yaping shou

Nilotinib is a rationally designed 2nd-generation bcr-abl inhibitor. It is ∼30-fold more potent than imatinib against wild-type bcr-abl and active against 32/33 imatinib-resistant bcr-abl mutants in preclinical models. In an open-label phase II study of nilotinib in imatinib-resistant or -intolerant CML-CP patients (pts), we assessed the occurrence of mutations and the efficacy stratified by BCR-ABL mutational status. Prior to therapy, 35 mutations affecting 28 amino acids in the BCR-ABL kinase domain were identified by direct sequencing in 39% (106/270) of the pts analyzed. The incidence of baseline mutation was higher in imatinib-resistant (100/183, 55%) versus imatinib-intolerant pts (6/86, 7%). After 12 months of therapy, complete hematologic response (CHR) was achieved in 85%, major cytogenetic response (MCR) in 60%, and complete cytogenetic response (CCR) in 45% of pts without baseline mutations versus 67, 49 and 29% of pts with mutations. Among patients with baseline mutations, responses were observed broadly in all genotypes identified, but rates of responses differed by the in vitro sensitivity of the mutant clone against nilotinib. Pts with sensitive mutations of ≤100 nM cellular IC50 had the best response rate and were comparable to pts without baseline mutations. Pts with less sensitive mutations (IC50 201–800nM:Y253H, E255K, E255V, F359C) had responses but the response rate were lower then those of the two other groups (IC50 101–200nM and 201–800nM). The nilotinib-resistant T315I mutation (IC50>800nM) was identified at baseline in 5 cases (one pt had a limited response followed by progression). The less sensitive mutations (IC50 201–800nM) and the T315I mutation occurred in 8% and 2% of all pts assessed for baseline mutations, respectively. With a median follow up of 12 months, progression occurred in 15% (25/164) versus 40% (42/106) of pts without and with baseline mutations. Nine of 18 with less sensitive baseline mutations and 3 of 5 with T315I progressed, but the baseline mutation most frequently associated with progression was F359V (7/9). In 67 cases of progression, mutational data at or within 3 months of progression were available in 28 cases. Among the 28 pts, 7 (25%) had no mutation; 9 (32%) had the same baseline mutation (including F359V in 3; Y253F/H in 3; E255K in 1; and T315I in 1). A further 12 (43%) pts showed new emerging mutations at progression, 4 with T315I, 4 E255K, 3 Y253H, and 1 F359C. The other 7 pts with emerging mutations had not progressed. In total 21 pts were found with emerging mutations, 19 (90%) had a different mutation at baseline. In summary, nilotinib responses were observed across a variety of BCR-ABL mutations. Preliminary data suggest that mutational status at baseline and/or the emergence of new mutations may influence disease progression. Less sensitive or resistant mutations represented 10% of the pt population and may be associated with less favorable responses. Longer follow up is required.

Supplementary Methods and Supplementary Table 1. The supplementary data file contains the supplemental methods section describing the source of the patient samples used in the initial validation of the five-gene signature assay and supplementary table 1 which lists the number of patients with MB with tumor samples assessed per the five-gene signature assay from each clinical study as a second validation set.

Background: Follicular lymphoma (FL) is a heterogeneous disease, and clinical presentation is highly variable. The Follicular Lymphoma International Prognostic Index (FLIPI-2) identifies prognostic factors at diagnosis, but does not predict in whom and when to initiate first-line therapy (1LT) (Federico 2009). Recommended therapies for 1LT vary by stage, symptomatology, and tumor burden, but include monotherapy with rituximab (R) or in combination with other chemotherapies. Survival of FL patients in the R era has greatly improved, but few studies have evaluated survival outcomes in patients seen in routine clinical care. This study aimed to evaluate survival outcomes in a United States (US) population of newly diagnosed FL patients seen in routine clinical care. Methods: A retrospective study was conducted in which the presence of ≥1 inpatient record or ≥2 outpatient records with FL diagnosis codes were used to identified newly diagnosed FL patients from Humedica, a large US electronic medical record database, between 01/01/08 and 07/31/15. The study index date was the first FL record. Patients who subsequently initiated 1LT with bendamustine+R or other R-based combinations were followed from the date of treatment initiation until death, loss to follow-up, or end of study (09/30/15) for the evaluation of the survival outcomes. Median progression-free survival (PFS) (defined as initiation of second-line therapy, evidence of supportive care >30 days after the end of a line of therapy, or death), median overall survival (OS), and PFS and OS rates at 2 years following initiation of 1LT were evaluated using Kaplan-Meier analyses. Cox proportional hazard models were used to further assess the impact of bendamustine+R and other R-based combinations on OS and PFS at 2 years. Results: 1,346 newly diagnosed FL patients who initiated 1LT met the patient selection criteria; of these, 362 and 417 received bendamustine+R and other R-based combinations, respectively. The majority of the other R-based combinations were R-CHOP (48.7%) and R-CVP (25.4%). The mean age (bendamustine+R, 65.3 [SD: 11.5] and other R-based combinations, 65.0 [SD: 11.6]) and proportion of males (bendamustine+R, 48.9% and R-based combinations, 48.0%) were similar between the two treatment groups. At baseline, 19.3% of patients treated with bendamustine+R and 15.3% of patients treated with other R-based combinations had a Charlson Comorbidity Index of ≥2. Unadjusted Kaplan-Meier analysis revealed that for patients treated with bendamustine+R and R-based combinations, 2-year OS rates were 90.2% and 86.2% (P=0.0916), respectively, and 2-year PFS rates were 76.7% and 56.0% (P Conclusion: In routine clinical practice, patients treated with bendamustine+R in 1LT had significantly better 2-year PFS than patients treated with other R-based combination therapy, while OS was similar between the groups. These results are similar to that of the clinical trial comparing bendamustine plus rituximab and R-CHOP, where PFS was found to be significantly better with bendamustine plus rituximab and OS was similar (Rummel 2009). Disclosures Galaznik: Takeda Pharmaceuticals: Employment, Equity Ownership. Bell: Takeda Pharmaceuticals: Employment, Equity Ownership. Hamilton: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Ogbonnaya: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Hennenfent: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Eaddy: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Shou: Takeda Pharmaceuticals: Employment, Equity Ownership.

Megakaryocytes are rare hematopoietic cells comprising only about 0.02-0.05% of the bone marrow nucleated cell population. Because of the relative infrequency of megakaryocytes in the bone marrow and their fragility in vitro, studies to characterize expression of platelet-specific genes have mostly been carried out in continuous cell lines originating from leukaemic marrow or blood cells that express a range of megakaryocytic phenotypic properties. HEL cells, which are representative of such cell lines, were instrumental in getting the molecular analysis of megakaryocytes and platelets established, and although these cells are still useful for many studies, it has become clear that they have significant limitations. These limitations include the fact that these lines only approximate megakaryocytes. These lines do not contain α-granules, do not demarcate or release platelets, respond appropriately to thrombopoietin (TPO), or express the high levels of such platelet-specific proteins such as the integrin αIIb and platelet factor 4 (PF4). Other proteins such as the platelet-restricted G protein G(z)α has not been detected in any of these cell lines. Further, these cell lines often express a mixture of multiple different lineages and can be easily shifted from one lineage to another.

6513 Background: Response dynamics in pts treated with nilotinib for imatinib failure may be different than imatinib in front line. Many pts treated with nilotinib in the second line achieved cytogenetic responses early (median time to MCyR and CCyR of 2.8 mo and 3.3 mo). A previous landmark analysis demonstrated BCR-ABL% (IS) at 3 months (mo) on nilotinib predicted achievement of subsequent cytogenetic response. Here, we investigated whether early molecular response before 3 mo was associated with subsequent cytogenetic response. Methods: CML-CP pts (N = 321) with imatinib resistance or intolerance were grouped by 1 mo BCR-ABL% (IS) and landmark analyses were performed to evaluate probability of cytogenetic response with a minimum follow-up of 24 mo. Results: Early molecular response of BCR-ABL% (IS) ≤ 10 occurred in 19% of pts who received nilotinib. Pts with BCR-ABL% (IS) >1 – ≤10 (n = 37) had higher probability of MCyR by 12 mo (84%) compared with pts with BCR-ABL% (IS) >10 (55%) (n = 202). Pts with B...

BACKGROUND Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. METHODS This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. FINDINGS Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. INTERPRETATION Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. FUNDING Trillium Therapeutics.

6502 Background: In ENESTnd, nilotinib has demonstrated superior efficacy vs imatinib in newly diagnosed CML-CP pts. Baseline (BL) BCR-ABL mutation status and emergence of new mutations with minimum 24 month (mo) follow-up are reported here. METHODS CML-CP pts received nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg qd (n = 283). Mutation testing was performed by direct sequencing of the kinase domain in a central laboratory at: BL, 5-fold increase in PCR levels, < MMR at 12 mo, loss of MMR, or treatment end. RESULTS No pt (N = 846) had a mutation at BL. Twice as many new mutations occurred on imatinib vs nilotinib and were more frequent in pts with High or Intermediate Sokal risk. A similar number of pts had new mutations on nilotinib 300 (4%) and 400 mg bid (3%), with a similar mutation profile. Emergence of T315I mutations and the number of pts with multiple mutations was similar across arms. Majority of mutations on imatinib were nilotinib-sensitive (imatinib-resistant). Seven of 20 pts with new mutations on imatinib progressed to AP/BC on treatment and of the 13 pts who did not progress, all but 2 discontinued due to suboptimal response or treatment failure. CONCLUSIONS The incidence of new mutations was higher on imatinib vs nilotinib, with nilotinib-sensitive (imatinib-resistant) mutations mostly observed in the imatinib arm. More pts with new mutations progressed to AP/BC on imatinib than on nilotinib. [Table: see text].

Resistance or intolerance to imatinib in CML-CP occurs in ~20–30% of cases. The most frequent cause of resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I) indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy. The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50 ≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to nilotinib in vitro (IC50 >150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, after 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 28% of pts. In pts with detectable mutations, 51% achieved MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib (MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations: 34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11). Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29% vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline mutations.

Table S1. Summary of most common drug-related AEs, by dosing schedule; Table S2. Summary of pharmacokinetic parameters of TAK-117 on day 1 of cycle 1 across different dosing schedules (pharmacokinetics-evaluable population); Table S3. Summary statistics of TAK-117: multiple-dose pharmacokinetic parameters across different schedules (pharmacokinetics-evaluable population).

Background: DLBCL is the most common histologic subtype of non-Hodgkin lymphoma, accounting for about 33% of all NHL cases. However, the healthcare burden associated with DLBCL has not been extensively studied in a US population. We evaluated the costs of care and healthcare utilization (HCU) of DLBCL patients treated during routine care in the US. Methods: The Optum claims database was used to identify adult patients (≥18 years old) with newly diagnosed DLBCL between 01/01/08 and 10/31/15. DLBCL diagnosis was based on ≥1 inpatient claim or ≥2 outpatient claims with DLBCL diagnosis codes, with the index date being the first DLBCL claim. Patients were followed from index date until end of continuous enrollment, death, or end of study period (12/31/15) for the assessment of HCU and costs. DLBCL-related and non-DLBCL-related HCU and costs incurred during follow-up were evaluated. DLBCL-related HCU and costs were medical claims with a primary diagnosis of DLBCL or DLBCL-related treatments (chemotherapy, radiation, stem cell transplant (SCT), supportive care) and pharmacy claims for DLBCL treatment. Proportions of patients with HCU were reported. Costs were calculated as per-patient-per-month (PPPM) costs and reported as mean and standard deviation (SD). Patients with a capitated payment plan were excluded from the cost analysis. Results: 1,267 treated DLBCL patients were identified. Median follow-up from index diagnosis date was 19.5 months (interquartile range: 8.8, 37.3). Over the follow-up period, 66.0% of patients had ≥1 inpatient admission, with more patients having a non-DLBCL-related than DLBCL-related admissions (Table 1). 60.0% of patients had ≥1 emergency room visit over the follow-up period; visits were predominately for non-DLBCL-related. Nearly all patients had ≥1 physician office visits (92.4%) and other outpatient visits (99.6%). The mean PPPM costs incurred during the follow-up period was $11,890 (SD: $11,515) (Table 1), and costs were higher in Year 1 ($14,402, SD: $10,951) than in Year 2 ($4,190, SD: $8,076). About 55% of costs overall were related to DLBCL-medical services ($6,532 PPPM, SD: $6,457). DLBCL-related medical PPPM costs decreased substantially from Year 1 ($8,327, SD: $5,925) to Year 2 ($1,443, SD: $4,349). This decrease was driven by the decreases in chemotherapy and supportive care medical services from Year 1 to Year 2. Non-DLBCL-related medical costs accounted for about 42% of the overall PPPM costs ($4,955, SD: $7,210); and a decrease was observed from Year 1 ($5,640, SD: $7,468) to Year 2 ($2,447, SD: $5,456). Inpatient admission was the main component of non-DLBCL-related costs, and associated costs decreased from Year 1 to 2. Conclusions: The economic burden associated with the treated DLBCL population is high, with the majority of costs incurred during the first year of diagnosis. Between the first and second year of diagnosis, costs decrease mainly because of the decrease in the DLBCL-related treatment costs. In addition, HCU for DLBCL-related services decreased in Year 1 vs Year 2. Disclosures Galaznik: Takeda Pharmaceuticals: Employment, Equity Ownership. Bell: Takeda Pharmaceuticals: Employment, Equity Ownership. Hamilton: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Ogbonnaya: Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Hennenfent: Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Eaddy: Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Shou: Takeda Pharmaceuticals: Employment, Equity Ownership.

Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging Fcγ receptors. Here we report updates from the first-in-human study of TTI-621 (NCT02663518) in hematologic malignancies. Methods Study Part 1 tested increasing weekly intravenous doses of TTI-621 based on 3+3 escalation. The maximum tolerated dose was initially determined to be 0.2 mg/kg based on dose limiting toxicity (DLT) of thrombocytopenia [Grade (Gr) 4 of any duration]. Expanded testing followed in patients (pts) with hematologic malignancies, including leukemia, lymphoma, and multiple myeloma. In Part 2, most pts received 0.2 mg/kg. However, based on investigator discretion, a subset of pts received escalating doses up to 0.5 mg/kg. In Part 3, pts with T-cell lymphomas received stepwise dose escalations from 0.2 to 0.5 mg/kg over the first 5−8 weeks. In over 200 pts tested in Parts 1−3, thrombocytopenia did not increase with dose, typically recovered within 2−4 days, and was not associated with clinical sequelae. Part 4 was then undertaken to optimize TTI-621 dosing and is currently escalating doses in a 3+3 manner through pre-planned dose levels (0.5, 0.7, 1, and 1.4 mg/kg) in pts with cutaneous T-cell lymphoma (CTCL). The DLT criteria was modified to require Gr 4 thrombocytopenia lasting >72 hours. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) per CTCAE v 4.03. Blood samples are obtained for pharmacokinetics (PK) and for pharmacodynamic (PD) assessments of receptor occupancy (RO) on normal peripheral T cells. Disease assessments are performed per Olsen's criteria. Results In Parts 1−3 (n=214), the most common related AEs were infusion-related reaction (IRR, 43%; 3% Gr ≥3), thrombocytopenia (30%; 22% Gr ≥3), chills (21%; 0% Gr ≥3), and fatigue (15%; 1% Gr ≥3). Objective responses to single agent TTI-621 were achieved in 14/71 (20%) NHL pts including CTCL (n=42, 1 CR, 7 PRs), PTCL (n=22, 2 CRs, 2 PRs) and DLBCL (n=7, 1 CR, 1 PR). In Part 4, as of July 10, 2020, 15 pts (9M/6F, median age 67 years) have enrolled into 4 dose cohorts (0.5−1.4 mg/kg). CTCL subtypes include mycosis fungoides (MF, n=10) and Sézary syndrome (n=5) with advanced (≥IIB) disease in 9 (60%) pts who received a median of 3 (range 1−12) prior systemic therapies. Related AEs have occurred in 11 (73%) pts including IRR (n=10) and thrombocytopenia (n=3); Gr ≥3 AEs have occurred in 4 (27%) pts including thrombocytopenia (n=3), IRRs (n=2), and exfoliative dermatitis (n=1). Thrombocytopenia generally occurred on dosing days, recovered in 2-4 days, and has not worsened with increasing doses. IRRs typically occurred during initial infusions. The Gr 3 IRR events occurred in 2 pts in the 1 and 1.4 mg/kg cohorts; low Gr IRRs have occurred across doses in 8 pts. IRRs typically resolved without recurrence and low Gr events often resolved allowing for completion of infusions. For initial infusions, the Gr 3 IRRs prompted increasing infusion times from 1 hour up to 4 hours and discretional use of steroid pre-medication. The exfoliative dermatitis occurred Day 80 and led to treatment discontinuation in 1 pt with MF whose underlying disease confounded the etiology. PK results reveal dose dependent increases in exposure; PD studies indicate ~60% RO at end of infusion up to 1 mg/kg. Antitumor activity to date includes 1 PR and 1 skin CR in 6 evaluable pts in the 1 mg/kg cohort; 2 responding pts bridged to allogeneic transplantation. The mean % change in mSWAT scores were -0.4%, -27%, and -37% for 0.5, 0.7 and 1 mg/kg cohorts, respectively. 1.4 mg/kg cohort results will be presented at the meeting. Conclusions In Parts 1−3, TTI-621 doses of 0.05 to 0.5 mg/kg were well-tolerated and demonstrated single agent activity in multiple hematologic malignancies. Preliminary data from Part 4 dose optimization indicate that weekly infusions of TTI-621 up to 1.4 mg/kg are well-tolerated without dose limiting or cumulative thrombocytopenia. Antitumor activity was seen at 1 mg/kg; dose escalation is continuing at 2 mg/kg. Disclosures Horwitz: Janssen: Consultancy; Verastem: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; ASTEX: Consultancy; Portola: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Myeloid Therapeutics: Consultancy; Vividion Therapeutics: Consultancy; Infinity/Verastem: Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Affirmed: Consultancy;…

Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is found to be associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Methods TTI-622-01 is an ongoing multicenter, Phase 1 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of TTI-622 in adult patients with relapsed/refractory (R/R) lymphoma (NCT03530683). Based on a modified 3+3 scheme, weekly doses are escalated through pre-planned dose levels ranging from 0.05 to 8 mg/kg. The observation period for dose limiting toxicity (DLT) is the initial 3 weeks of treatment. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03. Blood samples are collected for PK analysis and assessment of receptor occupancy on normal peripheral T cells. Disease assessments are performed per Lugano criteria every 8 weeks within the first 6 months, every 3 months up to two years, and every 6 months thereafter until the end of treatment. Results As of the July 16, 2020 cutoff, 25 patients (12M/13F) with a median age of 68 years (range 24-86) have received dose levels of 0.05−8 mg/kg with testing at 8 mg/kg ongoing. Patients with the following histologies have been enrolled: diffuse large B-cell lymphoma (DLBCL; n=13), Hodgkin lymphoma (n=5), follicular lymphoma (FL; n=2), peripheral T-cell lymphoma (PTCL; n=2), cutaneous T-cell lymphoma with CD30 negative large cell transformation (CTCL-LCT, n=2), and mantle cell lymphoma (n=1). Disease stages at entry have been III or IV in 23 patients; patients had received a median of 3 (range 1-9) prior systemic therapies including CAR-T in 5 patients and HSCT in 6 patients. Treatment-related AEs have been reported in 12 (48%) patients. Most AEs have been grade 1 or 2. The most frequent treatment-related AEs include thrombocytopenia (n=4; 1 grade ≥3), neutropenia (n=3; 3 grade ≥3) and fatigue (n=3; 0 grade ≥3). Grade 4 thrombocytopenia occurred in 1 patient in the 8 mg/kg cohort and accounted for the only DLT and treatment-related serious AE reported to date. This event that occurred on Day 8 was not associated with bleeding and resolved within 1 day after prophylactic platelet transfusion. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. No other grade ≥3 thrombocytopenia have been observed in the 4 other DLT evaluable patients dosed with 8 mg/kg to date. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. PD results indicate that end-of-infusion CD47 receptor occupancy (RO) is above 60% at doses ≥2 mg/kg and that RO is more sustained with TTI-622 doses ≥1 mg/kg compared to lower doses. Objective responses have been achieved in 5 patients, including 1 complete response (CR) in DLBCL (0.8 mg/kg) and 4 partial responses (PR) in PTCL (2 mg/kg), DLBCL (4 mg/kg), CTCL-LCT and FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 5 responders including initial PR in the patient who subsequently achieved CR at week 36 (See Figure 1). In the dose range of 0.8-8 mg/kg, objective responses occurred in 31% (5/16) of patients with ≥1 post-treatment response assessment (See Table 1). Two of 4 response evaluable patients in the ongoing 8 mg/kg cohort achieved a PR, and 2 other patients have been on treatment for <8 weeks. Conclusions Results to date from this ongoing Phase 1 study in patients with R/R lymphomas indicate that weekly doses of TTI-622 up to 4 mg/kg are well tolerated with dose-dependent increases in exposure and RO. TTI-622 has shown activity in R/R lymphoma with objective responses across a broad dose range (0.8-8 mg/kg) and in multiple histologies. The study is currently evaluating the 8 mg/kg dose level. Disclosures Patel: Pharmacyclics: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kite: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle…

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway–activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway–activated medulloblastoma.Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded.Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment. Clin Cancer Res; 21(3); 585–93. ©2014 AACR.

6567 Background: CML patients with different types of BCR-ABL transcript may vary in disease prognosis and responses to therapy. An analysis was conducted to investigate the correlation between BCR-ABL transcript type and responses to nilotinib in the second-line setting. Methods: CML-CP pts (n = 321) with imatinib resistance or intolerance were included. In order to determine if transcript type influenced response dynamics, BCR-ABL transcript types were analyzed in 301/321 (94%) of pts. In addition, the BCR-ABL transcript dynamics were modeled as previously described (Stein et al. Blood. 2009;114(22):209). Results: Median nilotinib exposure was 561 days. The majority of pts (95%) were observed to have typical b3a2 (63%) and b2a2 (32%) BCR-ABL transcript types; 3% of pts had both typical transcripts and 2% had atypical transcripts (e1a2, e19a2, b3a3). The incidence of BL mutations was higher in patients with b3a2 transcripts compared with b2a2 (46% vs. 32%, p = 0.03). Response to nilotinib was similar reg...

Nilotinib (AMN107) is a novel, orally active aminopyrimidine-derivative, which selectively inhibits the BCR-ABL tyrosine kinase with greater potency compared with imatinib (Im). In preclinical models, nilotinib was 20–50 times more potent than imatinib in Im-sensitive CML cell lines, and 3–7 times more potent in Im-resistant cell lines. Activity of nilotinib was also demonstrated in 32/33 Im-resistant mutant cell lines. We sought to investigate the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations. We have investigated peripheral blood samples from 101 CML patients (pts, 63m, 38 f) with a median age of 61 yrs (range, 23–85) who had been enrolled in an international phase II study investigating the efficacy and safety of 400mg nilotinib bid after Im failure (chronic phase, CP, n=64; accelerated phase, AP, n=22; blast crisis, BC, n=15). Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. The proportion of the mutated clone was estimated from sequencing plots by comparison to plots from serial standard dilutions of Ba/F3 cell lines harboring various concentrations of mutated BCR-ABL. Hematologic and cytogenetic response data are available for a median of 4 mo (range, 1–10) after start of nilotinib therapy. Prior to nilotinib, 28 different BCR-ABL mutations involving 22 amino acids were detected in 61/101 pts (60%). Nine pts showed two, three pts three, and one patient four mutations. Mutations were observed in 37 pts in CP (49%), 15 pts in AP (68%), and 9 pts in BC (60%). In pts with mutations, the overall rate of hematologic response was 70% (78% in CP, 75% in AP, 25% in BC) compared with 88% in pts without mutations. In CP CML, complete cytogenetic response was achieved within 3–6 mo in pts with mutations with high in vitro sensitivity to nilotinib according to O’Hare et al., Cancer Res 2005 and Weisberg et al., Br J Cancer 2006 (M244V, 38nM, n=2; M351T, 15nM; H396R, 41nM; D276G+M351T, 69 and 15nM; E355G+L387F, 47 and 46nM). 4 pts with mutations resulting in relatively higher cellular IC50 to nilotinib had progressed (Y253F+E255K, 125 and 200nM; L248V, 102nM; Y253H, 450nM; F359V, 175nM). 2 pts with small clones (ratio mutated BCR-ABL/ABL 0.14% and 8.6%) harboring the BCR-ABL mutation T315I being highly resistant to Im and nilotinib in vitro did not show signs of relapse after one and 11 mo of nilotinib therapy, respectively. During therapy, novel BCR-ABL mutations (Y253F, E255V, T315I, and F359V) appeared in 4 pts. In conclusion, preliminary data suggest that nilotinib may overcome most of the mutation-associated resistance to Im, and may have an important therapeutic role in Im resistance and in frontline CML therapy to prevent emergence of resistant clones. Response dynamics depend on the individual type of the mutation which may be the basis for individualized dosage of nilotinib according to the mutation pattern. The molecular analysis of the total phase II study population will be reported at the meeting.

Background Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic kinase that binds to phosphorylated immunoreceptor tyrosine-based activating motifs and mediates cellular proliferation and survival. SYK plays a key role in B-cell receptor signaling-driven tumorigenesis; thus, inhibition of SYK represents a viable therapeutic approach for various B-cell malignancies. Preclinical studies of TAK-659, an investigational, reversible SYK inhibitor, demonstrated inhibition of SYK activity and cell proliferation in vitro and dose-dependent tumor growth inhibition in vivo in lymphoma xenograft models. The primary objectives of this first-in-human phase 1 study (NCT02000934) are to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659. Secondary objectives include evaluation of the preliminary antitumor activity and the pharmacokinetics (PK) of TAK-659. Methods Pts aged ≥18 yrs with advanced solid tumors or lymphoma, for which standard treatment was either not available or no longer effective, received oral TAK-659 daily (QD, 60-120 mg) in 28-d cycles. For MTD determination, dose escalation proceeded via a modified titration design based on dose-limiting toxicities (DLTs) or drug-related grade ≥2 adverse events (AEs) during cycle 1 (C1). Cell of origin classification data (activated B cell [ABC] vs germinal center B cell [GCB] subtype via immunohistochemistry) were collected from pts with diffuse large B-cell lymphoma (DLBCL). AEs were assessed per NCI-CTCAE v4.03. Blood samples for plasma PK assessments were collected pre-dose and at multiple times post-dose on d1 and d15 of C1. Response per RECIST v1.1 (solid tumors) and per IWG modified criteria (lymphoma) was assessed between d22 and d29 (pre-dose, d1 next cycle) of C2, C4, and C6, and then every 3 cycles. Results At data cut-off (June 15, 2015), 24 pts had been enrolled (14 solid tumor pts; 10 lymphoma pts) at 4 dose levels of TAK-659 (60, 80, 100, 120 mg). Overall, the median age was 58 years [range 43-80], 67% were male, and 58% had ≥4 prior lines of therapy. Of 10 lymphoma pts, 7 had DLBCL (5 GCB and 2 ABC subtypes) and 3 had follicular lymphoma (FL). Six pts remain on the study; 2 solid tumor and 4 lymphoma pts. The median number of TAK-659 cycles was 2 (range 1-4) for solid tumor pts and 4 (1-12) for lymphoma pts (Figure 1). C1 DLTs occurred in 5 pts; 1 pt at 60 mg (grade 3 asymptomatic aspartate aminotransferase [AST] elevation) and 4 pts at 120 mg (grade 3 and 4 asymptomatic lipase elevation, grade 3 mucositis, and grade 3 generalized edema). MTD determination is ongoing. All grade drug-related AEs occurred in 18 pts (75%) overall; the most common were fatigue (25%), elevated AST (21%), anemia (17%), and diarrhea (17%). Grade ≥3 drug-related AEs occurred in 8 pts (33%); anemia (1 pt at 60 mg, 2 pts at 120 mg), hypophosphatemia (2 pts at 80 mg), and increased lipase (2 pts at 120 mg) were seen in ≥1 pt. Four pts discontinued due to AEs (1 considered related to TAK-659, grade 3 pneumonia); 5 pts died on study (deaths were not considered related to TAK-659). Preliminary plasma PK of TAK-659 (n=24, 60-120 mg) showed rapid absorption (median Tmax 2 hrs), moderate variability in steady-state exposures (54% coefficient of variation for d15 dose-normalized AUCtau), mean peak-to-trough ratio of 4, and accumulation of 2.3-fold after repeated QD dosing for 15 d. Of 7 response-evaluable DLBCL pts, 2 pts (1 at 60 mg [GCB], 1 at 80 mg [ABC]) achieved partial responses (PRs), and a 3rd pt (at 120 mg [GCB]) achieved a PR post data cut-off (Figure 1). One GCB-DLBCL responder with multiple prior therapies including autologous hematopoietic stem cell transplantation is ongoing in C12. Two of 3 FL pts (both at 100 mg) were response-evaluable - 1 achieved a PR after 2 cycles (ongoing in C5) and 1 achieved a complete response after 2 cycles (ongoing in C4). Updated results will be presented at the meeting. Conclusions Oral TAK-659 60-100 mg QD appears to have an acceptable safety profile with an acceptable PK profile that supports continuous oral QD dosing. Early antitumor activity in DLBCL and FL pts is evident. Expansion cohorts are planned in pts with DLBCL and chronic lymphocytic leukemia. In addition, TAK-659 is also a potent FLT-3 inhibitor; a separate ongoing clinical trial is investigating the dual SYK and FLT-3 inhibitory activity of TAK-659 in relapsed/refractory acute myelogenous leukemia (NCT02323113). Disclosures Petrich: Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Off Label Use: This is a first-in-human phase 1 study of TAK-659, an investigational…

CD47 is frequently overexpressed on tumor cells and is an attractive therapeutic target. The mechanism by which anti-CD47 immunotherapy eliminates cutaneous lymphoma has not been explored. We utilized CRISPR/Cas-9 CD47 knock-out, depletion of NK cells, and mice genetically deficient in IFN-γ to elucidate the mechanism of anti-CD47 therapy in a murine model of cutaneous T cell lymphoma (CTCL). CD47 was found to be a crucial factor for tumor progression since CD47 KO CTCL exhibited a delay in tumor growth. The treatment of CD47 WT murine CTCL with anti-CD47 antibodies led to a significant reduction in tumor burden as early as four days after the first treatment and accompanied by an increased percentage of cytotoxic NK cells at the tumor site. The depletion of NK cells resulted in marked attenuation of the anti-tumor effect of anti-CD47. Notably, the treatment of CD47 WT tumors in IFN-γ KO mice with anti-CD47 antibodies was efficient, demonstrating that IFN-γ was not required to mediate anti-CD47 therapy. We were able to potentiate the therapeutic effect of anti-CD47 therapy by IFN-α. That combination resulted in an increased number of cytotoxic CD107a + IFN-γ-NK1.1 cells and intermediate CD62L + NKG2a-NK1.1. Correlative data from a clinical trial (clinicaltrials.gov, NCT02890368) in patients with CTCL utilizing SIRPαFc to block CD47 confirmed our in vivo observations.

2501 Background: PI3K signaling is aberrantly activated in many solid tumors; isoform-selective targeting may enable robust inhibition of this pathway in PIK3CA mutant tumors while sparing signaling in normal tissues. This study (NCT01449370) evaluated the safety, MTD, preliminary antitumor activity and pharmacokinetics/pharmacodynamics (PK/PD) of an investigational PI3Kα isoform-selective inhibitor, MLN1117. Methods: Pts age ≥ 18 with advanced solid tumors (except primary brain tumors) and known PIK3CA mutation status received oral MLN1117 once daily (QD, 100–300 mg) or 3 days per wk (MWF, 200–1200 mg, or MTuW, 200–900 mg) in 21-d cycles. Dose escalation proceeded via a 3+3 design based on cycle 1 (C1) DLTs. Plasma concentrations of MLN1117 for PK analyses were evaluated in C1. PI3K pathway biomarkers were assessed in skin biopsies via immunohistochemistry. Results: At data cut-off, 76 pts had enrolled; 24/29/23 pts to QD/MWF/MTuW schedules; median of 3 cycles per group. C1 DLTs occurred in: 2 QD pts (AL...

TPS3104 Background: TAK-659 is an investigational, reversible, potent dual inhibitor of SYK and FLT-3. In ongoing early-phase studies (NCT02000934; NCT02323113), TAK-659 demonstrated an acceptable pharmacokinetic and safety profile, with evidence of preliminary activity in pts with DLBCL, follicular lymphoma, CLL, and AML (Kaplan et al. Blood 2016;128:624/2834). In preclinical studies, TAK-659 in combination with nivolumab, an anti-PD-1 checkpoint inhibitor, resulted in loss of myeloid suppressor cells (MDSCs), increased T-cell activation, and complete tumor growth suppression (Kannan et al. Eur J Cancer 2016;69:S92). This first-in-human combination study will investigate the efficacy and safety of TAK-659 and nivolumab in pts with advanced solid tumors. Methods: This open-label, multicenter, phase 1b study (NCT02834247) will include dose-escalation and expansion phases. Pts with advanced solid tumors who have failed ≥1 prior lines of therapy and have no effective therapeutic options available by investigator assessment will be eligible for the dose-escalation phase. Pts will receive oral TAK-659 at doses of 60–100 mg QD in a standard 3+3 schema, plus nivolumab 3 mg IV on days 1 and 15 of 28-day cycles. The expansion phase at the recommended phase 2 dose (RP2D) will include 3 cohorts of pts with relapsed/refractory metastatic triple-negative breast cancer, locally advanced/metastatic NSCLC, or locally advanced/metastatic head and neck squamous cell carcinoma (n = 30 response-evaluable pts in each cohort; 24 naïve, 6 relapsed/refractory to prior anti-PD-1/PD-L1 therapy). Ten pts in each cohort will receive 2 weeks of single-agent TAK-659 before starting combination therapy; the other 20 pts will receive combination therapy throughout. The primary endpoints are maximum tolerated dose/RP2D (dose-escalation phase) and overall response rate by investigator per RECIST v1.1 (expansion phase). Secondary endpoints include adverse events, disease control rate, duration of response, progression-free survival, overall survival, and TAK-659 pharmacokinetics. There are currently 7 pts enrolled; recruitment to the 100 mg dose-escalation cohort is ongoing. Clinical trial information: NCT02834247.

Background Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic protein kinase and a key mediator of immunoreceptor signaling that has been shown to play an important role in the pathogenesis of both B-cell and myeloid malignancies. SYK has also been shown to directly bind and activate FMS-like tyrosine kinase 3 (FLT-3), a Class III receptor tyrosine kinase that is commonly mutated in approximately 30% of pts with AML (Puissant et al. Cancer Cell 2014;25:226-42). TAK-659 is an investigational, reversible, and potent dual inhibitor of SYK and FLT-3. Preclinical studies with TAK-659 have demonstrated growth inhibition of cell lines and xenograft tumor models of B-cell lymphoma or AML origin. Moreover, TAK-659 has exhibited antitumor activity in lymphoma pts in an ongoing clinical trial (Petrich et al. Blood 2015;126:2693). The primary objectives of the phase 1b dose-finding portion of this study are to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659, as well as preliminary efficacy in the phase 2 expansion study. Secondary objectives include evaluation of TAK-659 pharmacokinetics (PK) in this pt population. Methods During dose escalation using a 3x3 schema, adult pts with R/R AML received oral TAK-659 daily (QD) in 28-d cycles (C) starting with a dose of 60 mg. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Response per IWG criteria for AML was assessed between d22 and d28 of C1, C2, and C4. Blood samples for plasma pharmacokinetic (PK) assessments were collected pre-dose and at multiple times post-dose on d1 and d15 of C1. The pharmacodynamic effect of TAK-659 was assessed at multiple time points by measuring the phosphorylation of ribosomal protein S6 (pS6) in peripheral AML blasts using flow cytometry. FLT-3 mutation status (wild type [FLT-3-WT], FLT-3-ITD, or point mutation [FLT-3-D835Y]) was assessed using a PCR-based assay at a central laboratory. The effect of TAK-659 treatment on FLT-3-ITD phosphorylation was evaluated using a plasma inhibitory assay (PIA) as previously described (Levis et al. Blood 2006;108:3477-83). Results At data cut-off (June 9, 2016), 15 pts had been enrolled at TAK-659 QD 60 mg (n=4), 100 mg (n=7), or 120 mg (n=4). No dose-limiting toxicity per protocol has been observed. Dose escalation is currently ongoing at 160 mg QD. In the safety population (n=13), median age was 67 yrs (range 25-86), 69% of pts were male, and 38% had received ≥4 prior lines of therapy. Baseline mutation data was available for 12 pts: 6 pts were FLT-3-WT, 3 pts had FLT-3-ITD, 1 pt had FLT-3-D835Y, and 2 pts had concurrent FLT-3-ITD/D835Y mutations. In the safety population, all-grade drug-related AEs occurred in 12 (92%) pts overall; the most common were elevated AST (31%), ALT (23%), and amylase levels (23%). Grade ≥3 drug-related AEs occurred in 7 (54%) pts including: increased ALT, AST, and amylase levels, cataract, positive fungal test, macular fibrosis, pancreatitis, pneumocystis jirovecii pneumonia, rash, and fungal sinusitis (each 1pt). Blood LDH levels were increased in almost all pts (significance unknown). Three pts discontinued TAK-659 due to AEs and 3 pts died on study; none of these events were considered related to the study drug. Preliminary plasma PK of TAK-659 (n=11, 60-100 mg) was characterized by rapid absorption (median Tmax of 2 hours), moderate variability in steady-state exposures (42% coefficient of variation for C1 d15 dose-normalized AUCtau), and mean accumulation of 2.1-fold after repeated QD dosing for 15 days. Of 9 pts evaluated to date, pS6 was detected at baseline and reduced after dosing in 4 pts (2 FLT-3-ITD; 2 FLT-3-WT). At 60 mg and 100 mg TAK-659, up to 70% inhibition of FLT-3-ITD phosphorylation was observed as assessed by PIA. Early signs of clinical activity were observed, with decreases in peripheral blood myeloblasts observed in some pts. Assessment is ongoing and preliminary efficacy data will be presented. Conclusions TAK-659 has a unique mechanism of action with dual inhibition of SYK and FLT-3. Dose escalation to determine the MTD/RP2D is ongoing. TAK-659 exhibits an acceptable PK profile in R/R AML pts, supporting continuous oral QD dosing. Disclosures Kaplan: Seattle Genetics: Research Funding; Janssen: Research Funding. Morris:Boehringer-Ingelheim: Speakers Bureau. Altman:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wise-Draper:Merck: Research Funding. Collins:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kannan:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of…

Abstract 1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months…

PDF file - 71K, Supplementary data includes a table summarizing cohort enrollment and dose-limiting toxicities (Table S1) and a table showing the association between tumor response and Hh pathway activity in medulloblastoma and basal cell carcinoma (Table S2).