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Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a median overall survival (OS) of 6 months. Most approved therapies have overall response rates (ORR) of < 30%, low complete response (CR) rates, and short progression free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies, the latter based on accelerated approval. DUV monotherapy demonstrated an ORR of 50% in patients (pts) with R/R PTCL in a Phase 1 study across multiple subtypes (Horwitz, Blood 2018). In the Phase 2, open-label, multi-center, PRIMO trial of DUV in R/R PTCL, the initial results of the dose-optimization phase (N=33) showed a 54% ORR in the 75 mg BID (N=13) and 35% in the 25 mg BID (N=20) cohorts by investigator assessment (INV) , the primary endpoint (Horwitz, ASH 2019). We report mature dose-optimization results and the initial results of a planned preliminary assessment (N=20) of the dose-expansion (NCT03372057; supported by Verastem Oncology). In the dose-optimization phase, pts received DUV at 25 mg (Cohort 1) or 75 mg BID (Cohort 2). Pts were evaluable if they completed 1 cycle (28 days) of DUV and had ≥ 1 efficacy assessment. The dose-expansion phase is ongoing with a targeted enrollment of 100 pts; pts were eligible if they had histologically confirmed R/R PTCL after ≥2 cycles of a prior standard regimen and a CD4 lymphocyte count of ≥ 50/mm3 (0.05 x 109/L). Based on the initial dose-optimization results, it was determined pts will receive DUV starting at 75 mg BID for 2 cycles to achieve more rapid tumor control, followed by 25 mg to try to maintain long-term disease control and mitigate the potential for later onset toxicities. Pts were to be maintained on therapy continuously until progressive disease (PD) or unacceptable toxicity. For those at 25mg BID, it was permitted for the dose to be re-escalated to 75 mg BID if an assessment shows PD and the pt had not required a dose modification due to toxicity. The primary endpoint is ORR by an Independent Review Committee (IRC), and secondary endpoints include duration of response (DOR), PFS, OS, disease control rate, and safety; all analyses consisted of pts that received at least 1 dose of DUV. The statistical analysis plan was amended to take a preliminary assessment of ORR after approximately 20 pts were evaluated for response in the dose-expansion phase, consistent with the number of pts that were evaluated in the dose-optimization phase (Cohort 2). Dose-Optimization Phase Efficacy Update: As of the data cutoff, 2 pts (1 each cohort) remain on treatment. Efficacy data are summarized in Table 1. Of those pts that achieved a CR, 1 in each cohort proceeded to undergo stem cell transplant or consolidated radiation therapy with curative intent, and are censored in the DOR assessment . Dose-Expansion Phase Initial Summary: As of the data cutoff of 23 March 2020, a total of 25 pts have been dosed, 20 of whom underwent at least 1 disease response assessment (Table 1). Pts had a median age of 61 years (range, 21-86 years) and a median of 2 prior therapies (range, 1-6). Forty-five percent (9/20) of pts remain on treatment (5 responders, 3 with assessments not yet performed, 1 on treatment with stable disease);11 pts discontinued due to PD (n=7), adverse events (n=2) , or to under go transplant (n=2). Responses occurred in 8/20 pts: PTCL-NOS (4 CR, 1 partial response [PR]), ALCL (1 PR), AITL (1 CR) and SPTCL (1 CR). The most frequent adverse events seen were neutrophil count decreased (25%), ALT increased (21%), WBC decreased (21%) and lymphocyte count decreased (21%). In summary, the DUV data observed to date show consistent response rates in a R/R PTCL pt population. The safety profile observed in PRIMO to date is consistent with the current safety profile of DUV. The mature dose-optimization phase results demonstrated a median DOR of 12.2 months for the 75 mg BID cohort. The preliminary results from the PRIMO dose-expansion cohort (75 mg BID followed by 25 mg BID dosing) show an ORR of 40 % and CR rate of 30% (6/20) by INV assessment. These data support continued evaluation of DUV as a treatment option for R/R PTCL. Updated data from the planned interim analysis after 40 pts enroll (occurred June 2020) will be presented. Disclosures Pro: Verastem Oncology: Research Funding. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Jacobsen:Takeda: Honoraria; Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Acerta, AstraZeneca, Merck: Consultancy. Mehta-Shah:Corvus: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Bristol Myers-Squibb: Research Funding; Genetech/Roche: Research Funding; C4 Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy. Zain:Seattle Genetics: Research Funding; Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding. Zinzani:Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lustgarten:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Youssoufian:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Horwitz:Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; ASTEX: Consultancy; Affirmed: Consultancy. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least 2 prior systemic therapies, the latter based on accelerated approval. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Duvelisib is not approved for Peripheral T-Cell Lymphoma. This study is investigating treatment or outcomes that have not received approval from a Health Authority. The information presented is not intended to convey conclusions of safety or efficacy. There is no guarantee that the outcome of these studies will result in approval by a Health Authority.

Introduction Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) carries a poor prognosis, with most approved therapies having response rates of < 30% and limited progression-free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies. DUV exhibited potent activity against T-cell lymphoma cell lines in vitro, and DUV monotherapy at 25 or 75 mg BID demonstrated clinical activity in patients (pts) with R/R peripheral T-cell lymphoma (PTCL) in phase 1 studies [overall response rate (ORR), 50%] across multiple subtypes (Horwitz et al. Blood 2018; Horwitz et al. 2019 ICML). The phase 2 PRIMO trial was designed to determine an optimal regimen of DUV monotherapy in R/R PTCL and characterize the efficacy and tolerability of DUV in this disease. We report the results for the dose-optimization phase of the PRIMO trial (NCT03372057). Methods In the dose-optimization phase, pts with R/R PTCL, ECOG performance score of ≤ 2, and no history of allogeneic stem cell transplant were randomized to receive DUV 25 mg BID with an option for dose escalation (cohort 1) or DUV 75 mg BID (cohort 2) continuously until development of progressive disease or unacceptable toxicity (cycle = 28 days). The primary endpoint was investigator-assessed ORR, and secondary endpoints included duration of response and safety. Results A total of 33 pts (cohort 1, n = 20; cohort 2, n = 13) were treated in the dose-optimization phase (Table). Pts had a median of 1.5 years (range, 0.3-12.7 years) from initial diagnosis and a median of 2 prior therapies (range, 1-8). Patients were evaluable if they completed 1 cycle of DUV and had ≥ 1 efficacy assessment. Nonevaluable patients could be replaced. Response was assessed in the evaluable and overall populations. All patients in cohort 2 and 13 of 20 patients in cohort 1 were able to complete 1 cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Low CD4 counts (< 50 cells/mm3; Common Terminology Criteria for Adverse Events grade 4) were associated with early discontinuation of DUV. Most responses (cohort 1, 5/7; cohort 2, 6/7) were observed at the end of cycle 1. At a median follow-up of 20 weeks, the majority of responders (cohort 1, 4/7; cohort 2, 6/7) were still in response at the time of their last assessment. ORR as assessed by blinded independent central review could be determined for 31 patients and was 42% in cohort 1 and 67% in cohort 2. Table. Analysis Populations and Investigator-Assessed Response Pharmacokinetic analysis demonstrated a dose-related increase in exposure, with ≈ 2-fold increase in the steady-state exposure of DUV at the 75 vs 25 mg BID dosage, suggesting that adequate exposure can be more rapidly and reliably achieved with a higher dose of DUV. No differences were observed in pharmacodynamic markers (pAKT in monocytes and B cells) at 25 and 75 mg dose levels. The most common (≥ 3 patients) grade ≥ 3 adverse events (AEs) in all patients receiving DUV were neutropenia (7), thrombocytopenia (5), and sepsis (4), with disease progression, pneumonia, aspartate aminotransferase elevation, lymphopenia, dyspnea, and rash observed in 3 patients. Serious AEs occurring in ≥ 2 patients were colitis, pyrexia, disease progression, sepsis, pneumonia, hyponatremia, dyspnea, pneumonitis, and respiratory failure. Overall, 12% of pts receiving DUV discontinued due to an AE. Conclusions These findings confirm that both 25 and 75 mg BID starting dosages of DUV are clinically active in pts with R/R PTCL, with complete responses in both cohorts. There were no unexpected toxicities. Early progression was seen more frequently in the 25 mg cohort, and higher initial exposure may be important in aggressive diseases. The expansion phase of the PRIMO trial will investigate DUV starting at 75 mg BID for 2 cycles to achieve rapid tumor response, followed by 25 mg BID to maintain long-term disease control and mitigate the potential for later onset toxicity. Disclosures Horwitz: Miragen: Consultancy; Celgene: Consultancy, Research Funding; Aileron: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kura: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Jacobsen:Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding. Casulo:Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Haney:Verastem Inc: Employment, Equity Ownership. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Weaver:Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership; FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor. Baglio:Verastem Oncology: Employment. Narasimhan:Verastem: Employment, Equity Ownership. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Background: Myelofibrosis (MF) is a life-threatening disease characterized by splenomegaly, constitutional symptoms, and shortened survival. Although ruxolitinib, a JAK1/2 inhibitor, is approved for Intermediate or High-risk MF and can reduce the spleen size and improve quality of life, many patients discontinue due to loss of efficacy. In preclinical models, the activity of mutated JAK2 is tightly regulated by epichaperomes, a complex network of proteins which forms under cellular stress, such as cancer, and nucleates on heat shock protein 90 (Hsp90), which in turn assumes a specific conformation in its ATP binding domain. PU-H71 is a first-in-class inhibitor of tumor epichaperome-specific Hsp90, which potently kills cancer cells via disruption of the epichaperome and degradation of JAK2 as well as other client proteins. Prior dose-ranging studies of PU-H71 administered intravenously to patients with cancer identified a safe and tolerable dose. In this study, we assess an oral formulation of PU-H71 and evaluate the hypothesis that its cancer-specific mechanism combined with ruxolitinib may result in added clinical benefit as well as a wider therapeutic window. Methods: This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in patients with PMF, Post-PV MF, Post ET MF. Up to 24 patients who have active disease and receiving ≥3 months of ruxolitinib therapy (and on a stable dose for 8 weeks before starting therapy with PU-H71) will be enrolled. Evidence of persistent or worsening disease consisting of disease-related symptoms and splenomegaly of at least 5 cm below the costal margin as measured by physical examination are required. Additional inclusion criteria include a baseline platelet count of ≥50,000/mL and AST/ALT ≤2 x Upper Limit of Normal. Patients with a QT interval corrected using Fridericia's formula (QTcF) >480 ms (corrected) or left ventricular ejection fraction (LVEF) ≤50% are excluded. The study will employ a standard 3+3 dose escalation design beginning with 50 mg/day to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), with additional patients treated in a dose expansion cohort. Response to treatment will be assessed by the 2013 revised International Working Group-Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net. Additional assessments will include symptom burden assessment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow histology, JAK2V617F allele burden, serum cytokine profiles, flow cytometry of peripheral blood mononuclear cells for epichaperome status, and pharmacokinetic studies. Enrollment is ongoing. Clinical trial information: NCT03935555. Disclosures Pemmaraju: abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Gundabolu:Samus Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Jazz pharmaceuticals: Consultancy. Pettit:Samus Therapeutics: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; AI Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau. Eisenberg:Samus Therapeutics: Research Funding. Youssoufian:Samus Therapeutics: Consultancy. Duggan:Samus Therapeutics: Employment. Wallner:Samus Therapeutics: Employment. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Gilead: Research Funding; Protaganist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding.

Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Studies have previously described the feasibility of receptor-mediated protein transfer in a cell culture model of Fanconi anemia (FA) group C. This study explores the versatility of this approach by using an antibody single-chain fusion protein to correct the phenotypic defect in FA group F cells. A 68.5-kd chimeric protein (His-M195FANCF) was expressed, consisting of a His tag, a single-chain antibody to the myeloid antigen CD33, and the FANCF protein, as well as a 43-kd His-FANCF fusion protein lacking the antibody motif, inEscherichia coli. The nickel-agarose–purified His-M195FANCF protein bound specifically to the surface of HeLa cells transfected with CD33 and internalized through vesicular structures. The fusion protein, but not CD33, sorted to the nucleus, consistent with the known nuclear localization of FANCF. No similar binding or internalization was observed with His-FANCF. Pretreatment of the transfected cells with chloroquine abolished nuclear accumulation, but there was little change with brefeldin A, indicating a minimal if any role for the Golgi apparatus in mediating transport from endosomes to the cytosol and the nucleus. The intracellular half-life of His-M195FANCF was approximately 160 minutes. Treatment of CD33-transfected FA group F lymphoblastoid cells with 0.1 mg/mL His-M195FANCF conferred resistance to mitomycin C. No similar protection was noted in CD33− parental cells or CD33+ FA cells belonging to groups A and C. These results demonstrate that antibody-directed, receptor-mediated protein transfer is a versatile method for the delivery of biologically active proteins into hematopoietic cells.

The stimulation of regulated exocytosis in vascular endothelial cells (EC) by a variety of naturally occurring agonists contributes to the interrelated processes of inflammation, thrombosis, and fibrinolysis. The Weibel-Palade body (WPB) is a well-described secretory granule in EC that contains both von Willebrand factor (vWF) and P-selectin, but the mechanisms responsible for the targeting of these proteins into this organelle remain poorly understood. Through adenoviral transduction, we have expressed human growth hormone (GH) as a model of regulated secretory protein sorting in EC. Immunofluorescence microscopy of EC infected with GH-containing recombinant adenovirus (GHrAd) demonstrated a granular distribution of GH that colocalized with vWF. In contrast, EC infected with an rAd expressing the IgG1 heavy chain (IG), a constitutively secreted protein, did not demonstrate colocalization of IG and vWF. In response to phorbol ester, GH as well as endogenously synthesized vWF were rapidly released from GHrAd-infected EC. By immunofluorescence microscopy, granular colocalization of GH with endogenous tissue-type plasminogen activator (tPA) was also demonstrated, and most of the tPA colocalized with vWF. These data indicate that EC are capable of selectively targeting heterologous proteins, such as GH, to the regulated secretory pathway, which suggests that EC and neuroendocrine cells share common protein targeting recognition signals or receptors.

About 80% of all cases of Fanconi anemia (FA) can be accounted for by complementation groups A and C. To understand the relationship between these groups, we analyzed the expression pattern of the mouse FA group-A gene (Fanca) during embryogenesis and compared it with the known pattern of the group-C gene (Fancc). Northern analysis of RNA from mouse embryos at embryonic days 7, 11, 15, and 17 showed a predominant 4.5 kb band in all stages. By in situ hybridization, Fanca transcripts were found in the whisker follicles, teeth, brain, retina, kidney, liver, and limbs. There was also stage-specific variation in Fanca expression, particularly within the developing whiskers and the brain. Some tissues known to express Fancc (eg, gut) failed to show Fancaexpression. These observations show that (1) Fanca is under both tissue- and stage-specific regulation in several tissues; (2) the expression pattern of Fanca is consistent with the phenotype of the human disease; and (3) Fanca expression is not necessarily coupled to that of Fancc. The presence of distinct tissue targets for FA genes suggests that some of the variability in the clinical phenotype can be attributed to the complementation group assignment.

Current methods for direct gene transfer into hematopoietic cells are inefficient. Here we show that functional complementation of Fanconi anemia (FA) group C cells by protein replacement can be as efficacious as by transfection with wild-type FAC cDNA. We expressed a chimeric protein (called His-ILFAC) consisting of the mature coding portion of gibbon interleukin-3 (IL-3) and full-length FAC inEscherichia coli. The purified bacterial protein is internalized by hematopoietic cells via IL-3 receptors. The intracellular half-life of His-ILFAC is approximately 60 minutes, which is comparable to that of the transgene-encoded FAC protein. In this cell-culture model His-ILFAC completely corrects the sensitivity of FA group C cells to mitomycin C, but it has no effect on FA cells that belong to complementation groups A and B. We suggest that receptor-mediated endocytosis of cytokine-fusion proteins may be of general use to deliver macromolecules into hematopoietic progenitor cells.

The FAC protein encoded by the Fanconi anemia (FA) complementation group C gene is thought to function in the cytoplasm at a step before DNA repair. Because FA cells are susceptible to mitomycin C, we considered the possibility that FAC might interact with enzymes involved in the bioreductive activation of this drug. Here we report that FAC binds to NADPH cytochrome-P450 reductase (RED), a microsomal membrane protein involved in electron transfer, in both transfected COS-1 and normal murine liver cells. FAC-RED interaction requires the amino-terminal region of FAC and the cytosolic, membrane-proximal domain of the reductase. The latter contains a known binding site for flavin mononucleotide (FMN). Addition of FMN to cytosolic lysates disrupts FAC-reductase complexes, while flavin dinucleotide, which binds to a distinct carboxy-terminal domain, fails to alter FAC-RED complexes at concentrations similar to FMN. FAC is also functionally coupled to this enzyme as its expression in COS-1 cells suppresses the ability of RED to reduce cytochrome c in the presence of NADPH. We propose that FAC plays a fundamental role in vivo by attenuating the activity of RED, thereby regulating a major detoxification pathway in mammalian cells.© 1998 by The American Society of Hematology.

Fanconi anemia (FA) is an autosomal recessive disease characterized by chromosomal instability, bone marrow failure, and a high risk of developing malignancies. Although the disorder is genetically heterogeneous, all FA cells are defined by their sensitivity to the apoptosis-inducing effect of cross-linking agents, such as mitomycin C (MMC). The cloned FA disease genes, FAC and FAA, encode proteins with no homology to each other or to any known protein. We generated a highly specific antibody against FAA and found the protein in both the cytoplasm and nucleus of mammalian cells. By subcellular fractionation, FAA is also associated with intracellular membranes. To identify the subcellular compartment that is relevant for FAA activity, we appended nuclear export and nuclear localization signals to the carboxy terminus of FAA and enriched its localization in either the cytoplasm or the nucleus. Nuclear localization of FAA was both necessary and sufficient to correct MMC sensitivity in FA-A cells. In addition, we found no evidence for an interaction between FAA and FAC either in vivo or in vitro. Together with a previous finding that FAC is active in the cytoplasm but not in the nucleus, our results indicate that FAA and FAC function in separate subcellular compartments. Thus, FAA and FAC, if functionally linked, are more likely to be in a linear pathway rather than form a macromolecular complex to protect against cross-linker cytotoxicity.

The FAC protein encoded by the gene defective in Fanconi anemia (FA) complementation group C binds to at least three ubiquitous cytoplasmic proteins in vitro. We used here the complete coding sequence ofFAC in a yeast two-hybrid screen to identify interacting proteins. The molecular chaperone GRP94 was isolated twice from a B-lymphocyte cDNA library. Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic, but not nuclear, lysates of transfected COS-1 cells, as well as from mouse liver cytoplasmic extracts. Deletion mutants of FAC showed that residues 103-308 were required for interaction with GRP94, and a natural splicing mutation within the IVS-4 of FAC that removes residues 111-148 failed to bind GRP94. Ribozyme-mediated inactivation of GRP94 in the rat NRK cell line led to significantly reduced levels of immunoreactive FAC and concomitant hypersensitivity to mitomycin C, similar to the cellular phenotype of FA. Our results demonstrate that GRP94 interacts with FAC both in vitro and in vivo and regulates its intracellular level in a cell culture model. In addition, the pathogenicity of the IVS-4 splicing mutation in the FAC gene may be mediated in part by its inability to bind to GRP94.

Fanconi anemia (FA) is a genetically heterogeneous, inherited blood disorder characterized by bone marrow failure, congenital malformations, and a predisposition to leukemias. Because FA cells are hypersensitive to DNA cross-linking agents and have chromosomal instability, FA has been viewed as a disorder of DNA repair. However, the exact cellular defect in FA cells has not been identified. Sequence analysis of the gene defective in group C patients (FAC) has shown no significant homologies to other known genes. The FAC protein has been localized to the cytoplasm, indicating that FAC may either play an indirect role in DNA repair or is involved in a different cellular pathway. Recent evidence has indicated that FA cells may be predisposed to apoptosis, especially after treatment with DNA cross-linking agents. The demonstration that genes can suppress apoptosis has been accomplished by overexpression of such genes in growth factor-dependent cell lines that die by apoptosis after factor withdrawal. Using retroviral-mediated gene transfer, we present evidence that expression of FAC in the hematopoietic factor-dependent progenitor cell lines 32D and MO7e can suppress apoptosis induced by growth factor withdrawal. Flow cytometry and morphologic analysis of propidium iodide stained cells showed significantly lower levels of apoptosis in FAC-retroviral transduced cells after growth factor deprivation. Expression of FAC in both cell lines promoted increased viability rather than proliferation, which is consistent with other apoptosis-inhibiting genes such as Bcl-2. These findings imply that FAC may act as a mediator of an apoptotic pathway initiated by growth factor withdrawal. Furthermore, the congenital malformations and hematologic abnormalities characterizing FA may be related to an increased predisposition of FA progenitor cells to undergo apoptosis, particularly in the absence of extracellular signals.

Expression of the murine erythropoietin receptor (EpoR) gene was investigated in progenitor cell lines representing distinct stages of hematopoietic differentiation. In murine erythroid cell lines, the EpoR mRNA level was fivefold higher in the more mature murine erythroleukemia (MEL) cells than in CB-5 cells and very low in granulocyte/macrophage-like FDC-P1 cells. GATA-1 mRNA was present in equivalent levels in both erythroid cell lines, but at a low level in FDC-P1 cells. To account for the elevated levels of EpoR mRNA, the activity of the promoter and expression of DNase I hypersensitive sites were assessed as markers of transcriptional activity in various cell lines. Among a series of 5′ flanking restriction fragments linked to a reporter gene, a 83-bp fragment that includes binding sites for the transcription factors GATA-1 and Sp-1 gave low levels of erythroid- specific activity, and a 256-bp fragment that includes, in addition, two sites for the putative CACCC-binding protein gave the highest level of erythroid-specific transcription. DNase I footprinting showed binding of a constitutive factor to the proximal CACCC-binding site, and deletion or mutation of this site significantly reduced the overall expression while maintaining tissue-specificity. Three DNase I hypersensitive sites were detected in the 5′ flanking region of the EpoR gene, two of which were unique to MEL cells. These sites were situated over the promoter region and approximately 0.5 kb and 2.4 kb upstream of the transcriptional initiation sites. A 0.8-kb restriction fragment spanning the distal site caused approximately a four-fold rise in transcription from the endogenous or a heterologous promoter in MEL cells independent of its orientation and up to 1.5-fold rise in CB-5 cells, but it was inactive in COS-1 cells that were cotransfected with an expression plasmid encoding GATA-1. These results show that (1) basal activity as well as tissue specificity of the EpoR promoter can be accounted for by its interaction with GATA-1, and (2) upstream sites regulate the strength of the promoter. Expression of the distal DNase I hypersensitive site and the corresponding enhancer activity in MEL cells suggests a role for this element in stage-specific transcriptional control.

Background and Purpose: Although novel approaches to the treatment of acute myeloid leukemia (AML) are urgently needed, the heterogeneity of AML and the paucity of known actionable targets indicate that there is an important need for broadly active treatment approaches that are not limited to specific genetic subtypes. Selinexor, an oral selective inhibitor of nuclear export, inhibits XPO1 and causes differentiation and apoptosis of a variety of AML subtypes while sparing normal hematopoiesis. We therefore undertook a pilot study to determine the safety and to explore the efficacy of selinexor in combination with fludarabine and cytarabine in pediatric patients with relapsed leukemia. Patients and Methods: Twelve children and adolescents with relapsed or refractory AML (n=10) or mixed phenotype leukemia (n=2) have been enrolled on the study to date. Four patients previously received only chemotherapy, whereas eight had undergone at least one prior stem cell transplant. High-risk features included t(6;9), t(6;12), t(4;11), -7 (2 cases), and megakaryoblastic leukemia. Selinexor, initially at 30 mg/m2/dose, was given orally on days 1, 3, 8, 10, 22, and 24 and escalated according to a rolling-6 design. Fludarabine (30 mg/m2) and cytarabine (2 g/m2) were administered on days 15-19. Results: Among 11 patients who completed at least one cycle and were evaluable for toxicity and response, 3 were treated at dose level 1 (30 mg/m2), 3 at dose level 2 (40 mg/m2), 4 at dose level 3 (55 mg/m2), and 1 at dose level 4 (70 mg/m2). No dose-limiting toxicities were observed at any dose level. The most common Grade 3 non-hematologic toxicity related to selinexor was hyponatremia, which was observed in 10 patients and easily corrected in all cases. As expected, the combination of selinexor plus fludarabine and cytarabine resulted in Grade 3 neutropenia and thrombocytopenia in all patients. Mean pharmacokinetic parameters indicate that plasma exposure is generally dose proportional across selinexor doses, with no apparent accumulation. Plasma exposure in pediatric patients is similar to adult patients treated in phase I trials. Inhibition of XPO1 was assessed by qRT-PCR of XPO1, which is upregulated at the RNA level in response to XPO1 protein inactivation (PDn). Six of the first seven patients enrolled on the trial demonstrated at least 2-fold induction of XPO1 that persisted for at least 48 hours (see figure), indicating prolonged inhibition of the protein by selinexor. The overall response rate in this group of heavily pretreated, relapsed, and refractory patients was 55%. Five patients achieved complete remission (4 with complete count recovery) and 1 had a partial response. Eight of the 11 patients underwent subsequent stem cell transplantation. A trend toward stronger and persistent XPO1 inhibition (measured by PDn) was observed among patients who achieved CR compared to those who did not. Conclusion: Selinexor, given in combination with fludarabine and cytarabine, is tolerable in pediatric patients with relapsed leukemia. Selinexor pharmacokinetic parameters are generally dose proportional and are similar to those seen in adult patients. Most patients demonstrate XPO1 target inhibition. Response rates are encouraging and will be further explored in the Phase II portion of this trial. Figure 1. Figure 1. Disclosures Kaufman: Karyopharm Therapeutics Inc: Employment. Klebanov:Karyopharm Therapeutics Inc: Employment. Ellis:Karyopharm Therapeutics Inc: Employment. Landesman:Karyopharm Therapeutics: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Rashal:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm: Employment, Equity Ownership.

Background There is an increasing number of multiple myeloma patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and Carfilzomib (CFZ), necessitating development of novel effective therapeutics. Pre-clinical evaluation of selinexor, a novel orally available selective inhibitor of nuclear export (SINE), in human myeloma cell lines (HMCL), primary plasma cells derived from myeloma patients, and HMCL tumor-bearing mice demonstrated synergistic myeloma cell death with CFZ (Rosebeck et al. ASH 2013) and the ability to overcome resistance to CFZ (Rosebeck et al. ASH 2014). Aims The primary objective is to assess the maximum tolerated dose (MTD) of selinexor and CFZ in combination with DEX in RRMM pts and to provide preliminary evaluation of efficacy of this novel triplet regimen. Methods Pts with RRMM, including CFZ-refractory pts, who have failed at least two prior treatment regimens of myeloma therapy, were eligible for enrollment. Dose escalation follows the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 selinexor PO on days 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ given IV on days 1, 2, 8, 9, 15, 16, and DEX PO 20/10mg (cycles 1-4/cycles 5+) in 28-day cycles. At least 12 and up to 48 pts are planned for evaluation. Dose Limiting Toxicities (DLT) are measured for the Cycle 1 as well as Day 1 of Cycle 2. Dose modifications are allowed to manage toxicities. Response was assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2015 the study has enrolled 8 pts, 5 pts were treated at dose level 1 (30 mg/m2 selinexor, 20/27 mg/m2 CFZ, 20/10 mg DEX) and 3 patients were treated at dose level 2a (30 mg/m2 selinexor, 20/36 mg/m2 CFZ, 20/10 mg DEX). Pts had median age of 65.5 (range 55-73) and a median of 5 prior treatment regimens (range 2-5). Six pts were refractory to CFZ combinations at their last line of therapy, including 4 to CFZ, pomalidomide (POM), and DEX. Of the 2 remaining pts, 1 was refractory to high dose CFZ with DEX in prior line of therapy and both were refractory to last line of therapy. Six pts were DLT-evaluable and two pts required replacement for DLT evaluation (1 pt had DEX reduced in cycle 1 not due to DLT; 1 pt did not receive all scheduled cycle 1 doses due to progressive disease). There have been no DLTs and MTD is not yet established. Adverse events (AEs) were reversible and managed with concomitant therapy. G3/4 hematologic AEs include thrombocytopenia (75%), neutropenia (50%), leukopenia (37.5%), lymphopenia (25%), and anemia (25%). The most common G3/4 non-hematologic AEs included fatigue (25%) and upper respiratory tract infection (25%). The most common G1/2 AEs are fatigue (75%), dyspnea (62.5%), nausea (62.5%), anemia (50%), leukopenia (50%), and thrombocytopenia (50%). Response rates for all enrolled pts are 87.5% ≥MR, 75% ≥PR, 12.5% ≥VGPR. Responses occurred rapidly; after 1 cycle: 75% ≥MR, 63% ≥PR, 12.5% VGPR. As of the cut off date, 4 pts have progressed (after 1, 2, 4, and 4 months) and 4 pts remain on treatment (10+, 1+, 1+, and 1+ months); 1 pt did not respond and died due to progression of disease. Conclusions Although still very early, the combination of selinexor, CFZ, and DEX demonstrates encouraging activity with 75% PR or better and no unexpected toxicities in highly refractory MM pts, including those previously refractory to CFZ. Responses in pts refractory to very active CFZ combinations in the last line of therapy suggest that this regimen has the ability to overcome CFZ resistance. Disclosures Jakubowiak: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: The combination of Carfilzomib and Selinexor is being used for the treatment of Multiple Myeloma. Rosenbaum:Celgene: Speakers Bureau. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Rashal:Karyopharm Therapeutics Inc: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Henry:Karyopharm: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership.