ALBERT

Description: Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 1937 Background: Three-drug combinations with bortezomib (Bz) and/or either thalidomide or lenalidomide (Len) are highly active in frontline MM and appear superior to at least some 2-drug combinations with these agents. In an attempt to further improve treatment outcomes, we developed the 4-drug RVDD regimen of lenalidomide (Revlimid®, Len), Bz (Velcade®), pegylated liposomal doxorubicin (Doxil®, PLD), and dexamethasone (Dex), which demonstrates high activity in newly diagnosed MM. Here we present final results of this Phase I/II trial. Methods: Patients (Pts) received eight 3-week cycles with Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5-8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels and the maximum tolerated dose (MTD; Phase II). Responses were assessed by modified EBMT and IMWG criteria with the addition of nCR. Pts could proceed to autologous stem cell transplant (ASCT) or continue treatment, which after 8 cycles consisted of 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. The primary objectives were to evaluate MTD and VGPR rate at the end of 4 and 8 cycles. Results: The study enrolled 72 pts with a median age 60 (range 29–77); 53% ISS II/III; 46% any of the del 13q, t(4;14), t(14;16), or del 17p, of which 37 were treated at the MTD (including 6 in Phase I). Pts received a median of 4.5 cycles (range 2–31); 70 pts completed at least 4 cycles and 20 at least 8 cycles. Five pts developed DLTs, including 2 pts grade (G) 3 asymptomatic neutropenia, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 G3 hypophosphatemia. Based on the pre-determined definition of MTD, the maximum planned doses of Len 25 mg, Bz 1.3 mg/m2, PLD 30 mg/m2, and Dex 20/10 mg were selected as the maximum tolerated dose (MTD) for the Phase II portion of the study as the closest to, but not exceeding, a target rate of 20% DLTs. The most common toxicities (all grades) were fatigue (83%), infections (72%), constipation (69%), and sensory neuropathy (65%) of which 8%, 14%, 1%, and 6% were G3, respectively. Other G3/4 toxicities included neutropenia (19%), infections (16 %), thrombocytopenia (11%), hyperglycemia (10%), and DVT/PE (3%). There was 25% G1/2 palmar-plantar erythrodysesthesia and 1 pt experienced G1 asymptomatic and reversible decrease in ejection fraction attributed to PLD. Importantly, there was no treatment-related mortality. The best response rates for all pts were as follows: 96% ≥ PR, 66% ≥ VGPR, and 38% CR/nCR. At the end of 4 and 8 cycles, defined in the protocol for efficacy assessment, response rates were: 96% and 95% ≥ PR, 57% and 65% ≥VGPR and 29% and 35% CR/nCR; at the MTD ≥PR was 96%, ≥VGPR 66%, and CR/nCR 34%. Response rates were not statistically different in a subset of pts with any of del 13q, t(4;14), t(14;16), or del 17p. Forty-seven (65%) pts proceeded to ASCT, after collection of a median 6.7 × 106 CD34+ cells/kg (range 1.9–17.7). At 3 months post ASCT, ≥ VGPR and CR/nCR rates improved in 45 evaluable pts from 64% to 84% and from 38% to 60%, respectively. After a median of 15.5 months of follow-up, the estimated 18-month PFS for all pts is 84% and overall survival 99%. Conclusion: RVDD is generally well tolerated and highly active with rapid reduction of MM tumor burden seen (≥ PR 96%, ≥VGPR 57% and CR/nCR rate 29% at the completion of 4 cycles). Response rates further improved after additional treatment, both in pts who continued RVDD treatment (’VGPR 65%, CR/nCR 35%) and pts who proceeded to ASCT (≥VGPR 84%, and CR/nCR 60%), although some additional toxicity was noted. Whether the incorporation of a 4th agent in the form of PLD has made an impact in this pt population remains to be defined. At equivalent time points (i.e. at the completion of 4 and 8 cycles), the ≥VGPR and CR/nCR rates as well as the current estimated PFS appear to compare favorably to RVD, which provides the rationale for consideration of further studies with this regimen, including potential randomized trials in this setting. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Celgene: Unrestricted educational lectures, research funding, ad hoc advisory boards. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Campagnaro:NIH: Research funding for NIH K12 CA076917. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding. Anderson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson & Johnson Pharmaceutical Services: Employment, Equity Ownership. Esseltine:Millennium: The Takeda Oncology Company: Employment; Johnson & Johnson: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Flight test and modeling techniques were developed for efficiently identifying global aerodynamic models that can be used to accurately simulate stall, upset, and recovery on large transport airplanes. The techniques were developed and validated in a high-fidelity fixed-base flight simulator using a wind-tunnel aerodynamic database, realistic sensor characteristics, and a realistic flight deck representative of a large transport aircraft. Results demonstrated that aerodynamic models for stall, upset, and recovery can be identified rapidly and accurately using relatively simple piloted flight test maneuvers. Stall maneuver predictions and comparisons of identified aerodynamic models with data from the underlying simulation aerodynamic database were used to validate the techniques.

Description: A study was undertaken at NASA Langley Research Center to establish, demonstrate, and apply methodology for modeling and implementing the aerodynamic effects of MANPADS damage to a transport aircraft into real-time flight simulation, and to demonstrate a preliminary capability of using such a simulation to conduct an assessment of aircraft survivability. Key findings from this study include: superpositioning of incremental aerodynamic characteristics to the baseline simulation aerodynamic model proved to be a simple and effective way of modeling damage effects; the primary effect of wing damage rolling moment asymmetry may limit minimum airspeed for adequate controllability, but this can be mitigated by the use of sideslip; combined effects of aerodynamics, control degradation, and thrust loss can result in significantly degraded controllability for a safe landing; and high landing speeds may be required to maintain adequate control if large excursions from the nominal approach path are allowed, but high-gain pilot control during landing can mitigate this risk.

Description: An assessment of a draft AIAA standard for flight dynamics model exchange, ANSI/AIAA S-119-2011, was conducted on behalf of NASA by a team from the NASA Engineering and Safety Center. The assessment included adding the capability of importing standard models into real-time simulation facilities at several NASA Centers as well as into analysis simulation tools. All participants were successful at importing two example models into their respective simulation frameworks by using existing software libraries or by writing new import tools. Deficiencies in the libraries and format documentation were identified and fixed; suggestions for improvements to the standard were provided to the AIAA. An innovative tool to generate C code directly from such a model was developed. Performance of the software libraries compared favorably with compiled code. As a result of this assessment, several NASA Centers can now import standard models directly into their simulations. NASA is considering adopting the now-published S-119 standard as an internal recommended practice.

Description: A preliminary simulation of a generic T-tail transport airplane configuration has been developed at the National Aeronautics and Space Administration Langley Research Center. The primary purpose of this piloted simulation is to assess aerodynamic model fidelity requirements for training airline pilots to recognize and recover from full-stall flight conditions in a T-tail airplane. As a result, significant flexibility has been designed into the flight dynamics model. The flight dynamics model is based on newly acquired static and dynamic stability and control data from sources that include: wind tunnel, water tunnel, and computational fluid dynamics. Preliminary results for initial stall show an unstable stall pitch break (if the stick pusher is inhibited), un-commanded motions due to stall asymmetries, significantly reduced dynamic roll stability, and decreased control effectiveness. Preliminary studies indicated an insensitivity to the fidelity of the pitch damping model.

Description: It can take weeks or months to incorporate a new aerodynamic model into a vehicle simulation and validate the performance of the model. The Dynamic Aerospace Vehicle Exchange Markup Language (DAVE-ML) has been proposed as a means to reduce the time required to accomplish this task by defining a standard format for typical components of a flight dynamic model. The purpose of this paper is to describe an object-oriented C++ implementation of a class that interfaces a vehicle subsystem model specified in DAVE-ML and a vehicle simulation. Using the DaveMLTranslator class, aerodynamic or other subsystem models can be automatically imported and verified at run-time, significantly reducing the elapsed time between receipt of a DAVE-ML model and its integration into a simulation environment. The translator performs variable initializations, data table lookups, and mathematical calculations for the aerodynamic build-up, and executes any embedded static check-cases for verification. The implementation is efficient, enabling real-time execution. Simple interface code for the model inputs and outputs is the only requirement to integrate the DaveMLTranslator as a vehicle aerodynamic model. The translator makes use of existing table-lookup utilities from the Langley Standard Real-Time Simulation in C++ (LaSRS++). The design and operation of the translator class is described and comparisons with existing, conventional, C++ aerodynamic models of the same vehicle are given.