Sequential Dose-escalation Study Research Articles

Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors

BackgroundCheckpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with...

623. Preliminary Dosing for Adolescent Hematopoietic Stem-Cell Transplant (HSCT) Recipients Based on Pharmacokinetic (PK), Safety, and Efficacy Data of Letermovir (LET) for Cytomegalovirus (CMV) Prophylaxis

Abstract Background LET is a CMV terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic HSCT recipients. Objectives of this ongoing study are to evaluate PK, safety, and efficacy of LET for CMV prophylaxis in adolescent allogeneic HSCT recipients (aged 12 to < 18 years). Methods This is a Phase 2b nonrandomized, multicenter, open-label, sequential dose escalation study (NCT03940586). Participants (pts) were divided into 3 age groups, the oldest (AG1) comprising adolescents. AG1 pts received the recommended adult 480 mg LET dose (240 mg with cyclosporine A [CsA]) once-daily orally (PO) or intravenously (IV). Pediatric target exposures were based on model-predicted Phase 3 population PK simulations for adult HSCT recipients: 16,900 h.ng/mL (480 mg PO without [w/o] CsA) to 147,800 h.ng/mL (480 mg IV w/o CsA). PK parameters were determined by non-compartmental analysis for 14/28 AG1 pts. Results All 28 AG1 pts enrolled were CMV-seropositive (median age: 13.5 [range, 12–17] years; median weight: 53.8 [range, 28.7–95.0] kg; White: 53.6%). PK (N=14): Of 13 evaluable AG1 pts (weight, 30.4–87.7 kg), 8 received 480 mg LET alone (oral/IV; Table 1); 6/8 achieved exposures within the target range and 2/8 (oral, n=1; IV, n=1) achieved exposures above the target range but below the maximum observed in the development program. 5 AG1 pts received 240 mg LET (oral/IV) with CsA; 5/5 achieved exposures within the target range. Safety (N=28): No major safety concerns were reported for AG1 pts receiving LET, similar to the adult LET safety profile. Efficacy (N=25): The proportion of AG1 pts receiving LET with clinically significant CMV infection (CMV disease/pre-emptive treatment for CMV viremia) through week 24 post-HSCT was similar (24%) to that for adults receiving LET in the pivotal Phase 3 study (37.5%). Conclusion Administration of adult LET doses for CMV prophylaxis post-HSCT in this adolescent cohort resulted in exposures within the development program safety margins, and was associated with similar efficacy and safety to LET use in adult patients. Preliminary results support 480 mg (240 mg with CsA) as an oral and IV LET dose in adolescent HSCT recipients, with a final dose recommendation after study completion. Disclosures Andreas H. Groll, MD, Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & Dohme, and Pfizer: Advisor/Consultant|Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp & Dohme, and Pfizer: Served at the speakers’ bureau|Gilead Sciences, Merck Sharp & Dohme, and Pfizer: Grant/Research Support Johannes H. Schulte, MD, German Cancer Consortium (DKTK): Support by Ali Bulent Antmen, MD, PhD, Novo Nordisk, Pfizer, Roche, Takeda: Advisor/Consultant Valerie L. Teal, MS, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Barbara A. Haber, MD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Luzelena Caro, PhD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Jacqueline B. McCrea, PharmD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Craig Fancourt, PhD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Karsten Menzel, PhD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee Cyrus Badshah, MD, PhD, Merck & Co., Inc.: Stocks/Bonds|Merck Sharp & Dohme LLC: Current or former employee.

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20–30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 109/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response.

Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Results of a Prospective Dose Escalation Study of Linear Accelerator–Based Virtual Brachytherapy (BOOSTER) for Prostate Cancer; Virtual HDR Brachytherapy for Prostate Cancer

PurposeTo demonstrate feasibility and toxicity of linear accelerator–based stereotactic radiation therapy boost (SBRT) for prostate cancer, mimicking a high-dose-rate brachytherapy boost. Methods and MaterialsA phase 1 sequential dose escalation study of SBRT compared 20 Gy, 22 Gy, and 24 Gy to the prostate and 25 Gy, 27.5 Gy, and 30 Gy to the gross tumor volume in 2 fractions, combined with 46 Gy in 23 fractions of external beam radiation. Feasibility of dose escalation (volume receiving 125% and 150% of the dose) while meeting organ-at-risk dose constraints, grade 2 acute and late gastrointestinal and genitourinary toxicity, and freedom from biochemical failure were secondary endpoints. ResultsThirty-six men with intermediate- and high-risk prostate cancer were enrolled with a median follow-up of 24 months. Sixty-four percent of patients had high-risk features. Nine men were enrolled to dose level 1, 6 to level 2, and 6 to level 3. Another 15 patients were treated at dose level 3 on the continuation study. Dose level 3 achieved superior 125% (23.75 Gy) and 150% (28.5 Gy) dose compared to dose levels 1 and 2, with minimal differences in organ-at-risk doses. Kaplan-Meier estimate of freedom from biochemical failure at 3 years was 93.3%. There were no late grade 2 or 3 gastrointestinal events. The late grade 2 genitourinary toxicity at 2 years was 19.3%. Prostate-specific membrane antigen positron emission tomography was performed at 2 years with no local recurrences. ConclusionsWe have shown that a linear accelerator–based SBRT boost for prostate cancer is feasible and can achieve doses comparable to high-dose-rate boost up to the 150% isodose volumes. Rectal, bladder, and urethral doses remained low, and long-term toxicity was the same as or better than previous reports from high-dose-rate or low-dose-rate boost protocols.

Safety, Tolerability, and Pharmacokinetics (PK) of Posaconazole (POS) Intravenous (IV) Solution and Oral Powder for Suspension in Children With Neutropenia

BackgroundPOS, a triazole antifungal approved for prophylaxis and treatment of adults with invasive fungal infections, is available as an IV solution and 2 oral formulations: an oral suspension and a tablet with improved bioavailability. A novel powder for oral suspension (PFS) has been developed to offer the bioavailability of the tablet in a formulation optimized for weight-based dosing in children. The objective of this study is to evaluate the safety, tolerability, and PK of POS IV and POS PFS in pediatric patients (patients) aged 2 to 17 y with documented or expected neutropenia.MethodsThis is an ongoing, nonrandomized, multicenter, open-label, sequential dose-escalation study evaluating POS IV and POS PFS. Pts are divided into 2 age groups: 2 to <7 and 7 to 17 y. Each age group includes 2 dose cohorts: 3.5 mg/kg/d and 4.5 mg/kg/d. Patients received 10–28 d of POS initially as IV solution with the option to switch to PFS after 10 d for the remainder of the treatment period. PK sampling was conducted after 7–10 days on each formulation. Target PK exposure was ~90% of patients with Cavg 500–2,500 ng/mL. Cavg is defined as AUC over a dosing interval.Results57 of 66 patients (86%) who received POS IV were PK evaluable; 35 patients (53%) received POS PFS, of whom 30 (86%) were PK evaluable. Table 1 shows Cavg and proportion in target range of PK-evaluable patients by dose cohort and age group. The safety profiles of POS IV and PFS were similar to those previously reported for adults treated with oral/IV POS.ConclusionPOS PFS resulted in lower POS exposure than IV across age groups at both dose levels. POS exposure was substantially lower in the younger age group for both IV and PFS. At 4.5 mg/kg, the patients in this study achieved the predefined target but did not achieve systemic exposures (mean Cavg) comparable to those seen in adults with POS IV or tablet. These results suggest that study of POS IV and PFS dosing >4.5 mg/kg/d is warranted.Disclosures A. H. Groll, Merck Sharp & Dohme: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. T. Lehrnbecher, Merck/MSD: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Astellas: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Basilea: Scientific Advisor, Consulting fee. Gilead: Investigator, Scientific Advisor and Speaker’s Bureau, Research grant and Speaker honorarium.Pfizer: Speaker’s Bureau, Speaker honorarium. W. Steinbach, Merck: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Gilead: Consultant, Consulting fee. R. Murray, Merck: Employee, Salary. A. Paschke, Merck: Employee, Salary. E. Mangin, Merck: Employee, Salary. G. A. Winchell, Merck: Research Contractor, Consulting fee. C. J. Bruno, Merck: Employee and Shareholder, Salary and Stock.

Abstract CT137: First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors

Abstract Background: Tumor-associated macrophages (TAMs) may contribute to tumor growth and invasion and promote an immunosuppressive tumor microenvironment, making them an attractive target for cancer immunotherapy. TAMs can be activated by the binding of colony stimulating factor-1 (CSF-1) to its receptor CSF-1R (c-fms). AMG 820 is an investigational, fully human antagonistic antibody to CSF-1R that inhibits ligand-induced receptor activation. In this open-label, sequential dose-escalation study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of AMG 820. Methods: Key eligibility criteria: age ? 18 years, advanced solid tumors relapsed or refractory to standard treatment, measurable disease per RECIST 1.1, ECOG performance status ? 2, and no primary central nervous system tumors/metastases. AMG 820 was administered by IV infusion once weekly at a starting dose of 0.5 mg/kg (cohort 1). Dosing frequency was later amended to once every 2 weeks (Q2W) with planned escalation to 1.5, 3, 6, 10, 20, and 30 mg/kg (cohorts 2–7), following a 3 + 3 design until a maximum tolerated dose (MTD, highest dose at which &amp;lt; 33% of pts/cohort had a dose-limiting toxicity [DLT]) or highest dose was reached. Results: A total of 25 pts received ? 1 dose of AMG 820: 3 pts at 0.5, 1.5, and 6 mg/kg; 4 pts at 3 and 10 mg/kg; 8 pts at 20 mg/kg. Median (range) age: 63 (48–80) years. Women: 56%. ECOG 0/1/2: 20%/76%/4%. MTD was not reached. One DLT was observed (20 mg/kg): nonreversible grade 3 hearing impairment in a female pt with anal cancer with confounding factors (prior treatment [tx] with cisplatin). Most pts (76%) had tx-related adverse events (TRAEs). Most common TRAEs (in &amp;gt; 10% of pts overall) were periorbital edema (11, 44%), increased aspartate aminotransferase (7, 28%), fatigue (6, 24%), nausea (4, 16%), increased blood alkaline phosphatase (3, 12%), and blurred vision (3, 12%). Grade ? 3 TRAEs were observed in 28% of pts. There were no serious or fatal TRAEs. After the first dose of AMG 820 at 20 mg/kg, mean estimates of Cmax and AUClast (AUC from time 0 to time of last sample) were 619 μg/mL and 89,200 μg•hr/mL, respectively. Both AMG 820 AUClast and Cmax increased linearly with dose, with minimal accumulation (&amp;lt; 2-fold) after repeated dosing. AMG 820 dosing was associated with significantly reduced skin macrophage levels compared to predose levels. At all dose levels tested, AMG 820 resulted in increases in serum CSF-1 concentrations, which were maximal at doses greater than 6 mg/kg. Of the 21 pts evaluable by central read, 8 (38%) pts had a best overall response of stable disease, including 1 pt with a 20% reduction in tumor burden (0.5 mg/kg, non-small cell lung cancer). Of the 25 pts evaluable by local read, 1 (4%) pt had a partial response with a 40% reduction in tumor burden (10 mg/kg, paraganglioma with liver metastasis), and 6 (24%) pts had stable disease. Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg Q2W and showed linear PK, with PD response in CSF-1 serum levels and tx-related changes in skin macrophages. These results and an increasing understanding of the role of TAMs in tumor immunosuppression provide the rationale for combining AMG 820 with other immunotherapies. Citation Format: Kyriakos Papadopoulos, Larry Gluck, Lainie P. Martin, Anthony J. Olszanski, Gateree Ngarmchamnanrith, Erik Rasmussen, Benny Amore, Dirk Nagorsen, John S. Hill, Joe Stephenson. First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT137.

Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients (Pts) with Acute Myeloid Leukemia (AML)

Background: Aurora kinases form a family of highly conserved serine/threonine protein kinases that regulate key steps in mitosis. Aurora kinases A and B are amplified and/or overexpressed in many malignancies, including various types of leukemia, and are associated with high proliferation rates, poor prognosis, and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective, small-molecule pan-aurora kinase inhibitor that has shown single-agent activity in heavily pretreated pts with chemotherapy-resistant/refractory solid tumors. This open-label, multicenter, sequential dose escalation study (NCT01380756) assessed AMG 900 in adult pts with AML.Methods: The primary objectives of this study were to evaluate the safety and tolerability of AMG 900, to evaluate pharmacokinetics after multiple oral administrations, to determine the optimal dose schedule, and to determine the maximum tolerated dose (MTD). A secondary objective was to evaluate antitumor activity in pts with AML. Key inclusion criteria included definitively diagnosed AML that had failed standard treatments or for which no standard therapy was available, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and life expectancy > 3 months. Dose escalation included parallel evaluation of 2 schedules in separate groups. In group 1, AMG 900 was administered daily 4 days on/10 days off at doses of 15, 25, 40, 60, 80, 100, 125, and 150 mg. In group 2, AMG 900 was administered daily 7 days on/7 days off at doses of 30, 40, 50, 60, and 75 mg. Dose escalation was conducted using a 3+3+3 design; intrapatient dose escalation was not allowed. The relationship between gene expression at baseline and clinical response was an exploratory objective. RNA levels for preselected genes were measured by microarray in mononuclear cells obtained from bone marrow (BM) aspirates.Results: A total of 35 pts were enrolled: 22 in group 1 and 13 in group 2. Twenty-three pts (65.7%) were male, 27 (77.1%) were white, and mean (SD) age was 66.1 (12.2) years. ECOG status was 0 in 7 pts (20.0%), 1 in 22 pts (62.9%), and 2 in 6 pts (17.1%). Pts received a median (min, max) of 14 (4, 49) doses of AMG 900. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increased with increasing dose. Thirty pts (85.7%) had treatment-related adverse events (AEs). The most common AEs (in ≥ 10% of pts overall) were nausea (31.4%), diarrhea (28.6%), febrile neutropenia (28.6%), fatigue (22.9%), vomiting (17.1%), alopecia (14.3%), dyspnea (11.4%), epistaxis (11.4%), mucosal inflammation (11.4%), and rash (11.4%). Nine pts (25.7%) died during the study from lung infection and respiratory failure (2 pts each) and acute respiratory failure, cardiorespiratory arrest, respiratory distress, sepsis, and septic shock (1 pt each). Only respiratory failure and septic shock (1 pt each) were considered potentially related to AMG 900 by the investigators. All 35 pts discontinued treatment. Reasons for discontinuation were disease progression (65.7%), AEs (11.4%), death (8.6%), withdrawal of consent (5.7%), other reasons (5.7%), and requirement for alternative therapy (2.9%). Two pts (5.7%) experienced dose-limiting toxicities: 1 pt from group 1 (40 mg) had grade 3 pancytopenia, and 1 pt from group 2 (50 mg) had febrile neutropenia and grade 3 abdominal pain. The MTD of AMG 900 was not formally reached in either dose schedule. Three pts (8.6%) from group 1 (40 mg [2 pts] and 60 mg [1 pt]) had a best response of complete response with incomplete count recovery (CRi). Overall, the objective response rate for CRi was 8.6% (80% confidence interval: 3%, 18%). Higher gene expression of BIRC5, AURKB, AURKA, TTK, and CCNB1 was associated with objective response in univariate logistic regression models (P < .02), and was still significant after adjusting for average dose and percentage of blasts in the BM in a multivariate model (P < .01). Expression profiles of responders were clustered together in a principal component analysis.Conclusions: AMG 900 had an acceptable safety profile in this grievously ill population of adult pts with recurrent/refractory AML. Prolonged cytopenias hampered further dose escalation in this single-agent treatment setting. Combination of low doses of AMG 900 with other anticancer agents should be evaluated in future studies. DisclosuresSchuster:Amgen Inc.: Equity Ownership, Honoraria, Speakers Bureau. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gamelin:Amgen Inc.: Employment, Equity Ownership. Rasmussen:Amgen Inc.: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Chow:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Vogl:Amgen Inc.: Employment, Equity Ownership.

FRI0305 A Phase I Study of Staphylococcal Protein A in Patients with Active Rheumatoid Arthritis on Methotrexate

BackgroundStaphylococcal protein A (SpA) is a bacterial B cell superantigen that binds with high affinity to the Fc region of most Igs and to the Fab region of Igs in...

A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors

The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.

A Sequential Two-Stage Dose Escalation Study Evaluating The Safety and Efficacy Of Eltrombopag In Thrombocytopenic Patients With Myelodysplastic Syndrome (MDS) Resistant To Hypomethylating Agents (HMA)

▪ IntroductionThrombocytopenia remains a critical management challenge for MDS pts. The outcome of MDS Pts after HMA failure is poor. Eltrombopag is an oral, small non-peptide thormbopoeitin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We conducted an investigator initiated study with eltrombopag in MDS pts with thrombocytopenia after HMA failure. MethodsThe study is a phase 1, dose escalation design. Pts are allocated to dose cohorts of 50, 100, 150, 200, 250 and 300mg/day. Each dose cohort includes 6 pts. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. Pts must have at least one prior HMA treatment. The mean platelet count within a month of enrollment must be ≤ 50 X 109 /L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis ≥ grade 3, and prior TPO agonist use. The primary objective of the study is to determine the MTD. Dose-limiting toxicity (DLT) is defined as treatment related non-hematological grade 3-4 toxicity. If no DLTs were observed during the first 2 cycles of therapy, the next cohort of patients receives a higher dose of eltrombopag. Pts who did not receive treatment for 8 weeks were replaced for DLT assessment. The secondary endpoints include response, overall survival (OS) and leukemia free survival (LFS). ResultsThirty-one pts were enrolled. Table-1 summarizes baseline characteristics. Most pts had higher risk MDS who were heavily pretreated. The median interval from MDS diagnosis was 28 months. Six pts were enrolled in cohort 1 (50 mg), 10 pts in cohort 2 (100 mg) (4 pts replaced (2 deaths unrelated to treatment, 1 infection, 1 progressive disease (PD)), 12 pts were enrolled in cohort 3 (150 mg) where 6 pts were replaced (5 PD and 1 infection), and to date, 3 pts are enrolled in cohort 4 (200 mg).Table 1Baseline Characteristicsn=31N (%)Agemedian75 yearsGenderMale23 (74%)RaceWhite29 (94%)ECOG PS06 (19%)125 (81%)MyeloblastsMean %10%plateletsMean22 x 109 /LWHO classificationRCMD6 (19%)RAEB-17 (23%)RAEB-211 (36%)RAEB-t (AML)1 (3%)CMML4 (13%)MDS/MPN-U1 (3%)Del 5q1 (3%)IPSSLow0Int-112 (39%)Int-211 (35%)High8 (26%)R-IPSSVery low0Low2 (7%)Intermediate5 (16%)High13 (42%)Very High11 (36%)Prior TherapiesAzacitidine31 (100%)Decitabine6 (19%)Lenalidomide8 (25%)No protocol defined DLT have been encountered to date. No grade 3 or 4 treatment related adverse events have been reported. The most common adverse events that were deemed possibly, or probably related to study drug included fatigue (n=9), diarrhea (n=6), night sweats (n=3), headache (n=3), numbness (n=3). There were 2 pts with grade 2 pneumonia and grade 3 fatigue, and 2 grade 2 diarrhea events. Seven pts (23%) developed leukocytosis on treatment and 13 pts (42%) experienced an increase in circulating myeloblasts at some point during study treatment. Three of 27 pts developed higher grade bone marrow myelofibrosis (change from grade 0-1 to grade 2-3), one of whom received the 50 mg dose and 2 pts on the150 mg dose. Eleven pts (35%) progressed to AML, 9 out of 11 patients who progressed had RAEB-2 or RAEB-t and 5 had poor risk cytogenetics.The median follow up duration is 23 months. The best response on study per IWG 2006 criteria include marrow CR (mCR) + Hematological improvement (HI) (6%, n=2), mCR (3%, n=1), HI (13%, n=4), stable disease (SD) (29%, n=9), PD (36%, n=11) and not evaluable for response (13%, n=4). The overall response rate (HI+) was 22% (7 out 31 pts) and 26% among pts evaluable for response (7 out of 27 pts). HI included 6 platelet responses and 1 erythroid response. Among 20 pts who were platelet transfusion dependent, 6 became transfusion independent (30%). The median duration of response was 3.3 months. The median duration of treatment is 2 months. The most common reasons for eltrombopag discontinuation were PD (48%) and infection (10%). Median OS was 5 months whereas median OS was 8 months among HI+ responders. The median LFS was 3.5 months. ConclusionsEltrombopag yielded modest responses in heavily treated higher risk MDS pts after HMA failure. Leukocytosis, increased circulating myeloblasts and myelofibrosis were observed in subsets of pts. Future development of eltrombopag as a single agent in MDS should be in lower risk MDS or in combination with HMA in higher risk MDS. Disclosures:Off Label Use: Use of eltrombopag in MDS.

The TRUST Trial: Anti-Drug Antibody Formation In a Patient With Hemophilia With Inhibitors After Receiving The Activated Factor VII Product Bay 86-6150

▪ IntroductionUp to 30% of patients with hemophilia A and 5% of patients with hemophilia B develop neutralizing antibodies (inhibitors) against replacement factor VIII or factor IX, respectively. Acute bleeding episodes in these patients with inhibitors are treated with bypassing agents, which include activated recombinant factor VII (rFVIIa). BAY 86-6150 is a modified rFVIIa which in preclinical studies was shown to have prolonged half-life and improved potency compared with currently available rFVIIa. In a phase 1, randomized, double-blind trial, BAY 86-6150 was not associated with any clinically significant adverse events (AEs). We report the immunologic response to BAY 86-6150 in a phase 2/3 clinical trial in patients with hemophilia with inhibitors. MethodsTRUST (Treatment with Unique Recombinant FVII Study) was a multicenter, open-label, 2-part study (part A and part B) which included males aged 12−62 years with moderate or severe hemophilia A or B, with a history of high-titer inhibitors (≥5 Bethesda units), and ≥4 bleeding episodes in the 6 months prior to enrollment. Part A was a sequential dose-escalation study of 4 BAY 86-6150 dose levels (6.5, 20, 50, and 90 μg/kg body weight; n≥10/cohort). Dose escalation was dependent on both efficacy and an Independent Data Monitoring Committee (IDMC) approval of safety in 10 patients per cohort who had ≥1 bleeding episode treated with BAY 86-6150. Part B was designed as a single-arm investigation of the efficacy and safety of the recommended dose of BAY 86-6150 determined in all patients from Part A. Safety endpoints were AEs and immunogenicity. Anti-drug antibody testing was performed at screening (prior to exposure), after the second exposure, then every fifth exposure, and at the end of study visit in both part A and part B. Anti-BAY 86-6150 binding antibodies were measured using a validated enzyme-linked immunosorbent assay (ELISA). Samples that revealed a specific immunoreactivity in this assay were further characterized for neutralizing activity using a validated platelet-activated clotting assay. Additional functional assays were performed to determine the cross-reactive neutralizing effect on rFVIIa (NovoSeven®) of any detected anti-BAY 86-6150 antibodies. The presence of neutralizing antibodies was considered a serious adverse event (SAE) requiring prompt IDMC review. ResultsIn cohort 1, 10 patients (mean age, 27.4 years) were treated with 6.5 mg/kg BAY 86-6150. These patients had a total of 73 bleeding events and received a total of 84 study drug injections. No anti-drug antibodies or anti-FVIIa was detected in the patients at screening prior to exposure to the study drug. BAY 86-6150 was well tolerated in all patients with no clinical or laboratory symptoms or signs of venous thromboembolism. Binding antibodies to BAY 86-6150 were detected on a scheduled screening visit in 1 patient after 3 exposures to BAY 86-6150; these anti-BAY 86-6150 antibodies displayed neutralizing activity against BAY 86-6150 and were also cross-reactive and neutralizing for rFVIIa. The affected patient had received rFVIIa before entry into the study. At the time of diagnosis of binding and neutralizing antibodies, the affected patient was not bleeding and did not require emergency treatment. Exposure to BAY 86-6150 was stopped and the trial was terminated at the first cohort. Subsequent bleeding episodes in this patient were successfully managed with FEIBATM (Factor Eight Inhibitor Bypass Activity). No other treatment-related AEs or SAEs were reported in this study. Additionally, the IDMC has recommended safety follow-up assessments for all the patients who actively participated in the trial. ConclusionsThe TRUST trial has been discontinued as a precautionary measure because of potential safety concerns related to the detection of the antidrug antibodies in 1 patient. Development of neutralizing antibodies against BAY 86-6150 that had a cross-reactive neutralizing effect on rFVIIa was considered a serious risk because of the limited treatment options in patients with inhibitors. These results underline the fact that it is currently not possible to predict immunologic response based on preclinical and phase 1 studies. Disclosures:Hardtke:Bayer Pharma AG: Employment. Schroeder:Bayer Pharma AG: Employment.

Phase 1b, multicenter, single blinded, placebo‐controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy

Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5-fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained. A total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade > 2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 × 10(11) , 6 × 10(11) , and 1.2 × 10(12) colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted. AG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013-subjects versus placebo. All placebo subjects experienced ≥ 2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. AG013 was safe and well tolerated. Preliminary efficacy data support further study.

FRI0207 A phase I/II clinical trial of intra-articular administration of ARG098, an anti-FAS IGM monoclonal antibody, in knee joint synovitis of japanese patients with rheumatoid arthritis

BackgroundARG098, a chimeric anti-Fas IgM monoclonal antibody, possesses a novel mode of action totally different from those of currently available RA therapeutics including cytokine targeting biologics. The Fas molecule (also...

Sifalimumab, a Human Anti–Interferon‐α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose‐Escalation Study

ObjectiveTo evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).MethodsIn this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.ResultsOf 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.ConclusionThe observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

Phase Ib, multicenter, single-blinded, placebo-controlled, sequential dose-escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer (LAHNC) receiving induction chemotherapy (ICT).

9024 Background: Oral mucositis (OM) is a significant toxicity of ICT in LAHNC. AG013, a mouth rinse composed of a recombinant Lactococcus lactis (sAGX0085) engineered to secrete human Trefoil Factor 1 (hTFF1) and deficient in the gene encoding thymidylate synthase, was investigated in patients receiving ICT (cisplatin, 5-fluorouracil +/-docetaxel:PF+/-T). TFFs have wound-healing properties and are protective of mucosal tissues. Methods: To evaluate the safety, tolerability, PK profile and efficacy of AG013 in attenuating ICT-associated OM, 52 patients (pts) with newly diagnosed LAHNC receiving ICT (24TPF, 1PF) were screened in ICT cycle (Cy) 1 for symptomatic OM (SOM). 25 pts who developed SOM in Cy1 were enrolled into 3 successive groups of at least 7 pts each in the active phase and randomly assigned at the Baseline visit (d1 of ICT Cy2) in a 5:2 ratio to receive AG013 or placebo during ICT Cy2. Dose was escalated in successive groups from 1 x/day (qd) to 3 x/day (tid) and to 6 x/day, resulting in doses of 2 x 1011, 6 x 1011, and 1.2 x 1012 colony-forming units (CFU)/day respectively. Pts were assessed daily from Cy 2 d1 to d14 for OM using WHO criteria. Safety endpoints and PK (mucosal, salivary and blood samples) were assessed. Results: AG013-sAGX0085 could not be detected in blood. Recovered oral live bacterial levels were high immediately after dosing, decreased by 90 minutes post dose, and undetectable at study end. No differences in hTFF1 serum levels were seen. Pts in the placebo group had ulcerative OM (UOM) on nearly 60% of the days vs. 35-40% days in the AG013 group. 29 % pts who received AG013 had 0 or 1 day of UOM vs. at least 2 days of UOM in the placebo group. Pts who received AG013 on any dosing schedule had a lower % of days with OM, fewer unplanned office and emergency room visits compared to pts who received placebo. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement. Conclusions: Topical administration of AG013 appears safe, well tolerated and effective in reducing the severity and course of OM in patients receiving ICT for HNC.

An Open-Label, Sequential Dose-Escalation, Safety, and Tolerability Study of Rimabotulinumtoxinb in Subjects With Cervical Dystonia

ABSTRACTObjectives: Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. Methods: This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). Results: 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). Conclusion: BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.

Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

Peptide gonadotropin-releasing hormone (GnRH) antagonists are widely used to suppress the reproductive endocrine axis in women with endometriosis, fibroids, and other nonmalignant reproductive hormone-dependent disease states. Unlike treatment of sex-steroid-dependent tumors, management of endometriosis and fibroids does not require complete gonadal suppression; reduction of estrogen to low levels is sufficient. This phase I, randomized, double-blind, placebo-controlled, sequential dose escalation study evaluated the safety, tolerability, pharmacokinetics, and effect of single dose and 7-day doses of elagolix, a novel, orally available nonpeptide GnRH antagonist on gonadotropins and estrogen in healthy premenopausal women. The study subjects were 55 healthy, regularly cycling women ranging between 18 and 39 years. Of these, 30 participated in and completed the single-dose escalation phase of this study (the first study arm) and 25 participated in and 24 completed the multiple dose-escalation phase of this study (the second study arm). Cohorts in the first study arm received a single dose of elagolix (25, 50, 100, 200, or 400 mg) or placebo. Of the 25 women in the second study arm, 18 were given once-daily doses of elagolix (50, 100, or 200 mg) or placebo for 7 days, and 7 received 100 mg or placebo twice daily for 7 days. Initial administration was at 7 ± 1 days after onset of menses. Serum concentrations of LH, FSH, and estradiol were determined by validated methods. Elagolix was well tolerated during both the single-dose and multiple-dose escalation for 7 days. No clinically significant adverse events occurred in any of the cohorts. Oral bioavailability was rapid and serum levels of the gonadotropins declined quickly. Circulating LH was suppressed more than FSH. In the first study arm, estradiol was suppressed by 24 hours in all cohorts receiving at least 50 mg/day. In the second study arm, elagolix maintained low estradiol levels (17 ± 3 to 68 ± 46 pg/mL) throughout the 7 day treatment in most cohorts during the late follicular phase. Drug effects were rapidly reversed after discontinuation. These data show that an oral nonpeptide GnRH antagonist, elagolix, can achieve dose-related pituitary and gonadal suppression in premenopausal women and may prove to be useful for management of nonmalignant reproductive hormone-dependent disease states.

Clinical Pharmacokinetics and FLT3 Phosphorylation of AC220, a Highly Potent and Selective Inhibitor of FLT3

Several different FLT3 inhibitors have now been tested as monotherapy for AML patients and have met with only limited success. To date, none of these inhibitors have resulted in complete, sustained inhibition of phosphorylated FLT3 in vivo, as measured by immunoblotting techniques. AC220 is a novel FLT3 kinase inhibitor with greater potency and kinase selectivity than others previously characterized. To establish a dose of AC220 that will lead to complete, sustained inhibition of phosphorylated FLT3, a Phase I open-label, sequential dose escalation study investigating safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with relapsed or refractory acute myeloid leukemia is being conducted. AC220 is administered once daily as an oral solution for 14 days followed by a 14-day rest period, (one cycle) with a starting dose of 12 mg. Patients showing clinical benefit may continue to receive further cycles of therapy. The study is a standard 3+3 dose escalation design with 50% dose increments. Currently 52 patients have been enrolled and AC220 has been well tolerated and escalated to 450 mg daily (10th dose cohort) on this intermittent dosing regimen and PK has been evaluated up to 300 mg. AC220 is orally bio-available and has a long effective half-life, estimated to be 2.5 days, exhibiting minimal peak and trough variation of plasma levels. AC220 plasma exposure in AML patients is sustained between dose intervals and continues to increase in a dose-proportional manner from 12 mg to 300 mg daily, with steady-state plasma concentrations achieving greater than 1,500 nM at 300 mg. In addition, a pharmacologically active metabolite, AC886, has been identified in patient urine and plasma samples, which has similar potency and kinase selectivity to AC220 as determined by in vitro kinase binding and cell assays. The IC50s for AC220 and AC886 in FLT3-ITD-expressing cell lines and in primary FLT3-ITD AML patient blast samples are in the low nanomolar range (1.7 and 0.3 nM, respectively) and are in good agreement with cytotoxicity (Annexin V and MTT) assays. Both drugs display a high degree of selectivity for FLT3 in an IL-3 rescue assay. AC220 and AC886 also potently inhibit wild type FLT3 (3.6 and 4.2 nM, respectively). In standard immunoblot curves using AC220 and AC886 spiked into plasma, FLT3-ITD phosphorylation was completely inhibited at 50 and 200 nM, respectively. As predicted from the standard curve data, plasma from AC220-treated AML patients completely suppresses FLT3 phosphorylation on Day 1 and at steady-state in an ex vivo plasma inhibitory activity (PIA) assay, even at the lowest dose of 12 mg daily. AC220, with its metabolite AC886, is a potent, selective inhibitor of both mutant and wild type FLT3. It is orally bio-available with sustained plasma exposure, and the pharmacological impact of AC220 is further enhanced by the presence of AC886. In vivo, therefore, AC220 is expected to completely inhibit FLT3-ITD at >100 nM (achieved at the lowest AC220 dose of 12 mg) and FLT3-WT at 500 nM (achieved by the 60 mg dose). AC220 is the most potent and selective FLT3 inhibitor tested using the PIA assay thus far, and, unlike other FLT3 inhibitors that have been assessed in this assay, is the first to completely suppress FLT3 phosphorylation ex vivo at doses that are easily achievable and sustainable in the clinic. Therefore, AC220 should be able to effect substantial and prolonged target inhibition in patients. This makes it an ideal compound with which to test the hypothesis that complete, sustained inhibition of FLT3 activity will lead to clinical benefit in FLT3 mutant AML patients.