3 therapy or continual dosing of AC220 plus 5+3 induction therapy may provide additional benefit over chemotherapy alone. Disclosures:Belli:Ambit Biosciences: Employment, Equity Ownership. Dao:Ambit Biosciences: Employment. Wierenga:Ambit Biosciences: Equity Ownership. Armstrong:Ambit Biosciences: Employment, Equity Ownership.

Combination of Bendamustine, Lenalidomide, and Dexamethasone (BLD) in Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of Phase I/II Open-Label, Dose Escalation Study

Abstract 304 Background:Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This first multicenter, phase I/II trial investigated the combination of bendamustine, lenalidomide and dexamethasone (BLD) as a potentially effective treatment option for multiple myeloma (MM) patients, particularly for those with pre-existing or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods:We conducted an open-label, dose escalation study (Table 1). Patients were enrolled from June 2008 through February 2011. Eligible patients were aged ≥ 18 years with confirmed, measurable stage II or III MM that was refractory to or progressed after 1 or more prior therapies including lenalidomide. Patients were assigned to their dose levels in a classical 3+3 cohort design. Phase I was to assess the safety and to establish the MTD of the combination treatment. The phase II portion of the study was to assess the overall response rate (ORR) at the MTD. Intravenous bendamustine was given on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycle. Treatment was given until plateau of best response as determined by the International Myeloma Working Group uniform response criteria for a maximum of 8 cycles. The study doses were escalated through 3 levels, in a 3+3 dose escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level was associated with DLTs in ≥ 2 patients. Primary endpoint was the MTD. After determining the MTD, up to 12 additional patients were enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival.Dose levelBendamustine, mg/m2Lenalidomide, mgDexamethasone, mg175540275104031001040 Results:36 patients with a median age of 63 years (range 38 to 80) were enrolled. The median number of prior therapies was 3 with a range of from 2–9; 79% of the patients had prior lenalidomide, 48% had prior thalidomide, and 34% had both. 69% of the patients had a prior autologous stem cell transplant. The MTD was 75 mg/m2 for bendamustine and 10 mg for lenalidomide. DLTs included at dose level 2: 1 grade 4 neutropenia; at dose level 3: 2 grade 4 neutropenias and 1 delayed platelet recovery from grade 3 thrombocytopenia. 25 received at least 2 cycles and were included into the response assessment. A partial response or better was observed in 52% (n=13) of the patients, including 24% (n=6) VGPR. MR was observed in 24% (n=6), SD 16% (n=4), and PD 8% (n=2). BLD induced fast responses with a time to best response of 1.6 months (range 0.7–7.4). The response was independent of prior exposure to lenalidomide evidenced by the fact that 84% of patients with VGPR/PR had prior treatment with lenalidomide. The median follow up for patients at risk of progression is 8 months (range 4–13). The estimated median progression free survival (PFS) is 4.4 months (95% CI (3.4, 9.2). 4 patients have died and the median follow up for patients who are still alive is 13 months (range 6–33). The median OS survival has not been reached yet. We did not observe any unanticipated DLTs. The only grade 4 adverse events for all patients for all cycles included 24.1% neutropenia and 7% thrombocytopenia. No infection was associated with the neutropenia and all AE resolved successfully. Conclusions:This is the first phase I/II trial testing bendamustine, lenalidomide and dexamethasone in combination for relapsed and refractory MM. This regimen is safe and well tolerated even in older patients up to 80 years. Based on the mainly myelosuppressive side effects, concomitant treatment with filgastrim is recommended. This regimen induced fast responses and high response rates even in heavily pretreated MM patients. The high responses were also achieved in patients with prior exposure to lenalidomide suggesting that BLD overcomes resistance to lenalidomide and is a highly active regimen. [Display omitted] Disclosures:Lentzsch:Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria. Burt:Celgene Corp: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau. Roodman:Amgen: Consultancy; Millennium Pharmaceuticals: Consultancy. Agha:Novartis: Consultancy. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy.