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Background: Overexpression of AAK, a key regulator of mitosis, is seen in various solid tumors, including prostate cancer. This open-label, Phase 1 trial investigated the ...safety/tolerability of MLN8237, an oral selective AAK inhibitor, combined with DTX in pts with advanced solid tumors, including CRPC. Methods: Previously treated pts aged ≥18 y who were candidates for DTX received 21-day cycles of MLN8237 10–50 mg BID on days 1–7, escalated in 3+3 dosing cohorts, plus DTX 60 or 75 mg/m
2
on day 1. To manage toxicity, a 5-day MLN8237 regimen was later evaluated with DTX 60 or 75 mg/m
2
+ G-CSF support. Primary endpoints were safety/tolerability and recommended phase II dose/schedule (RP2D). Pharmacokinetics (PK) and antitumor activity (RECIST 1.1/PSA) were also assessed. Results: 35 pts (median age 63 y 25–87; 71% male; 17 CRPC) recruited into 8 cohorts received a median of 3 (1–33) cycles; 15 pts (11 CRPC) had ≥6 cycles. 14 DLTs were seen in 11 pts (5 CRPC) in Cycle 1: G4 neutropenia >7 days (n=3), G3/4 febrile neutropenia (FN; n=7), G3 stomatitis (n=3), and G3 urinary tract infection (n=1). The RP2D was MLN8237 20 mg BID on Days 1–7 + DTX 75 mg/m
2
in 21-day cycles without G-CSF. Common G≥3 drug-related AEs included neutropenia (86%), leukopenia (31%), FN (23%) and stomatitis (14%). 20 (57%) pts reported SAEs, most commonly FN (n=8). 2 pts withdrew due to AEs, inc. 1 death (G3 FN; G3 mucositis); 4 pts continue on study. On-study deaths (n=2; disease progression) were not considered drug-related. Steady-state MLN8237 exposure (AUC
ss
) increased approximately dose-proportionally over 10–30 mg BID when combined with DTX (n=16). Analysis of the effect of MLN8237 on DTX PK at RP2D is ongoing. Among 11 evaluable CRPC pts, 6 had PR (4 had PSA50) and 6 had SD (4 with PSA50). 2 other pts (bladder cancer and angiosarcoma) also had PR. Conclusions: The RP2D was MLN8237 20 mg BID on days 1–7 + DTX 75 mg/m
2
on day 1. Despite myelosuppression, the combination of MLN8237 and DTX had a generally manageable toxicity profile in pts with advanced solid tumors. Further clinical study of this combination, particularly in CRPC pts, is warranted. Clinical trial information: NCT01094288.
Background PTCL is an aggressive subgroup of NHL. Outcomes in R/R PTCL remain poor and alternative therapies are needed. Alisertib is an investigational, oral, selective inhibitor of Aurora A kinase, ...a key mitotic regulator that is overexpressed/amplified in various cancers, including lymphomas. Phase 2 data with single-agent alisertib in R/R NHL (Friedberg et al JCO 2014) and R/R PTCL (Barr et al JCO 2015) suggested promising antitumor activity. This international phase 3 trial evaluated single-agent alisertib vs investigator's choice in pts with R/R PTCL, and was the first initiated randomized trial in this setting.
Methods Adult pts with R/R PTCL (WHO criteria) after ≥1 prior conventional systemic cytotoxic therapy, who had measurable disease by 2007 IWG criteria, tumor biopsy for central hematopathology review, and ECOG PS 0-2, were eligible. Pts were randomized 1:1 (stratified by nodal vs extranodal disease, IPI score 0/1/2 vs 3/4/5, and region North America + EU vs Rest of World) to receive alisertib 50 mg twice daily as an enteric coated tablet on d 1-7 in 21-d cycles (alisertib arm), or investigator's choice of: pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles; romidepsin 14 mg/m2 IV on d 1, 8, and 15 in 28-d cycles; or gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 in 28-d cycles (comparator arm), until disease progression, unacceptable toxicity, or 2 yrs (extendable if benefit shown). Selected comparator drug could not have been previously received by the pt, and crossover to another study drug was not permitted. The primary endpoints were ORR (CR+PR) and PFS by IWG criteria per central (IRC) assessment. Secondary endpoints included OS, CR rate, DOR, and safety. The study employed an adaptive sample size reassessment approach, with two interim analyses (IA1, futility analysis; IA2) plus a planned final analysis. Sample size was determined to give 80% power to detect a difference in ORR (assumed 55% alisertib vs 30% comparator) at IA2, and ~85% power to detect a reduction in HR for PFS in favor of alisertib at the final analysis with a maximum of 354 randomized pts and a maximum of 261 PFS events. Conditional power calculation based on PFS at IA2 could determine whether the study would be stopped for futility or if sample size would be expanded for the final analysis. Here we report data from IA2 (17Sep2014 data cut-off).
Results 238 pts were randomized across 27 countries (120 alisertib, 118 comparator). Baseline characteristics were balanced between arms (alisertib vs comparator): median age 63 vs 64 yrs; male 68% vs 64%; Ann Arbor stage III/IV 74% vs 72%; bone marrow involvement at study entry 29% vs 35%. Efficacy data are shown in the Table. ORR by IRC with alisertib vs comparator was 33% vs 43% (OR 0.65 95% CI: 0.34-1.23), including 16% vs 25% CR. Median duration of follow-up was 9.5 vs 9.2 mos with alisertib vs comparator. Median PFS by IRC was 3.7 vs 3.4 mos (HR 0.939 95% CI: 0.681-1.293; Figure) and median OS was 9.9 vs 12.2 mos (HR 0.901 95% CI: 0.607-1.337; OS data not mature at current follow-up). Median treatment duration with alisertib vs comparator was 12 vs 10 weeks and 15% vs 5% of pts remained on treatment at data cut-off. With alisertib vs comparator, rates of Gr ≥3 AEs were 85% vs 81%, serious AEs 53% vs 55%, discontinuations due to AEs 9% vs 13%, and on-study treatment-related deaths 2% vs 2%. Gr ≥3 AEs (>20% all pts) were neutropenia 44% vs 27%, thrombocytopenia 29% vs 27%, and anemia 30% vs 11%.
Conclusion While alisertib showed activity in R/R PTCL, there was no significant efficacy benefit vs comparator. Based on IA2, there was a low probability of claiming superiority of alisertib for PFS at the final analysis; therefore, per IDMC recommendation enrollment was stopped at 271 pts and pts deriving benefit continue on treatment. The study was unblinded and final data are pending.
TableEfficacyAlisertibComparatorAllPralatrexateRomidepsinGemcitabineResponse, n (%)*†n=83n=80n=40n=17n=23ORR (CR+PR)27 ( 33)34 (43)16 (40)10 (59)8 (35)CR13 (16)20 (25)10 (25)5 (29)5 (22)PR14 (17)14 (18)6 (15)5 (29)3 (13)SD26 (31)18 (23)13 (33)2 (12)3 (13)PD30 (36)27 (34)11 (28)4 (24)12 (52)Median DOR*† (responders), mos5.05.8---PFS*‡n=120n=118n=67n=21n=30Events, n (%)78 (65)73 (62)45 (67)7 (33)21 (70)Median, mos3.73.43.48.01.9*IRC assessment†Response-evaluable pts (n=163); n=75 not evaluable (not dosed/ no post-baseline IRC assessment/ no central confirmation of PTCL)‡ITT analysis (n=238)
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O'Connor:Spectrum: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Off Label Use: Investigational Aurora A kinase inhibitor, alisertib, for patients with relapsed/refractory peripheral T-cell lymphoma.. Demeter:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Masszi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ramchandren:Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. d'Amore:Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Foss:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Merck: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; Roche: Research Funding. Zinzani:J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jung:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhou:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dansky Ullmann:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shustov:Seattle Genetics: Research Funding.
Background: Flavopiridol is a flavonoid with antiproliferative effects mediated, in part, by inhibition of cyclin-dependent kinases.
Clinical manifestations in a previous Phase I trial in patients ...with refractory malignancies treated with a 72-h flavopiridol
infusion included a proinflammatory syndrome consisting of fever, fatigue, and “local” tumor pain with concomitant alterations
in plasma acute-phase reactant proteins.
Purpose: The aim of this study was to determine whether the proinflammatory syndrome observed in this trial was associated with modulation
of plasma cytokines.
Methods: Patients receiving flavopiridol (n = 76) had serial plasma samples drawn preinfusion and during the infusion for evaluation
of interleukin (IL)-6, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, basic-fibroblast growth factor, transforming
growth factor-β, and tumor necrosis factor-α levels by standard ELISA assays. The Wilcoxon signed rank test was used to test
the significance of the difference between the baseline (time 0) plasma cytokine levels compared with the values of each subsequent
data collection time points (8, 24, 48, and 72 h).
Results: There was a significant and sustained increase in plasma IL-6 levels at all time points when compared with baseline values.
Paired values were used in the statistical analysis. Median plasma (interquartile range) values of IL-6 were elevated from
15.5 (9–52) pg/ml at baseline to 23 (4–48) pg/ml ( P < 0.01) at 8 h; from 15 (2–48) pg/ml at baseline to 46 (21–105) pg/ml ( P < 0.001) at 24 h; from 16 (9–52) pg/ml at baseline to 61 (32–170) pg/ml ( P < 0.001) at 48 h; and from 15.5 (6–48) pg/ml to 68 (40–200) pg/ml ( P < 0.001) at 72 h. Significance was maintained even when adjusted for multiple comparisons. The relative increase in IL-6
concentration was dose-dependent. Moreover, IL-6 elevation had a direct correlation with flavopiridol peak plasma concentration,
flavopiridol area under the curve, and plasma C-Reactive protein levels. A significant decrease in plasma granulocyte macrophage
colony-stimulating factor occurred at the 8-h sampling point: 50 pg/ml (interquartile range 10–205 pg/ml, P < 0.01) when compared with baseline plasma levels and 71 pg/ml (interquartile range 5–152 pg/ml, P < 0.01). No changes in the other pro or anti-inflammatory cytokines were observed. Immunohistochemistry studies in bone marrow
aspirates from a prospective group of patients in this trial demonstrated ∼4-fold induction of IL-6 (compared with baseline),
mostly in non-T cells.
Conclusion: Biochemical analysis of plasma in patients undergoing infusional flavopiridol found a significant dose-dependent induction
of IL-6. IL-6 elevation could be a marker for the process leading to the appearance of the proinflammatory syndrome observed
in patients treated with infusional flavopiridol. The mechanism(s) underlying IL-6 induction and its significance are still
unknown but may influence strategies to modulate flavopiridol’s clinical effects.
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605
Background: MLN8237 is an investigational oral AAK inhibitor being evaluated in pts with hematologic (Ph III) and non-hematologic malignancies. We report here Ph II results from a, ...5-arm study of single agent MLN8237 in pts with advanced, predominantly refractory, solid tumors (NCT01045421; closed for enrolment). Methods: Pts ≥18 years with relapsed/refractory disease measurable by RECIST, ECOG PS 0–1, and ≤2 prior (≤4 for BrC pts) cytotoxic chemotherapy regimens were enrolled. Pts with stable brain metastases were eligible. Pts were treated at the recommended Ph II dose; 50 mg BID for 7 d in 21-d cycles. For each cohort, a Simon’s 2-stage design was employed for Ph II, with ≥2 responses required in the first 20 response-evaluable pts to proceed to stage 2. The primary endpoint was overall response rate (ORR) by RECIST v1.1; safety and progression-free survival (PFS) were key secondary endpoints. Results: As of Dec 2012, 47 SCLC, 23 NSCLC, 49 BrC, 45 HNSCC and 47 GE pts in Ph II were response-evaluable (median age, 61 yrs range 30–88). NSCLC did not proceed to stage 2. ORR was 9%, 6%, and 4% in HNSCC, GE, and NSCLC pts, respectively; median PFS was 2.7, 1.5 and 3.1 months. BrC and SCLC data are shown in the Table. 92% of pts had a drug-related adverse event (DRAE). 57% of pts had Gr ≥3 DRAEs; including neutropenia (38%), anemia (10%), stomatitis (8%), and thrombocytopenia (6%). 22 pts died during the study; none were study-drug related. Conclusions: Single-agent activity of MLN8237 was evaluated across a range of solid tumors with a manageable toxicity profile. Encouraging Ph2 data in BrC and SCLC pts suggest that MLN8237 warrants further evaluation in these tumor types. Clinical trial information: NCT01045421. Table: see text
Abstract
Background: IPI-549 is a first-in-class, oral, potent, and selective PI3K-γ inhibitor being developed as an immuno-oncology therapeutic in multiple cancer indications. Preclinical studies ...demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with an anti-PD-! antibody (NCT02637531) in solid tumors.
Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and anti-PD-! antibody will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with an anti-PD-1 antibody will occur following the dose escalation phase.
All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment.
This trial is currently enrolling patients in the US. To date, 6 patients have been enrolled and dose escalation is continuing (updated data to be presented).
Citation Format: Anthony Tolcher, David Hong, Ryan Sullivan, James Mier, Geoffrey Shapiro, Joseph Pearlberg, Les Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard M. Stern, Jedd D. Wolchok. IPI-549-01: A Phase I/Ib first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced solid tumors abstract. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B070.
Objective
This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with ...advanced solid tumors.
Methods
Following overnight fasting for 10 h, a single 50 mg enteric-coated tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration.
Results
Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median
t
max
was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUC
inf
(fed- vs. fasted-state dosing) was 0.94 90 % confidence interval (CI) 0.68–1.32. The geometric mean
C
max
under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %).
Conclusions
Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food.
ClinicalTrials.gov Identifier
NCT00962091.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of ...alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients.
A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design.
The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37).
These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.
Amplification and/or over-expression of the mitotic Aurora A kinase (AAK) have been reported in a variety of tumors. The investigational, selective, AAK inhibitor MLN8237 (alisertib) has shown signs ...of anti-tumor activity in pts with hematologic malignancies including aggressive non-Hodgkin lymphoma (NHL). Over-expression of AAK leads to resistance to microtubule targeted agents such as vincristine (V) and inhibiting AAK leads to synergy in the presence of these agents (Mahadevan D et al. CCR 2012). The combination of MLN8237 (M) + rituximab (R) ± V has shown synthetic lethality in pre-clinical B-NHL mouse models (ibid) supporting clinical evaluation of this combination; we report the safety and recommended phase 2 dose (RP2D) from the phase 1 clinical data of this MR ± V combination in pts with aggressive B-NHL.
Adults with CD20+ B-NHL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2 were eligible. In part 1 (MR), pts received one dose level of M 50 mg BID days 1–7 + R 375 mg/m2 IV day 1 in 21-day cycles (up to 8) in combination, followed by single agent M. In part 2 (MRV), M dose escalation followed a 3+3 design (M starting dose: ∼50% of MR RP2D 30mg BID days 1–7 + R 375 mg/m2 IV on day 1 + V 1.4 mg/m2 max, 2 mg IV on days 1 and 8 of 21-day cycle). The RP2D was determined as the dose level at which <2 dose limiting toxicities (DLT) occurred in 6 pts in cycle 1. Primary objectives were safety/tolerability and determination of MR and MRV RP2Ds. Secondary objectives included M pharmacokinetics (PK), the effect of M on V PK, and anti-tumor activity.
As of 16 July 2013, 35 pts were enrolled (28 DLBCL, 1 transformed follicular, 1 Burkitt, and 5 mantle cell) with data entered for 32 pts (21 male) at time of data cut-off (part 1, n=13; part 2, n=19 MLN8237: 30 mg, n=4; 40 mg n=12; 50 mg, n=3). 1 pt in the MR cohort and 8 pts in the MRV cohorts continue on treatment. Pt demographics, exposure, and safety data are shown in the table. MR was well tolerated with 1 DLT; therefore M 50 mg BID x 7 d + R 375mg/m2 was the recommended regimen for this doublet. For the MRV triplet the RP2D was M 40 mg BID. Common grade (G) ≥3 drug-related AEs across the cohorts included: thrombocytopenia, leukopenia, neutropenia, fatigue and anemia. To date, 26 pts have discontinued treatment (15 progressive disease PD, 5 AEs including 2 unrelated deaths, unrelated G4 T7 spinal cord mass and compression, G1 related pulmonary fibrosis, G2 unrelated cough and dysphagia, 3 symptomatic deterioration, 2 other, 1 withdrawal by subject). An additional unrelated, on-study death occurred in a pt who had discontinued treatment due to PD. At the MR RP2D combination, MLN8237 median Tmax was 2 hr and geometric mean steady-state AUC0-12hr was 18,960 nM*hr (n=11, CV: 61.2%), which is consistent with what was achieved in M single agent at 50 mg BID. Assessment of the effect of MLN8237 on vincristine PK is ongoing. 12 pts administered MR were response evaluable; 1 50 y male pt with DLBCL had a complete response (CR), 2 pts had partial response (PR) including one 79 y male pt with DLBCL ongoing at 29 cycles, and 5 pts had stable disease (SD) for up to 13 cycles. 8 MRV pts are currently response evaluable (M 30 mg, n=3; 40 mg, n=5); one 78 y male pt with DLBCL in the 30 mg cohort had CR; at the RP2D (40 mg BID cohort) one 71 y male with non- germinal center B-cell-like DLBCL and having progressed following prior transplant had CR; one 66 y male pt with large B-cell had PR, 5 pts had SD. Response assessments are pending for 5 pts. Enrollment continues to the MRV RP2D to complete the required number of PK-evaluable pts.
MR ± V is overall well tolerated and has shown preliminary anti-tumor activity in pts with relapsed/refractory B-cell lymphomas.
Off Label Use: Use of the investigational agent MLN8237 in combination in patients with aggressive B-cell NHL. Persky:Millennium: The Takeda Oncology Company: Research Funding. Mahadevan:Novartis: Honoraria; Millennium: The Takeda Oncology Company: Honoraria. Miller:Spectrum: Research Funding; Abbott Laboratories: Research Funding. Hayslip:Celgene: Research Funding. Park:TEVA: Research Funding; Seattle Genetics, Inc.: Research Funding. Ruan:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rosen:Disney Family Cancer Center: Research Funding. Padmanabhan Iyer:Millennium: The Takeda Oncology Company: Research Funding. Zhang:Takeda Pharmaceutical Company Ltd.: Equity Ownership; Millennium: The Takeda Oncology Company: Employment. Zhou:Millennium: The Takeda Oncology Company: Employment. Dansky Ullmann:Millennium: The Takeda Oncology Company: Employment. Leonard:Millennium: The Takeda Oncology Company: Employment, Equity Ownership.
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