Tx-emergent Adverse Events Research Articles

CARTITUDE-2: Efficacy and Safety of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy, in Patients with Multiple Myeloma and Early Relapse after Initial Therapy

CARTITUDE-2: Efficacy and Safety of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy, in Patients with Multiple Myeloma and Early Relapse after Initial Therapy

Matching Adjusted Indirect Comparison (MAIC) of Oral Azacitidine (Oral-AZA) Versus Injectable AZA in Patients (pts) with Acute Myeloid Leukemia (AML) in First Remission after Intensive Induction Chemotherapy

INTRODUCTION: Oral-AZA was approved in the United States in September 2020 for continued treatment (Tx) of adult patients (pts) with AML in first remission after intensive chemotherapy (IC). The phase 3 QUAZAR AML-001 trial showed that Oral-AZA significantly improved overall and relapse-free survival (OS/RFS) vs placebo (PBO) and was generally well-tolerated (Wei, NEJM 2020). In the phase 3 HOVON97 trial, subcutaneous (SC) AZA maintenance Tx significantly improved disease-free survival vs observation, but did not show an OS benefit (Huls, Blood 2019). Although Oral-AZA and SC AZA contain the same active drug, they are not bioequivalent. Oral administration allows extended exposure to lower drug concentrations, which could increase the number of diseased progenitor cells exposed to AZA and maximize therapeutic effects (eg, drug incorporation into RNA leading to apoptosis), and may improve tolerability by decreasing AZA-related exacerbations of existing cytopenias.In the absence of head-to-head trials, a matching adjusted indirect comparison (MAIC), which adjusts for potential Tx effect modifiers, was previously conducted to evaluate the relative OS benefit with Oral-AZA vs SC AZA (Chen, EHA 2021). This MAIC was performed to determine the relative safety profile and health care resource utilization (HCRU) with Oral-AZA vs SC AZA maintenance therapy in pts with AML in first remission after IC.METHODS: Anchored MAIC analyses of serious Tx-emergent adverse events (SAEs) and HCRU were performed using individual pt data (IPD) from QUAZAR AML-001 to match to baseline (BL) summary statistics from HOVON97. IPD from QUAZAR AML-001 were removed when a pt did not meet HOVON97 eligibility criteria. Remaining QUAZAR AML-001 pt data were weighted using a method-of-moments propensity score model. Matched and adjusted variables were BL age, platelet count, neutrophil count, ECOG performance score, cytogenetic risk, and response status. Analysis endpoints were times to first SAE, hospitalization, and platelet or red blood cell (RBC) transfusion. In HOVON97, pts could receive SC AZA for up to 12 cycles; therefore, QUAZAR AML-001 outcomes were limited to the first 12 cycles of Tx. Hospitalizations for SC AZA administration only in HOVON97 were excluded from analyses.Endpoints are adjusted for pt-years of drug exposure and compared between studies by calculating relative risks (RR). Exposure to SC AZA in HOVON97 was imputed based on the number of pts entering each Tx cycle, and relies on the assumption that events/censoring happened at the end of the cycle and led to Tx discontinuation. Sensitivity analyses of model robustness relaxed these assumptions, comparing only the difference in cumulative hazard vs PBO/observation using a cloglog link binomial model.RESULTS: IPD for 398/469 pts (85%) in the QUAZAR AML-001 safety population (Oral-AZA n=203, PBO n=195) met the eligibility criteria of the HOVON97 population and were adjusted to the comparator. For all endpoints, rate ratios for Oral-AZA vs PBO were less than those for SC AZA vs observation (Table). MAIC-weighted safety comparisons showed the risk of SAEs was reduced by 65% for patients treated with Oral-AZA vs SC AZA (RR 0.35 [95% CI: 0.18-0.68]). Similarly, the risks of hospitalization requirements, platelet transfusion, and RBC transfusion were reduced with Oral-AZA vs SC AZA by 59% (RR 0.41 [95% CI: 0.24-0.71), 54% (RR 0.46 [0.23-0.93]), and 47% (RR 0.53 [0.28-1.00]), respectively. All findings were robust to the sensitivity analyses relaxing assumptions of imputed Tx exposure in HOVON97, which showed pts treated with Oral-AZA are 70% less likely to experience SAEs than pts treated with SC AZA (hazard ratio: 0.30 [95% CI: 0.09-1.02]), and hazard reductions for hospitalization and transfusions ranged from -51% to -58% (Table).CONCLUSIONS: These data suggest that in controlled clinical trials with pts in first remission after IC, Oral-AZA maintenance therapy not only significantly improves OS, but also provides a better safety profile and requires less HCRU than SC AZA maintenance therapy. Interpretation of results should be limited to the differences in the rate to first SAE while on Tx, as stronger generalizations are limited by competing risks and informative censoring. [Display omitted] DisclosuresChen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Huls: Universaity Medical Center Groningen: Current Employment. Cameron: Bristol Myers Squibb: Consultancy. Suero: Bristol Myers Squibb: Consultancy. Vasconcelos: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gaugler: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF): Updated Results from the Randomized, Placebo-Controlled, Phase III JAKARTA Trial

Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF): Updated Results from the Randomized, Placebo-Controlled, Phase III JAKARTA Trial

Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax.

8006 Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS <2, ANC >1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all <0.02%); 3 pending. The most common tx emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (39%), and diarrhea (39%). Grade ≥3 AEs in ≥5% pts were neutropenia (13%), thrombocytopenia (5%), rash (5%), and pneumonia (5%). Of 17 pts at high risk for TLS on C1D1, 2 cycles of BO reduced TLS risk to low/medium at Ven initiation in 15 (88%). No pts had laboratory/clinical TLS (Howard). Conclusions: BOVen is well tolerated and achieves rapid uMRD: currently 68% PB uMRD and 51% BM uMRD with limited follow up (to be updated on presentation). Ten (27%) have discontinued treatment thus far. The value of MRD directed treatment duration will be evaluated with continued follow up. Clinical trial information: NCT03824483 .

201P - Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial

Abstract Background Asymptomatic nmCRPC patients (pts) would benefit from treatments (Tx) that delay disease progression and maintain quality of life (QoL), with minimal Tx-related adverse events (AEs). In ARAMIS, darolutamide (DARO) prolonged metastasis-free survival vs placebo (PBO) (40 vs 18 months; HR 0.41; 95% CI 0.34–0.50; P Methods Pts were randomized to DARO 600 mg twice daily (n = 955) or PBO (n = 554), while androgen deprivation therapy continued in both arms. Secondary/exploratory endpoints included safety, time to cytotoxic chemotherapy, time to antineoplastic therapy, time to PSA progression, and QoL. Results DARO substantially delayed times to PSA progression (33 vs 7 months; HR 0.13; 95% CI 0.11–0.16; P 10% of pts. Discontinuation rates due to AEs were 8.9% with DARO and 8.7% with PBO. AEs noted with other androgen receptor inhibitors (including fracture, falls, seizures, hypertension and cognitive disorder) showed minimal or no difference in incidence between groups. DARO maintained QoL, and delayed the onset of pain and disease-related urinary symptoms compared with PBO. Conclusions DARO delays disease progression and subsequent Tx for metastatic castration-resistant prostate cancer vs PBO, maintaining QoL without increasing incidence of key AEs. Clinical trial identification NCT02200614. Editorial acknowledgement Medical writing support for the development of this abstract was provided by Lucy Smithers, PhD, and editorial support, including formatting, proofreading, and submission was provided by Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the study Orion Corporation, Orion Pharma and Bayer AG. Funding Orion Corporation and Bayer AG. Disclosure J.S-T. Pang: Non-remunerated activity/ies, Writing support: Bayer. N. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Myovant Sciences; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nymox. M.R. Smith: Honoraria (self): Amgen; Honoraria (self): Astellas; Honoraria (self): Bayer; Honoraria (self): Clovis; Honoraria (self): Gilead; Honoraria (self): Janssen; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer. T.L. Tammela: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (self): Lidds AB; Advisory / Consultancy, Research grant / Funding (self): Astellas. E. Vjaters: Research grant / Funding (self): Ipsen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Orion. M. Jievaltas: Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Janssen. M. Luz: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Research grant / Funding (self): Janssen; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Ferring; Speaker Bureau / Expert testimony: Sanofi. B. Alekseev: Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Astellas; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Ferring; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: MSD; Honoraria (self), Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi. I. Kuss: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M-A. Le Berre: Full / Part-time employment: Bayer Healthcare. A. Snapir: Full / Part-time employment: Orion Pharma. T. Sarapohja: Full / Part-time employment: Orion Corporation. K. Fizazi: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self): Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Curevac; Advisory / Consultancy: ESSA; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Roche/Genentech. All other authors have declared no conflicts of interest.

Age-related efficacy and safety of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in subgroups of patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Post hoc analysis of SPARTAN.

5024 Background: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC and PSA doubling time ≤ 10 mo, showed that, compared with PBO, addition of APA to ongoing ADT treatment (tx) prolonged metastasis-free survival (MFS) by > 2 y, reduced the risk of symptomatic progression by 55%, and increased second progression-free survival (PFS2), which is the time from randomization to disease progression on first subsequent anticancer tx, or death. The impact of APA in terms of benefit and safety profile was evaluated in pts aged < 65, 65-74, and ≥ 75 y. Methods: Pts with nmCRPC were randomized 2:1 to APA (240 mg QD) or PBO; ADT was continuous. APA effect was analyzed by Cox models and Kaplan-Meier methods across age subgroups. Results: Baseline characteristics among age groups were similar, although ECOG PS 1 vs 0 increased with age. MFS benefit with APA was highly significant for all age subgroups (Table). In pts ≥ 75 y, MFS risk with APA vs PBO was reduced by 59%; MFS risk was reduced by 86% and 76% for pts < 65 and 65-74 y, respectively. Risk of PFS2 with APA vs PBO was reduced across all age subgroups. PFS2 in pts < 65, 65-74, and ≥ 75 y: HR, 0.09 (p < 0.0001); HR, 0.56 (p = 0.0343); HR, 0.59 (p = 0.0092), respectively. Risk of symptomatic progression was lessened with APA vs PBO for all age subgroups (Table). There was a similar increase in incidence of tx-emergent adverse events (TEAE) with age in both tx arms that remained higher with APA. Incidence of grade 3/4 TEAE (≥ 75 vs < 65 y): APA, 50% vs 37%; PBO, 37% vs 28%. Conclusions: Pts in all age subgroups with high-risk nmCRPC had significant improvement in MFS with APA + ongoing ADT. The safety profile of APA was similar across age subgroups. Clinical trial information: NCT01946204. [Table: see text]

First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors.

3004 Background: ABBV-085 is an ADC (conjugated to monomethyl auristatin E, drug:antibody ratio of 2:1) directed against leucine-rich repeat containing 15 (LRRC15), a type 1 transmembrane protein highly expressed on the surface of sarcomas and cancer-associated fibroblasts in stroma of many other cancers. ABBV-085 induced antitumor activity in both in vitro and xenograft models of sarcoma. This phase 1, first-in-human, 2-part study assessed the safety/tolerability of ABBV-085 in patients (pts) with advanced solid tumors (NCT02565758). Methods: Eligible pts (≥18 yr; advanced solid tumors) received ABBV-085 intravenously in a 3+3 dose-escalation (DE) design; 0.3- to 4.8-mg/kg doses every 2 wk (8 cohorts). Pharmacokinetics (PK) were assessed in cycle 1 and cycle 3. Results: As of Dec 2018, 78 pts were enrolled in monotherapy DE and dose-expansion (EXP) cohorts (≤2.7 mg/kg, n = 21; 3.6 mg/kg, n = 45; 4.2 mg/kg, n = 6; 4.8 mg/kg, n = 6); median age: 58 yr (range 21–84); median treatment (Tx) duration: 6.2 wk (range 0.3–54.4). Overall, 77 (98.7%) pts reported ≥1 Tx-emergent adverse events (TEAEs). Fatigue (48.7%) was most common; 19 (24.4%) pts reported grade 1/2 blurred vision (reversible on study discontinuation). Grade ≥3 TEAEs were reported in 56 (71.8%) pts; anemia (14.1%) was the most common. Dose-limiting toxicities occurred at 3.6 mg/kg (n = 1; anemia), 4.2 mg/kg (n = 1; hypertriglyceridemia), and 4.8 mg/kg (n = 2; ileus and nausea); 3.6 mg/kg was chosen as the recommended phase 1b dose (RP1bD). PK exhibited dose-proportional increase in the area under the curve after single-dose administration; half-life was 2.84 days at the RP1bD. Of the 27 sarcoma pts (DE [n = 8]/EXP [n = 19] cohorts; undifferentiated pleomorphic sarcoma [n = 10], osteosarcoma [n = 10], and other sarcomas [n = 7]) treated at the RP1bD, 4 (14.8%) had confirmed partial response (PR; 2 [7.4%] unconfirmed), 8 (29.6%) had stable disease, 11 (40.7%) had progressive disease; 2 (7.4%) were not evaluable. The median duration of response (confirmed responders) was 7.6 mo (95% CI: 5.6–9.2). Updated safety and efficacy data will be reported. Conclusions: ABBV-085 was well tolerated with durable PR observed in pts with advanced sarcomas. Clinical trial information: NCT02565758.

Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07).

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.

Efficacy and Safety of Azacitidine (AZA) Versus Conventional Care Regimens (CCR) in Patients Aged ≥75 Years with Acute Myeloid Leukemia (AML) in the Phase 3 AZA-AML-001 Study

Efficacy and Safety of Azacitidine (AZA) Versus Conventional Care Regimens (CCR) in Patients Aged ≥75 Years with Acute Myeloid Leukemia (AML) in the Phase 3 AZA-AML-001 Study

Radium-223 (Ra-223) re-treatment (Re-tx): First experience from an international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC).

197 Background: Ra-223 tx for up to 6 injections (inj) is indicated for pts with symptomatic bone metastases. Ra-223 tx beyond 6 inj has not been previously reported. Herein we report the first safety and efficacy findings of Ra-223 re-tx from an international prospective trial in mCRPC pts. Methods: Pts with CRPC with ≥ 2 bone mets who completed 6 initial Ra-223 inj with no disease progression in bone and progressed after initial tx were potentially eligible for Ra-223 re-tx, provided that hematologic (heme) parameters were adequate. No concomitant cytotoxic agents were allowed; other agents were allowed at investigator discretion. Primary objective was safety. Exploratory objectives were time to radiographic bone progression, time to ALP progression, and radiographic progression-free survival (rPFS) based on MRI/CT and bone scans performed q 3 mo. Results: 44 pts had Ra-223 re-tx, 29 (66%) completed tx with all 6 inj; median (med) number inj = 6. Med time from initial Ra-223 tx = 6 mo. Besides prior Ra-223, all pts had ≥ 2 hormonal regimens; 45% had ≥ 1 chemotherapy regimen. 32 (73%) failed novel hormonal agents, eg, abiraterone and enzalutamide. Baseline characteristics were comparable to ALSYMPCA (Table). No new safety concerns were noted; incidence of tx-emergent adverse events (TEAEs) in re-tx pts was comparable to or lower than ALSYMPCA (Table). Only 2 re-tx pts had grade 3 heme TEAEs. Only 1 pt had radiographic bone progression; med time to ALP progression was not reached. Med rPFS = 9.9 mo. Conclusions: Ra-223 re-tx was well tolerated in this highly selected population, with minimal heme toxicity, and provided continued control of disease progression in bone. Clinical trial information: NCT01934790. [Table: see text] [Table: see text]

The Safety and Tolerability of Azacitidine (AZA) Are Comparable in Patients with Acute Myeloid Leukemia (AML) or Higher-Risk Myelodysplastic Syndromes (MDS)

The Safety and Tolerability of Azacitidine (AZA) Are Comparable in Patients with Acute Myeloid Leukemia (AML) or Higher-Risk Myelodysplastic Syndromes (MDS)

CC-486 (Oral Azacitidine) Monotherapy in Patients with Acute Myeloid Leukemia (AML)

Background: When administered subcutaneously (SC), the epigenetic modifier, azacitidine (AZA) is shown to improve overall survival in patients (pts) with AML compared with conventional care regimens (Fenaux, JCO, 2010; Dombret, Blood, 2015). CC-486, the oral formulation of AZA, is in clinical development for use in hematologic malignancies. An early dose-finding study of CC-486 administered on a 7-day schedule showed it to be safe and clinically active in pts with AML (Garcia-Manero, JCO, 2011; Gore, Blood, 2011). Extending CC-486 dosing for more than 7 days may increase AZA exposure to leukemic cells over the treatment (Tx) cycle to improve response.Objective: Evaluate the safety and efficacy of CC-486 administered in extended dosing schedules (14 days or 21 days per 28-day cycle) in pts with AML.Methods: Pts with AML from two phase I/II studies were sequentially assigned to receive CC-486 in 1 of 4 extended dosing regimens: 300mg QD x14 days (d)/28d (14-QD), 300mg QD x21d/28d (21-QD), 200mg BID x14d/28d (14-BID), or 200mg BID x21d/28d (21-BID). Hematologic responses (complete remission [CR], partial remission [PR], CR with incomplete hematologic recovery [CRi], marrow CR [mCR]), were assessed using IWG criteria for AML (Cheson, J Clin Oncol, 2003), and hematologic improvement (HI) and transfusion independence (TI) were assessed using IWG criteria for MDS (Cheson, Blood, 2006). Tx-emergent adverse events (TEAEs) were graded by NCI-CTCAE v3.1 or v4.0.Results: In all, 23 pts with AML participated in the studies: 14-QD n=4, 21-QD n=12, 14-BID n=4, 21-BID n=3. Median age was 68 years (range 44 - 93), 48% were male, 22% and 78% had ECOG performance status scores of 0-1 or 2, respectively, median % bone marrow blasts was 25%, and median baseline hematology counts were: Hgb 9.1 g/dL (7.4 - 11.7), platelets 33 x 109/L (3 - 435), and ANC 0.3 x 109/L (0 - 6.4). Median time from diagnosis was 1.1 month (range -0.2 - 82.1). Eleven pts (52%) had prior MDS and 13 pts (57%) had received prior Tx for MDS (n=5) or AML (n=8), including 5 pts (38%) who had received hypomethylating agents (HMAs). The median number of CC-486 Tx cycles for all pts was 4 (1 - 9) (Figure). Overall response (CR, PR, CRi, mCR, HI or TI) rate was 48% (11/23), with generally comparable responses and response rates across the 4 dosing regimens (Table 1). Responses were observed in 4 pts (50%) who were relapsed/refractory to prior AML Tx. Two pts (40%) who had received prior HMA Tx responded, 1 of whom attained CR. HI was achieved by 32% (7/22) of pts, and 20% (3/15) of RBC transfusion-dependent pts attained RBC TI. Six pts with prior MDS (55%) responded during Tx. One pt proceeded to transplant. Febrile neutropenia (30%) and anemia (22%) were the most common grade 3-4 TEAEs (Table 2). Incidences of grade 3-4 TEAEs were generally similar across the 4 CC-486 dosing regimens.Conclusions: CC-486 administered in extended 14- or 21-day per cycle schedules was well tolerated. One-half of these older pts with AML had a hematologic response, including pts who had prior MDS, or AML that failed or lost response to prior Tx. Interestingly, pts who previously received injectable HMA Tx had hematologic responses (including CR) with CC-486, likely due to the alternative methylation pattern obtained with prolonged oral administration (Laille, Plos One, in press). Ease of administration of CC-486 can facilitate long-term Tx for sustained disease modification, provide an additional option for failure of IV/SQ HMA therapy, and may improve outcomes in combination Tx regimens, which warrant investigation. [Display omitted] [Display omitted] [Display omitted] DisclosuresSavona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Kolibaba:Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Cell therapeutics: Research Funding; GSK: Research Funding; Novartis: Research Funding; Genentech, Inc.: Research Funding; Seattle Genetics: Research Funding. Ukrainskyj:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Hetzer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership.

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

CC-486 in Patients with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML): Safety, Tolerability, and Response

Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent ( Disclosures Savona:Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.

Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

521P - Interim Safety Results from Steam: a Randomized Phase 2 Trial of Sequential and Concurrent Folfoxiri–Bevacizumab (Bev) Vs Folfox–Bev for the First-Line (1L) Treatment (Tx) of Patients (Pts) with Metastatic Colorectal Cancer (Mcrc)

ABSTRACT Aim: Recent randomized trials of FOLFOXIRI–BEV in mCRC showed improved progression-free survival (PFS) and overall response rates (ORR) vs either FOLFIRI–BEV or FOLFOX–BEV. The efficacy and safety of FOLFOXIRI–BEV have yet to be investigated in the US. Methods: STEAM (NCT01765582) is a randomized, open-label, US-based, phase 2 trial. Pts are randomized 1:1:1 to FOLFOXIRI–BEV (arm A), sequential FOLFOXIRI–BEV (FOLFOX or FOLFIRI every 2 weeks [q2w] alternating every 2 cycles; arm B), and FOLFOX–BEV (arm C) q2w in previously untreated mCRC (BEV 5 mg/kg in each arm). After a 4- to 6-mo induction phase, pts receive 5-fluorouracil (5-FU)/leucovorin + BEV (5 mg/kg) q2w or capecitabine + BEV (7.5 mg/kg) q3w as maintenance tx until disease progression (PD). Pts receive second-line (2L) 5-FU–based chemotherapy (physician's choice) + BEV (2.5 mg/kg/qw) until 2L PD. Primary objectives are to evaluate 1L ORR (arm A vs arm C), 1L PFS (arms A + B vs arm C), and safety. Adverse events (AEs) were analyzed per a preplanned interim analysis. Results: At data cutoff (12/3/13), 94/280 pts were randomized, and 93 pts had received ≥1 dose of study tx. Pt characteristics were similar across tx arms. The overall AE profile was generally balanced across tx arms; more grade (gr) ≥3 AEs occurred in arm A than in arms B or C (Table). Five (15%) gr 4 neutropenia AEs occurred in arm A; all pts recovered within a week after temporary dose reduction and/or receiving growth factors, and they continued study tx per protocol. One pt in arm A died from unknown reasons; 2 pts died in arm B from PD. Conclusions: The overall AE profile of FOLFOXIRI–BEV in the STEAM trial is similar to previous trials of FOLFOXIRI–BEV. Rates of tx-emergent AEs in the sequential FOLFOXIRI–BEV arm appear similar to the FOLFOX–BEV arm. The trial is continuing with no changes in dosing or design. Adverse Event Category, n (%) Arm A (FOLFOXIRI–BEV) n = 33 Arm B (Sequential FOLFOXIRI–BEV) n = 30 Arm C (FOLFOX–BEV) n = 30 Any TEAE 32 (97) 30 (100) 29 (97) Any gr ≥3 TEAE 26 (79) 15 (50.0) 16 (53) Any gr 4 TEAE Neutropenia Diarrhea CO2 embolism during surgical procedure 6 (18) 5 (15) 1 (3) – ––– – 1 (3)–– 1 (3) Deaths 1 (3) 2 (7) – Any serious TEAE 10 (30) 6 (20.0) 8 (27) Any TEAE of special interest to BEV Bleeding/hemorrhage Hypertension Venous thromboembolic events Proteinuria Wound-healing complications Arterial thromboembolic events Gastrointestinal perforation Congestive heart failure Fistula/abscess Posterior reversible encephalopathy syndrome 15 (45) 8 (24) 6 (18) 1 (3) 2 (6) 2 (6)–1 (3)–– – 15 (50) 10 (33) 6 (20) 4 (13)–––––– – 12 (40) 6 (20) 3 (10) 3 (10) 3 (10) 2 (7) 1 (3)–––– Any gr ≥3 AESI to BEV 6 (18) 4 (13) 6 (20) Any TEAE to dose reduction, tx interruption, or tx discontinuation 26 (79) 12 (40) 18 (60) Any TEAE leading to withdrawal from study tx 8 (24) 1 (3) 4 (13) Any TEAE leading to premature study discontinuation 2 (6) – 1 (3) BEV, bevacizumab; CO2, carbon dioxide; gr, grade; TEAE, treatment-emergent adverse event; tx, treatment Disclosure: H. Hurwitz: Research support and compensated consultant: Genentech, Inc., F. Hoffmann-La Roche, Ltd., Pfizer, Sanofi, Regeneron, Bristo-Meyers Squibb, Eli Lilly, Merck KGA, Novartis, Incite, Threshold Also compensated consultant for GSK; B. Tan: Corporate-sponsored research: Genentech; H. Lenz: Advisory board: Genentech and Roche ad boards Corporate-sponsored research: Clinical trial support, Support through SWOG: Genentech; H. Hochster: Advisory board: Genentech; R. Laeufle: Stock ownership: Roche Other substantive relationships: Genentech employee; N. Sommer: Stock ownership: Roche Other substantive relationships: Genentech employee; J. Young: Stock ownership: Genentech, standard S-SARs Other substantive relationships: Employee, Genentech; M. Byrtek: Stock ownership: Roche Other substantive relationship: Employment at Genentech, a member of the Roche Group; All other authors have declared no conflicts of interest.

Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).

8519 Background: PoV and PiV, antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in Phase I. The current study aims to compare PoV and PiV + RTX in R/R DLBCL and R/R follicular lymphoma (FL). Methods: Pts were randomized to receive PoV or PiV + RTX (ADC 2.4 mg/kg + RTX 375 mg/m2) every 21 days. Tumor assessments were performed every 3 months. Results: As of 8 November 2013, 58 received PoV + RTX (38 DLBCL; 20 FL), 63 PiV + RTX (42 DLBCL; 21 FL). Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced between treatment arms; 46% were RTX refractory. Median treatment (tx) cycles in DLBCL: 5 for both ADC (1-15); FL: 8.5 PoV (3-15) and 6 PiV (1-13). Overall safety profiles of both regimens were similar. Tx-emergent adverse events (AE) >25%: fatigue (52%), diarrhea (42%), nausea (37%), peripheral neuropathy (PN) (32%), constipation (26%). Grade ≥ 3 AE >3%: neutropenia (21%), diarrhea (6%), dyspnea (4%), febrile neutropenia ...

Decreased NSAID Associated Treatment Emergent Dyspepsia and Increased Patient Satisfaction Associated with Ibuprofen/Famotidine Combination Tablet: SODA Results from a 12-Month Trial

Purpose: Dyspeptic symptoms often lead to the use of co-prescribed acid suppressive agents or discontinuation of NSAID use. Adherence with coprescribed GI protective therapies is often suboptimal and associated with reduced functional efficacy. Double-dose H2 receptor antagonists provide benefit in decreasing NSAID-associated upper GI injury. A single combination tablet of ibuprofen (IBU; 800 mg) and famotidine (FAM; 26.6 mg) tid; total daily dose of 2400 mg IBU and 80 mg FAM (DUEXIS®), was shown previously to significantly reduce endoscopic upper GI ulcers at 6 months as compared to IBU (800 mg) alone tid (REDUCE-1 and REDUCE-2). Here we report SODA (Severity of Dyspepsia Assessment) questionnaire results from a 12-month open label study. Methods: This was an open-label long-term safety study of IBU/FAM single tablet tid for up to 12 months (mos) of treatment (tx) in patients (pts) 40-80 years (yrs) with OA, RA or moderate pain expected to require daily NSAID therapy for ≥12 mos. Pts were to have no history of NSAID GI complications, active cardiac, renal and/or hepatic disease. Pts were allowed to continue on concomitant low-dose aspirin/anticoagulant (LDA/OAC) therapy. Serious adverse events (SAEs), and tx emergent adverse events (TEAEs) were collected. SODA was administered at baseline and every six weeks to assess tolerability. Results: 86 pts enrolled and 56 pts (65.1%) completed one year of tx. 30 pts (34.9%) discontinued early with the highest incidence due to adverse events (dyspepsia/GERD) in 18/86 pts (20.9%). Independent of discontinuations, the most frequently reported TEAEs by preferred term were dyspepsia and abdominal distention (11.6% each). Of the 25 patients who reported dyspepsia related events, approximately half (12/25) reported them within the first 8 weeks of the 54 week trial. At both 24 and 54 weeks, all mean SODA subscale scores improved and the changes from baseline were statistically significant (see Table).Table: Table. SODA subscale mean change from baseline scoresConclusion: Safety results up to 54 weeks with the IBU/FAM combination tablet were consistent with the known safety profiles of famotidine and ibuprofen and US labeling. IBU/FAM as compared to historical data with NSAIDS alone was associated with lower rates of dyspepsia related symptoms. SODA subscale scores improved over time from baseline. In conjunction with the previous findings of a significant decrease in upper GI endoscopic ulcers, these results demonstrate that IBU/FAM combination tablet offers a potential new option for patients who require long-term NSAIDs. Disclosure: Dr. Goldstein - Grant/Research Support: Pozen Inc, Logical Therapeutics, and Pfizer. Honoraria: Pozen, Inc., Boehringer-Ingelheim, and Astra-Zeneca Pharmaceuticals. Consultant/Advisory Board: Pozen, Inc, AstraZeneca Pharmaceuticals, and Horizon Pharma USA, Inc. Dr. Lakhanpal - Consultant: Horizon Pharma USA, Inc Dr. Cohen - Consultant: Horizon Pharma USA, Inc. Dr. Bello - Consultant: Horizon Pharma USA, Inc. Ms. Ball - Employee: Horizon Pharma USA, Inc. Ms. Grahn - Employee: Horizon Pharma USA, Inc. Dr. Kivitz - Consultant: Horizon Pharma USA, Inc. This research was supported by an industry grant from Horizon Pharma USA, Inc.