Abstract: AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count 〉 1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response

Abstract: Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with 〉 =1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged 〉 =20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where 〈 =2 of 6 patients experienced a DLT in phase I. The primary endpoint for phase II was ORR; secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), and toxicity. Toxicity was assessed per NCI CTCAE version 3.0. Efficacy was assessed per modified 1999 IWG response criteria for non-Hodgkin lymphoma, descriptive statistics, and Kaplan-Meier method. Pharmacokinetic (PK) assessments included all patients in phase I with concentration-time data to enable PK parameter calculations for 〉 =1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were 〉 =65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for 〉 =36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade 〉 =3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts ( 〈 200 uL) were observed in 82% of patients, opportunistic infection occurred only in 1 patient (3%). Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P 〈 0.0001, one sample binomial test, H0: P 〈 =0.1). The ORR was not different across PTCL subtypes: 44% (8/18) AITL, 41% (7/17) PTCL-NOS, and 100% (2/2) ALCL. In 17 responding patients, the median TTR was 1.8 months (range, 1.6-2.3) and median DOR was 11.1 months (95% CI, 1.6 to not reached). Median TTP was 5.6 months (95% CI, 3.3-12.9; n=40). For 2 patients with CTCL in phase I, best responses (investigator assessment) were 1 PR (9 mg/m2 cohort) and 1 stable disease (14 mg/m2 cohort). Pharmacokinetic analysis indicated a dose-proportional relationship, with no accumulation following multiple doses; results were similar to data reported for non-Japanese patients. Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura: Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.

Abstract: Introduction: Adult T-cell leukemia-lymphoma (ATL), a distinct subtype of peripheral T-cell lymphoma (PTCL), is caused by human T-lymphotropic virus type-I (HTLV-1). Although rare in the rest of the world, ATL accounts for 25% of PTCL cases diagnosed in Japan, where ATL cases are clustered in areas endemic for HTLV-1 infection. Studies of lenalidomide, an oral immunomodulatory agent that has antiproliferative and direct antineoplastic activity in cutaneous T-cell lymphoma and PTCL, have reported encouraging clinical activity. On the basis of the results from the ATLL-001 dose-finding study of lenalidomide (Uike et al. ASH 2012. Abstract 2737), this multicenter phase II study (ATLL-002) was designed to investigate the efficacy and safety of single-agent lenalidomide in Japanese patients with relapsed ATL. Methods: Patients with relapsed acute, lymphoma, or the unfavorable chronic subtype of ATL who were at least 20 years of age, had ECOG performance status 0-2, no prior allogeneic stem cell transplant, and who had failed at least 1 chemotherapy were included in the study. Patients refractory to their last prior therapy were excluded. Treatment consisted of oral lenalidomide 25 mg/day administered continuously until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Response was assessed by central review using the criteria proposed by Tsukasaki et al in their international consensus report (J Clin Oncol. 2009;27:453-459.); safety was assessed per NCI CTCAE v4.0 criteria. The estimated number of patients required was 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required ORR to a new drug for relapsed or recurrent ATL is 5% and the expected ORR to lenalidomide is 25%. Results: Twenty-six patients were enrolled and received lenalidomide. The median age was 68.5 years (range, 53-81), with 15 (58%) acute, 7 (27%) lymphoma, and 4 (15%) unfavorable chronic type ATL patients. Patients had received a median of 2 (range, 1-4) prior chemotherapeutic or antibody agents for ATL, 11 (42%) of whom received prior mogamulizumab (anti-CCR4 antibody). At a median 3.8-month follow-up, lenalidomide met the primary endpoint by exhibiting an ORR of 42% (11/26; 95% CI, 23-63) (acute 33% [5/15], lymphoma 57% [4/7] , unfavorable chronic 50% [2/4]), including 5 (19%) complete responses (CR)/CR unconfirmed (95% CI, 7 to 39; Table 1). Stable disease was 31%, and progressive disease was 27%. The median time to response was 1.9 months (95% CI, 1.8 to 3.7). Although the data were immature at the time of analysis, median DOR for all responders was not reached (NR) (95% CI, 0.5 months to NR), median PFS was 3.8 months (95% CI, 1.9 months to NR), and median OS was 20.3 months (95% CI, 9.1 months to NR). At the time of the data cut-off, 5 (19%) patients remained on lenalidomide treatment. The most common grade 3/4 adverse events (AEs), accounting for at least 10% of all cases, were neutropenia (65%), leukopenia (39%), lymphopenia (39%), thrombocytopenia (23%), anemia (19%), and hypokalemia (12%). Serious AEs were reported in 9 (35%) patients; only thrombocytopenia (2 patients [8%] ) was observed in 〉 1 patient. AEs led to dose reduction/interruption in 17 (65%) patients and study discontinuation in 6 (23%). Seven deaths occurred during the study, 6 due to disease progression and 1 due to pneumonia unrelated to lenalidomide treatment. Conclusions: In this multicenter, open-label, phase II study, lenalidomide monotherapy demonstrated a 42% ORR and acceptable tolerability profile. These results support the potential for lenalidomide monotherapy becoming a treatment option for patients with relapsed ATL. Table. Best response to lenalidomide in relapsed ATL ATL type All patients (N = 26) Acute (n = 15) Lymphoma (n = 7) Unfavorable chronic (n = 4) ORR, n (%) 11 (42) 5 (33) 4 (57) 2 (50) CR/CRu, n (%) 5 (19) 3 (20) 2 (29) 0 PR, n (%) 6 (23) 2 (13) 2 (29) 2 (50) SD, n (%) 8 (31) 6 (40) 0 2 (50) PD, n (%) 7 (27) 4 (27) 3 (43) 0 CR, complete response; CRu, CR unconfirmed; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Disclosures Fujiwara: Celgene: Honoraria, Other: Research funding to my institution; travel, accommodations, expenses. Off Label Use: Lenalidomide to treat ATL. Ishida:Celgene K.K.: Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution. Moriuchi:Celgene: Other: Research Funding to my institution; travel, accommodations, expenses, Speakers Bureau. Jo:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria. Ishizawa:Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Research Funding; GSK: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai:Gilead Sciences: Research Funding. Tsukasaki:Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Mundipharma: Research Funding; Kyowa Kirin Hakkou: Research Funding. Ogura:Mundipharma: Consultancy, Research Funding; MeijiSeika Pharma: Consultancy; Zenyaku: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Solaisia: Research Funding. Midorikawa:Celgene K.K.: Employment; Celgene Corporation: Equity Ownership. Ruiz:Celgene K.K.: Employment. Ohtsu:Celgene: Employment, Equity Ownership, Other: travel, accommodations, expenses.

Abstract: AMG 531 is a novel thrombopoiesis-stimulating peptibody currently being investigated for the treatment of chronic immune thrombocytopenic purpura. This study was a double-blind, phase 1 evaluation of safety (including a platelet aggregation analysis), pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531:placebo) to each of 3 sequential dose cohorts (0.3, 1, and 2 μg/kg) of 10 subjects each. A single dose of AMG 531 or placebo was administered by subcutaneous injection, and subjects were evaluated for 6 weeks. Concentrations of 0.2 and 2 μg/mL collagen and 0.5 and 2 μmol/L adenosine phosphate were used as reagents in the platelet aggregation analysis conducted on day -1, day 2, day 15, and at the end of the study. No enhancement or reduction in platelet aggregation was detected in samples collected from subjects treated with AMG 531 compared with either pretreatment or placebo samples. Overall, adverse events were similar between the AMG 531 and placebo groups. Treatment-related adverse events (headache, “feeling hot,” migraine without aura, and/or malaise) were reported for 5 of 24 subjects treated with AMG 531. Four of 8 subjects who received the 1 μg/kg dose and 7 of 8 subjects who received the 2 μg/kg dose had platelet count increases ≥ 1.5-fold over baseline, and 3 of 8 subjects who received the 2 μg/kg dose had platelet count increases ≥ 2-fold over baseline, a pharmacodynamic effect similar to that seen in previous studies of non-Japanese subjects. Serum concentrations of AMG 531 were below the lower limit of quantification in all but 2 subjects who received the 2 μg/kg dose. In summary, platelets in subjects treated with AMG 531 functioned normally compared with pretreatment and placebo samples. AMG 531 was generally well tolerated and was effective at raising platelet counts after a single subcutaneous administration.

Abstract: Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression & lt; 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.