scholarly journals AGMT MALT-2: A Phase II Study of Rituximab Plus Lenalidomide in Patients with Extranodal Marginal Zone B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT lymphoma)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3973-3973 ◽  
Author(s):  
Barbara Kiesewetter ◽  
Richard Greil ◽  
Wolfgang Willenbacher ◽  
Peter Neumeister ◽  
Michael A. Fridrik ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Malt Lymphoma ◽  
Research Funding ◽  
Systemic Treatment ◽  
Phase Ii Study ◽  
Gastric Malt Lymphoma ◽  
Best Response ◽  
Disseminated Disease

Abstract Background: Chemotherapy-containing regimens are effective for the treatment of advanced MALT lymphoma. However, due to the indolent course of this disease immunomodulatory strategies appear reasonable. Lenalidomide was active as monotherapy for MALT lymphoma and addition of rituximab (R) achieved promising results in several B-cell malignancies. Methods: The AGMT MALT-2 study is a multicenter phase II study for the treatment of MALT lymphoma with R-lenalidomide (also referred to as "R2"). Treatment consisted of R 375 mg/m2 day 1 and lenalidomide 20 mg day 1-21 in a four-week cycle. In the case of gastric MALT lymphoma and Helicobacter pylori (HP)-infection patients had to be refractory to HP-eradication prior to inclusion. HP-negative or extragastric patients were directly eligible. In case of complete remission (CR) after 6 courses treatment stopped while those with partial remission (PR) or stabilization (SD) were eligible for 8 courses. All patients received prophylactic ASA (100 mg/day) during treatment and allopurinol (300 mg/day) for the first 8 weeks. The primary endpoint of the study was the objective response rate (ORR) defined by radiological or GELA histological response criteria, respectively. The secondary endpoint was safety. These are our final results. Results: A total of 50 patients were enrolled but four patients were excluded and replaced according to protocol, including two patients who withdrew informed consent before the first dose of treatment due to personal reasons. Of 46 evaluable patients 28 (60.9%) were female while 18 (39.1%) were male. Median age at initiation of treatment was 64 years with an interquartile range of 53-72 years. 28.3% (13/46) of patients had primary gastric MALT lymphoma while the majority of patients i.e. 71.7% (33/46) had primary extragastric manifestations (28% ocular adnexa, 11% lung, 11% disseminated disease, 7% parotid gland and 15% other localizations). 63.0% (29/46) of patients had localized disease and 37.0% (17/46) presented with advanced/ disseminated disease. ECOG status was 0 or 1 in 97.8% (45/46) of patients. 23.9% (11/46) of patients had received prior systemic treatment including one patient pretreated with lenalidomide and 9 pretreated with R-containing regimens. Treatment with R-lenalidomide resulted in an ORR of 80.4%. 54.3% (25/46) achieved CR, 26.1% (12/46) PR, and 17.4% (8/46) SD as best response. One patient progressed at cycle three but received successful salvage treatment. Median time to best response was 5.2 months (95% CI; 2.8-5.7). The mean number of applied treatment cycles was 6 (95% CI; 5.6-6.6). Fourteen patients (30.4%; 14/46) benefited from the extended treatment phase and converted to a deeper response between restaging at cycle three and restaging at cycle 6 (11/14) or 8 (3/14), respectively. Univariate analysis for response according to gender (male vs. female) (p = 0.691), primary localization of MALT lymphoma (gastric vs. extragastric) (p = 0.654), prior systemic treatment (p = 0.895), and localized vs. disseminated disease (p = 0.197) was not significantly different for groups. 48 patients received at least one dose of R-lenalidomide and were included in the toxicity analysis. Tolerability in terms of non-hematologic adverse events was good with no toxicity grade IV reported. 37.5% (18/48) of patient experienced mild infusion reactions following R. Common adverse reactions to lenalidomide consisted of mild fatigue in 33.3% (grade I/II = 16), musculoskeletal pain in 41.7% (I/II = 18, III = 2), cough or respiratory infections in 33.3% (I/II = 13, III = 3), diarrhea in 22.9% (I/II = 10, III = 1) and mild vertigo in 22.9% (I/II = 9, III = 2). Typical lenalidomide-associated exanthema occurred in 45.8% patients but was usually mild (I/II = 19, III = 3). Hematologic adverse events were rare with a rate of grade III/IV neutropenia below 20% (18.8%; 9/48). Dose reduction of lenalidomide due to adverse events was necessary in 34.8% (15 mg = 12, 10 mg = 4). Four patients discontinued treatment early due to adverse events. After a median follow-up of 27.2 months (range; 13.2-36.3) three patients have relapsed at 5.0-8.8 months suggesting durable responses in the majority of cases. No second malignancies were observed. Conclusion: This is the first study on efficacy of R-lenalidomide for MALT lymphoma. With an ORR of 80% and a CRR of 54% we could improve the results achieved with lenalidomide-monotherapy in a prior pilot trial. Disclosures Off Label Use: lenalidomide for MALT lymphoma. Greil:AOP Orphan: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Celgene: Consultancy; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding. Willenbacher:Roche, Celgene: Consultancy, Honoraria, Research Funding. Fridrik:Roche: Consultancy, Honoraria. Markus:Celgene, Roche, EISAI, Novartis, IPSEN: Honoraria.

scholarly journals A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

Haematologica ◽  
2012 ◽  
Vol 98 (3) ◽  
pp. 353-356 ◽  
Author(s):  
B. Kiesewetter ◽  
M. Troch ◽  
W. Dolak ◽  
L. Mullauer ◽  
J. Lukas ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Marginal Zone ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

Interim Analysis of Phase II Study of the Bortezomib-Melphalan-Prednisolone Induction Therapy Followed By Lenalidomide-Plus-Dexamethasone Consolidation and Lenalidomide Maintenance in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma.

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3043-3043
Author(s):  
Tadao Ishida ◽  
Hideo Kimura ◽  
Koumei Kubo ◽  
Kazutaka Sunami ◽  
Shuji Ozaki ◽  
...  
Keyword(s):  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Phase Ii Study ◽  
Staging System ◽  
Best Response ◽  
Need To Evaluate ◽  
Treatment Number ◽  
Reduced Intensity

Abstract Background In Japan, the phase II study of bortezomib-melphalan-prednisolone (VMP) for NDMM using the same protocol of VISTA trial revealed that there were more treatment discontinuation in this study than in the VISTA study. We planned five cycles of reduced intensity VMP therapy as an induction. And it is reported that lenalidomide plus low dose dexamethasone (Rd) therapy is very effective regimen after VMP therapy. In order to further improve its outcome, patients are treated with six cycles of Rd and maintenance of lenalidomide after VMP induction. Patients and methods We included 82 pts with NDMM. Pts were received 5 cycles of VMP followed by 6 cycles of Rd. After Rd, pts received maintenance of lenalidomide. VMP included the IV or SQ administration of weekly bortezomib at 1.3 mg/m2 in combination with oral melphalan 6 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4 of a 35-day cycle. Rd treatment consisted of lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly of a 28-day cycle. Lenalidomide maintenance therapy consisted of lenalidomide 10 mg daily on days 1-21 of a 28-day cycle. Results In total, 82 pts were recruited in the trial by 27 Japanese centers between 10/2012 and 8/2014. Median age were 73.5 years (range 61-84), 37.8% were 75 years of age or older, 45.1% were male, 48.8% had International Staging System (ISS) stage II and 20.7% had ISS stage III. Fifty four patients had IgG-type myeloma (65.8%), 19 had IgA-type (23.2%), and 9 had Bence Jones-type (11%). Of the cases analyzed by FISH (N=80), 16.3% had t(4;14), 10% had del 17p and 41.3% had +1q21. Eight patients (10%) had t(4;14) and +1q21, five patients (6.3%) had del 17p and +1q21 and only one patient (1.3%) had t(4;14), del 17p and +1q21. The best response during VMP therapy (the maximum treatment number was 5 cycles) could be evaluated. After five course of VMP therapy, the rates of partial response (PR) or better were 68% including sCR (5%), CR (6%),VGPR (20%) and PR (37%). The best response rate after VMP+Rd (maximum treatment number of Rd was 6 cycles) was also evaluated. The rates of PR or better were 90% including sCR (6%), CR (16%), VGPR (39%) and PR (29%). The most commonly observed grade 3 or higher adverse events during VMP therapy were anemia (30%), neutropenia (16%), thrombocytopenia (5%) and GI toxicity (6%). Summary The induction therapy of reduced intensity VMP was safe and effective. The best response rate after VMP+Rd was very effective. However, we need to evaluate consolidation of Rd and maintenance of lenalidomide after longer follow up. Disclosures Ishida: Takeda: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria. Sunami:Ono: Research Funding; Takeda: Research Funding.

scholarly journals A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
N Rates

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

A phase II study of dasatanib (BMS 354825) in recurrent or metastatic ckit-expressing adenoid cystic (ACC) and non-ACC malignant salivary glands tumors (MSGT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6022-6022
Author(s):  
Stuart J. Wong ◽  
Ezra E.W. Cohen ◽  
Theodore Karrison ◽  
David N. Hayes ◽  
Merrill S. Kies ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Study Drug ◽  
Protein Product ◽  
Stage I ◽  
Stage Ii ◽  
Best Response ◽  
Grade 3

6022 Background: ACC is a rare disease, accounting for 1/3rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of five oncogenic PTKs/kinase families including ckit. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Methods: In a two-stage design, adult patients (pts) with recent radiographic progressive, recurrent or metastatic ACC, + cKIT, were treated with dasatinib 70 mg PO BID. Pts with non-ACC MSGT of other histologic types, were treated as a separate cohort. Response was assessed every 8 wks by imaging using RECIST criteria. The study design stipulated enrollment of n=40 ACC patients (20 in stage I and 20 in stage II) and 25 non-ACC patients (14 in stage I and 11 in stage II). Results: Fifty-four pts were enrolled, 40 ACC and 14 non-ACC. One additional pt was a screen failure. Baseline data on 54 pts are: M:F = 28:26, median age 56.6 yrs (range 20-82), PS 0:1:2 = 24:28:2, prior radiation:chemotherapy = 44:21. The most frequent adverse events experienced (as % of pts, worst grade 2 or higher and at least possibly related to study drug) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (11%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), and non-cardiac chest pain (6%). No grade 4 adverse events occurred and only 15 pts experienced a grade 3 adverse event (at least possibly attributed to study drug), primarily dyspnea (4 patients) and fatigue (3 patients). Significant cardiac toxicity was observed in one pt (grade 3 prolonged QT corrected interval). Among ACC pts, best response to dasatinib: 0 pts (0%) had PR, 21 pts (52%) had SD (range 2.8-13.8 months), 12 pts (30%) had PD, and 2 died prior to cycle 2. Median PFS was 4.8 mos. For 14 evaluable non-ACC pts, none had an objective response, triggering early stopping. 7 had SD (range 1.4-6.6 months), and 4 PD. Conclusions: Although there were no objective responses, dasatinib is well tolerated, with tumor stabilization achieved by 52% of ACC pts. Dasatinib demonstrated no activity in non-ACC MSGT. Clinical trial information: NCT00859937.

Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

Weekly Temsirolimus and Bortezomib For Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma: A Wisconsin Oncology Network Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3035-3035 ◽  
Author(s):  
Timothy S. Fenske ◽  
KyungMann Kim ◽  
Chong Zhang ◽  
John P. Farnen ◽  
Adedayo A. Onitilo ◽  
...  
Keyword(s):  
Partial Response ◽  
Adverse Events ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Mtor Inhibitors ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Background Proteosome inhibitors and mammalian target of rapamycin (mTOR) inhibitors are each known to have activity for various B-cell malignancies, and affect distinct cellular pathways. Preclinical data show synergy between bortezomib and various mTOR inhibitors, supporting this combination in non-Hodgkin lymphoma (NHL). We conducted a phase II trial of temsirolimus and bortezomib in relapsed and refractory B-cell NHL, using a weekly dosing scheme that was previously tested in multiple myeloma (Ghobrial et al, Lancet Oncology, 2011; 263-272). Methods Wisconsin Oncology Network study HO10407 is a single-arm phase II study of IV bortezomib and temsirolimus for patients with relapsed and refractory B-cell NHL. A 35 day cycle was employed with bortezomib given at 1.6 mg/m2 and temsirolimus given at 25 mg IV weekly on days 1, 8, 15, and 22. Initially temsirolimus was also given on day 29 but, due to a high rate of thrombocytopenia, after the first 14 patients were enrolled the protocol was amended and the day 29 temsirolimus dose was removed. Patients were enrolled from 10 sites within the Wisconsin Oncology Network. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS). The secondary endpoints were to determine safety, tolerability, complete response (CR) rate, duration of response (DOR), and overall survival (OS). Results Forty patients were enrolled between February 2011 and May 2013; however one patient withdrew consent immediately after enrollment and was never treated. We are therefore reporting results for 39 patients. The median age was 68, with 72% male. NHL subtypes consisted of diffuse large B-cell lymphoma (DLBCL, n=17), follicular lymphoma (FL, n=10), mantle cell lymphoma (MCL, n=7), small lymphocytic lymphoma (SLL, n=3), and marginal zone lymphoma (MZL, n=2). Patients received a median of 4 prior therapies (range 1 to 11). Three patients were previously treated with bortezomib, one of whom was refractory to a prior bortezomib-containing regimen. As of July, 24, 2013, two patients remained on protocol therapy. The median number of cycles given was 3. Out of 39 patients, CR was achieved in 3 patients (7.7% (95% CI: 1.6% - 21%)), partial response (PR) in 9 patients (23% (95% CI: 11% - 39%)), and stable disease in 9 patients (23% (95% CI: 11% - 39%)). The ORR was therefore 12/39 (31% (95% CI: 17-48%)). Among responders, the DOR ranged from 1.7 to 13.8 months, with a median DOR of 8.5 months (95% CI: 2.9-11.5). The median PFS was 4.7 months (95% CI: 2.1-7.8). The ORR for DLBCL was 18% (3/17, with 2 CR), for FL was 50% (5/10, with no CR), and for MCL was 57% (4/7, with 1 CR). In one patient, protocol therapy led to a partial response which served as a bridge to allogeneic stem cell transplantation. Grade 3/4 adverse events were experienced by 69% of patients. The grade 3/4 adverse events that occurred in at least 10% of patients were anemia (13%), lymphopenia (15%), neutropenia (23%), thrombocytopenia (38%), and gastrointestinal toxicities (15%). Conclusions In this phase II study, the combination of temsirolimus and bortezomib demonstrated activity in a group of heavily pre-treated patients. In some patients dramatic responses were seen, including two DLBCL patients who achieved complete remission after having previously progressed following autologous hematopoietic cell transplantation. Toxicities were manageable and treatment was delivered on an outpatient basis. Further studies with this combination or other proteosome inhibitor + mTOR inhibitor combinations are warranted in specific subtypes of NHL. Disclosures: Fenske: Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy. Off Label Use: Use of the combination of bortezomib and temsirolimus for relpased and refractory B-cell non-Hodgkin lymphoma. Ahuja:Bayer healthcare pharmaceuticals: Consultancy. Kahl:Millennium: Consultancy.

PILLAR-1: Preliminary Results of a Phase II Study of mTOR Inhibitor Everolimus In Patients with Mantle Cell Lymphoma (MCL) Who Are Refractory or Intolerant to Bortezomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3963-3963 ◽  
Author(s):  
Owen A. O'Connor ◽  
Leslie Popplewell ◽  
Jane N. Winter ◽  
RuiRong Yuan ◽  
Anna Robeva ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Initial Diagnosis ◽  
Survival Duration ◽  
Employment Equity ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Stage 1

Abstract Abstract 3963 Introduction: MCL remains incurable with current therapeutic approaches. Bortezomib is approved for patients with relapsed MCL, though the duration of response is limited. As such, there is a critical need for novel therapeutic strategies and targeted agents. The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many hematologic malignancies. Studies of monotherapy everolimus, an oral inhibitor of mTOR, have shown substantial antitumor activity in relapsed aggressive non-Hodgkin's lymphoma and other types of relapsed or refractory lymphomas, including MCL. Methods: PILLAR-1 (PIvotaL Lymphoma triAls of RAD001-1) is an open-label, US-based, multicenter, single-arm, phase II study (clinicaltrials.gov: NCT00702052) of oral everolimus (RAD001) 10 mg/d in patients with pathologically confirmed MCL who are bortezomib refractory (defined as radiological progression ≤12 months after the last bortezomib-containing combination or monotherapy) or intolerant (defined as requiring discontinuation due to toxicity). Study treatment with everolimus continued until disease progression, unacceptable toxicity, death, or study discontinuation. Eligible patients have received ≥1 prior antineoplastic agent other than bortezomib either separately or in combination with bortezomib. The primary endpoint is objective response rate (ORR including complete response [CR] and partial response [PR]). Secondary endpoints include progression-free survival, overall survival, duration of response, and safety. A Simon two-stage design was used and was based on ORR among 34 treated patients in Stage 1. If ≥3 CR or PR occurred in Stage 1, an additional 23 patients would be treated in Stage 2; otherwise, the study would be stopped. Results presented here are based on a data cut-off of April 26, 2010. Results: A preliminary analysis of efficacy and safety included 26 patients (65% male) with the following baseline characteristics: median age 65 y (range, 50–83); 77% were >2 y post initial diagnosis; 72% had previously received ≥3 therapies; 89% had previously relapsed ≤6 months before enrollment; 73% were stage IV at initial diagnosis; 73% had prior bone marrow involvement; 92% had ECOG performance status ≤1; 85% were refractory and 12% were intolerant to bortezomib. Median duration of exposure to everolimus was 58 days (range, 13–221). Efficacy analysis of best overall disease response revealed no CR, 3 PR (12%), 14 SD (54%), 3 PD (12%), and 6 unknown (23%). ORR (CR+PR) was 12% (95% CI, 2–30) and met the requirement for full recruitment in Stage 2 of the study ahead of the Stage 1 enrollment target. A total of 19 patients discontinued from the study, 7 (27%) due to adverse events, 9 (35%) due to PD, and 3 (12%) withdrew consent. In the safety analysis, grade 3 or 4 adverse events suspected to be related to study treatment in ≥2 patients (>7%) were anemia, thrombocytopenia (including 1 grade 4), diarrhea, hyperglycemia (including 1 grade 4), and pneumonitis. Conclusion: Early analysis from this ongoing phase II study (stage I) shows that oral everolimus 10 mg/d has promising single-agent activity with 12% PR and 54% SD and good tolerability in bortezomib-refractory and intolerant MCL. The efficacy results support continuing to stage II enrolling more patients into this study. Disclosures: O'Connor: SAB-Pharma: Research Funding. Winter:Novartis Pharmaceuticals: Consultancy, Research Funding. Yuan:Novartis Pharmaceuticals: Employment, Equity Ownership. Robeva:Novartis Pharmaceuticals: Employment, Equity Ownership. Cauwel:Novartis Pharmaceuticals: Employment, Equity Ownership. Chau:Novartis Pharmaceuticals: Employment, Equity Ownership. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

scholarly journals Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 814-814
Author(s):  
Craig A. Portell ◽  
Opeyemi Jegede ◽  
Nina D. Wagner-Johnston ◽  
Grzegorz S. Nowakowski ◽  
Christopher D. Fletcher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumor Burden ◽  
Type I ◽  
High Tumor Burden ◽  
Grade 3

Abstract Background: Chemoimmunotherapy is considered standard initial therapy for follicular lymphoma (FL) with high tumor burden (HTB). Obinutuzumab and Bendamustine (OB) with maintenance Obinutuzumab (mO) is considered a standard therapy for the frontline treatment of HTB FL (GALLIUM, Marcus et al, NEJM 2017). Venetoclax (VEN), an oral BCL2 inhibitor, is an attractive target in FL given the high BCL2 expression; though single agent activity has been disappointing (Davids et al. JCO 2017). BCL2 inhibition is thought to be synergistic with chemotherapy. Thus, the PrE0403 study evaluated the OB-VEN combination in frontline HTB FL. Here we present end of induction (EOI) outcomes. Methods: The primary objective of this Phase II study was to estimate the complete remission (CR) rate at EOI. Potential participants must have had a histologically confirmed diagnosis of FL grade 1, 2, or 3a with HTB defined by GELF or high risk defined by FLIPI-1 criteria. They must have had adequate performance status and organ function. Notably, creatinine clearance must have been ≥50 mL/min. Participants must have not had prior treatment for FL. Eligible participants were treated with Bendamustine IV 90 mg/m2 Day (D) 1 & 2, Obinutuzumab IV 100 mg D1, 900 mg D2, 1000 mg D8 and D15 of Cycle (C) 1 then D1 of each cycle, and VEN 800 mg orally daily D1-10 every 28 days for 6 total cycles. Due to a high rate of laboratory tumor lysis syndrome (TLS) during C1 in the first 21 patients, VEN was removed from C1 and given in C2-6 only. Participants with a CR at EOI were treated with mO IV 1000 mg D1 every 8 weeks for 2 years. Those with a partial response (PR) or stable disease (SD) were treated with mO as well as VEN 800 mg orally daily for 2 years. Pneumocystis jiroveci Pneumonia (PJP) and antiviral prophylaxis was required as was G-CSF support. Response was assessed via Lugano Criteria at EOI including PET/CT and bone marrow assessment. Adverse Events (AEs) were evaluated using CTCAE v5.0. To be considered promising, OB-VEN should improve the null hypothesis CR rate of 50% (OB) to 65%. With an 85% power and a one sided 15% type I error, 56 participants would be needed with an estimated 51 eligible. Support for the study was from Genentech, Member of the Roche Group. Results A total of 56 participants were enrolled and treated between 12/2017 and 11/2020; baseline characteristics are listed in Table 1. TLS was closely monitored in C1 and 8/21 participants developed TLS when VEN was administered in C1; 0/35 when it was not. However, monitoring for TLS in C1 became less stringent when VEN was not administered. Treatment related Grade ≥3 toxicities occurred in 47/56 participants (83.9%) with serious adverse events in 31 of 56 (55.5%). Atypical infections were seen; there was one treatment related death on study due to cytomegalovirus (CMV) encephalitis as well as PJP pneumonia which occurred after induction C6. Enrollment was temporarily suspended and CMV monitoring was implemented with no further occurrences. Another participant receiving mO later developed BK virus nephropathy following mO C6 and now requires ongoing hemodialysis. Another was diagnosed with Respiratory Syncytial Virus pneumonia 30 days after C6 and later PJP pneumonia after C2 of mO. Common (incidence &gt;10%) AEs during induction are listed in Table 2. 45 of 56 (80.4%) participants were able to receive all 6 cycles of OB-VEN. CR was seen in 41 of 56 participants (73.2%, 2 sided 95% Confidence Interval (CI) 59.7-84.2%) at the EOI. 30 participants (53.5%) went onto maintenance. With a median follow up of 20.9 months, estimated 2 year Overall Survival (OS) and Progression-Free Survival (PFS) (90% CI) is 94.4% (82.4-98.3%) and 85.8% (68.8-93.9%) respectively. Conclusions This Phase II study of OB-VEN in untreated HTB FL showed high CR rate and met its primary endpoint with early signs of prolonged PFS. Laboratory TLS was identified but it was unclear if attributed solely to VEN, as baseline laboratory TLS rate for OB is unknown. The rate of Grade ≥3 AE of 83.9% (compared to 69% for OB in GALLIUM, Hiddeman JCO 2018) and the observation of opportunistic infections including CMV encephalitis, PJP pneumonia and BK nephropathy, suggests the combination is highly immunosuppressive. Therefore, while the study met its primary outcome, the combination of OB-VEN at 800 mg for 10 days, plus mO, does not have an acceptable risk/benefit profile. Participants will continue to be followed for efficacy and safety during the maintenance phase. Figure 1 Figure 1. Disclosures Portell: Acerta/AstraZeneca: Research Funding; SeaGen: Research Funding; Pharmacyclics: Honoraria; Xencor: Research Funding; Aptitude Health: Honoraria; BeiGene: Honoraria, Research Funding; Abbvie: Research Funding; TG Therapeutics: Honoraria, Research Funding; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Morphosys: Honoraria; Targeted Oncology: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Nowakowski: MorphoSys: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Selvita: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. OffLabel Disclosure: Venetoclax is not approved for follicular lymphoma or in combination with bendamustine and obinutuzumab

scholarly journals Durable Responses Observed with JAK Inhibition in T-Cell Lymphomas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2922-2922 ◽  
Author(s):  
Alison J. Moskowitz ◽  
Eric Jacobsen ◽  
Jia Ruan ◽  
Jonathan H. Schatz ◽  
Obadi Obadi ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Objective Response ◽  
Response To Therapy ◽  
Serious Adverse Events ◽  
T Cell Lymphomas ◽  
Stat Pathway

Abstract Introduction: The JAK/STAT pathway is frequently activated in peripheral T-cell lymphomas (PTCLs) and cutaneous T cell lymphomas (CTCLs) however the utility of JAK inhibition as a therapeutic strategy in these diseases is not known. We hypothesize that JAK/STAT pathway alteration (defined by elevated phospho-STAT3 (pSTAT3) expression or presence of JAK or STAT mutations) will predict for sensitivity to JAK inhibition in PTCL and CTCL. We are conducting a phase II study of ruxolitinib, a JAK1/2 inhibitor, in which we assess its efficacy in a cohort of patients (pts) with PTCL and CTCL enriched for JAK/STAT pathway alterations. Methods: This is an investigator-initiated multi-center phase II study evaluating the efficacy of ruxolitinib 20mg twice daily in PTCL and CTCL. Pts with relapsed or refractory (rel/ref) PTCL or CTCL following at least 1 systemic therapy are eligible to enroll onto one of three of the following cohorts: Cohort 1: Disease determined to have JAK or STAT mutations. Cohort 2: Disease with functional evidence of JAK/STAT activation (defined as ≥ 30% pSTAT3 expression by immunohistochemistry). Cohort 3: Disease does not meet criteria for cohort 1 or 2. Pts initially enrolled onto cohort 3 and determined to have JAK/STAT mutations or functional JAK/STAT activation after enrollment are moved to cohorts 1 or 2. Cohorts 1, 2, and 3 are enrolling up to 17, 17 and 18 pts respectively by Simon 2-stage design. Pts receive treatment until progression and are assessed for response to therapy after cycles 2, 5 and every three cycles thereafter. Results: The first stage has been completed for cohorts 1 and 3 and 33 out of planned 52 pts enrolled to date. Details regarding histology, mutations, and treatment course appear in the table and figure. For Cohort 1, 10 out of planned 17 pts enrolled. Mutations involved JAK1 (1), JAK3 (3), STAT3 (4), and STAT5B (4). Out of 8 evaluable pts, overall response rate (ORR) was 38% with 3 partial responses (PR). In addition, 3 pts have ongoing stable disease (SD) lasting 8-18 months. Altogether, 75% achieved clinical benefit (objective response or SD >6 months). For Cohort 2, 5 out of planned 17 pts enrolled. Among the 5 evaluable pts, ORR was 40% with 1 complete response (CR) and 1 PR. For Cohort 3, 18 pts out of planned 18 pts enrolled. Out of 14 evaluable pts, ORR was 21% with 3 PRs. Grade 3 or higher drug-related adverse events (AEs) observed among the 33 pts enrolled included anemia (4), neutropenia (7), thrombocytopenia (2), and lymphopenia (7). Treatment related serious adverse events (SAEs) included 1 episode each of HSV-1 stomatitis, spontaneous bacterial peritonitis, febrile neutropenia, and herpes zoster. Conclusion: Responses observed across all three cohorts of pts with PTCL and CTCL with a trend towards higher rates and more durable responses among pts with JAK/STAT alterations. Efficacy of ruxolitinib in PTCL and CTCL provides proof of concept that JAK/STAT activation is a viable target in T-cell lymphomas. Enrollment onto cohorts 1 and 2 and assessment for JAK/STAT alternations among pts in cohort 3 continues. Figure. Figure. Disclosures Moskowitz: Incyte: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Takeda: Honoraria. Jacobsen:Merck: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy. Weinstock:Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus: Consultancy.

scholarly journals An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1718-1718 ◽  
Author(s):  
Anas Younes ◽  
Gilles Salles ◽  
R. Gregory Bociek ◽  
Giovanni Martinelli ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Non-Hodgkin's lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), is associated with a high unmet need in the relapsed and refractory setting. The PI3K/AKT/mTOR pathway has been shown to play a key role in the pathogenesis of NHL. Overexpression of PIK3CD (encoding the PI3Kd isoform) is common in B-cell malignancies and is therefore widely viewed as a therapeutic target in NHL. PIK3CA and PIK3CB are also expressed in B-cell malignancies, with PIK3CA overexpression seen particularly at relapse, thereby justifying exploration of pan-PI3K inhibitors in the relapsed or refractory setting. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor which has demonstrated activity in patients with solid tumors as well as in in vitro and in vivo models of hematologic malignancies. Methods: The primary objective of this Phase II study (NCT01693614) was to evaluate the efficacy of buparlisib in three parallel cohorts of adult patients with relapsed or refractory DLBCL, FL, or MCL. Secondary objectives were to evaluate safety and tolerability, progression-free survival, duration of response, and overall survival. Inclusion criteria were: patients with relapsed or refractory disease who have received at least one prior line of therapy; at least one measurable nodal lesion (≥2 cm); ECOG performance status ≤2; and adequate bone marrow and organ function. Patients with DLBCL must have received, or be ineligible for, autologous or allogeneic stem cell transplant. All patients received single-agent buparlisib 100 mg orally QD continuously until progression, intolerance, or patient withdrawal. Tumor response was evaluated by investigators per standard criteria (Cheson, 2007). Results: At data cut-off (June 19, 2014), 64 patients had been enrolled; 26 DLBCL, 24 FL, and 14 MCL. Here, results are presented for the DLBCL cohort only. Updated results from the DLBCL cohort including biomarker analyses and results for the FL cohort will be presented at the meeting. The MCL cohort is currently enrolling. For the DLBCL cohort, median age (range) was 63.5 (28–81) years and 69% were male. The median (range) number of prior therapy regimens was 3 (1–12). Specific prior therapies included: rituximab (n=25, 96%) and bendamustine/carmustine (n=8, 31%); all patients had received prior anthracycline and an alkylating agent (e.g. cyclophosphamide), and 6 (23%) patients had undergone prior stem cell transplantation. The most common (≥15%) AEs (all grades) regardless of causality were hyperglycemia and nausea (39% each), depression (31%), anxiety and fatigue (23% each), vomiting and diarrhea (19% each), and abdominal pain (15%). Alanine transaminase or aspartate transaminase elevations were rare (4% each, with no Grade 3/4 AEs). The most common (>5%) Grade 3/4 AEs regardless of causality were hyperglycemia (23%), and nausea, depression, anxiety, urinary tract infection, and neutropenia (8% each). Six (23%) patients discontinued therapy due to AEs (potentially treatment-related). Seven on-treatment deaths were reported: 6 were disease-related and 1 was suspected to be treatment-related (unexplained death following a gastrointestinal [GI] bleed in a patient with massive GI lymphoma involvement). Overall response rate was 12% (95% CI = 2.4, 30.2) with 3 responses: 1 complete response (4%) and 2 partial responses (8%). Five patients had stable disease (19%). Eight patients (31%) experienced some decrease in tumor burden (Figure 1). At data cut-off, 2 patients demonstrated durable responses, as they were still on study treatment after 9.2 and 7.4 months, respectively. Figure 1 Figure 1. Conclusions: Early results from this Phase II study of the pan-PI3K inhibitor, buparlisib, demonstrate encouraging clinical activity, and a favorable safety profile in heavily pretreated patients with relapsed or refractory DLBCL. These data suggest that targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL. Future combination studies with buparlisib will take a mechanism-based approach. Disclosures Younes: Novartis, Curis, J&J: Research Funding; Bayer, BMS, Celgene, Incyte, Janssen R&D: Honoraria; Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Mukherjee:Novartis Healthcare Pvt. Ltd. India: Employment. Williams:Novartis: Employment. Herbst:Novartis: Employment. Tavorath:Novartis: Employment. Kim:Novartis, Celgene, Takeda: Research Funding.

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