Ian W Flinn

Sarah Cannon Research Institute, Nashville, Tennessee, United States

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Publications (135)1126.27 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m(2) and oral prednisone 60 mg/m(2), days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m(2), days 1, 8, 15, and 22). The primary end point was progression-free survival. After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2015; DOI:10.1200/JCO.2014.58.7618 · 17.88 Impact Factor
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    ABSTRACT: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 04/2015; 16(6). DOI:10.1016/S1470-2045(15)70128-2 · 24.73 Impact Factor
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    ABSTRACT: Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10(12)) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.
    Proceedings of the National Academy of Sciences 03/2015; 112(14). DOI:10.1073/pnas.1503587112 · 9.81 Impact Factor
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    ABSTRACT: The safety and efficacy of ibrutinib, an oral inhibitor of Bruton's tyrosine kinase, were evaluated in combination with chemoimmunotherapy (CIT) in a multicenter, phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to six 28-day cycles with continuous daily ibrutinib 420 mg until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously-treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was consistent with that expected from either CIT or single-agent ibrutinib. The objective response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, that increased to 40.0% with the extension period; including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression free, respectively. All 3 patients treated with ibrutinib-FCR are in CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for investigation of this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as NCT01292135. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(19). DOI:10.1182/blood-2014-09-585869 · 9.78 Impact Factor
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    ABSTRACT: ABSTRACT Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F versus FC trial in untreated, symptomatic CLL (NCT00003764, clinicaltrials.gov). With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 versus 48.1 months for F (N=109) and FC (N=118) respectively (p<0.0001), while median overall survival (OS) was 88.0 versus 79.1 months respectively (p=0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were older age (p=0.002, p<0.001), Rai stage ≥II (p=0.006, p=0.02) and sex (p=0.03, PFS only). Occurrence of del(17)(p13.1) predicted shorter PFS and OS (p<0.0001 for each), as did del(11q)(22.3) (p<0.0001 and p=0.005, respectively), trisomy 12 with mutated Notch1 (p=0.003 and p=0.03, respectively) and unmutated IGHV (p=0.009 and p=0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.
    Leukemia and Lymphoma 02/2015; DOI:10.3109/10428194.2015.1023800 · 2.61 Impact Factor
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    ABSTRACT: ABSTRACT The purpose of this study is to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose of 4 planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on Days 1, 3, 5, 15, 17, 19. Carfilzomib was administered Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued to the trial, 13 in the Phase I and 31 in the Phase II portion of the study. Median age was 66 years and the median number of prior therapies was 5. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m2 carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. With a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival has not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. The combination of panobinostat and carfilzomib is feasible and effective in relapsed/refractory multiple myeloma patients. (Trial registered at ClinicalTrials.gov: NCT01496118). Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; 100(5). DOI:10.3324/haematol.2014.119735 · 5.87 Impact Factor
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    ABSTRACT: CD19 is ubiquitously expressed on CLL cells and is therefore an attractive candidate for antibody targeting. XmAb(®)5574 (aka MOR00208) is a novel humanized CD19 monoclonal antibody with an engineered Fc region to enhance Fc gamma receptor binding affinity. Here we report results of a first in human Phase I trial of XmAb5574 in patients with relapsed or refractory CLL. 27 patients were enrolled to 6 escalating dose levels, with expansion at the highest dose level of 12 mg/kg. 9 doses of XmAb5574 were infused over 8 weeks. No maximal tolerated dose was reached, and the drug was generally well tolerated, with infusion reactions of grades 1 and 2 being the most common toxicities. Grade 3 and 4 toxicities occurred in 5 patients and included neutropenia, thrombocytopenia, increased aspartate aminotransferase, febrile neutropenia, and tumor lysis syndrome. XmAb5574 showed preliminary efficacy, with 18 patients (66.7%) responding by physical exam criteria and laboratory studies, and 8 patients (29.6%) responding by CT criteria. Pharmacokinetics showed a half-life of 14 days with clearance that was not dose-dependent. In conclusion, this Phase I trial demonstrates safety and preliminary efficacy of a novel Fc engineered CD19 monoclonal antibody XmAb5574 and justifies movement into the Phase II setting. Trial is registered on clinicaltrials.gov: NCT01161511.
    Blood 10/2014; 124(24). DOI:10.1182/blood-2014-08-593269 · 9.78 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):1879-1879. DOI:10.1158/1538-7445.AM2014-1879 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):CT103-CT103. DOI:10.1158/1538-7445.AM2014-CT103 · 9.28 Impact Factor
  • Clinical Lymphoma, Myeloma and Leukemia 09/2014; 14:S137-S138. DOI:10.1016/j.clml.2014.06.069 · 1.93 Impact Factor
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    ABSTRACT: The E2997 Phase III trial included preservation of valuable chronic lymphocytic leukemia (CLL) patient specimens and relevant clinical outcome data. Using a novel high-resolution technology on a flow cytometry platform, we assessed 79 E2997 samples for the expression of 27 analytes that reflected the activity of signaling pathways and apoptosis. We found that the expression levels of ZAP70 segregated the samples into two subpopulations with the distribution showing a peak-trough-peak configuration. Although prior assessment of ZAP70 by standard procedures did not reveal any prognostic information, we found by using the trough in the distribution as a cutpoint that ZAP70 expression levels were significantly correlated with both progression-free survival and overall survival. Additionally, the cells expressing high versus low levels of ZAP70 demonstrated distinct molecular organization as indicated by the other analytes assessed. Our analysis demonstrates the value of ZAP70 expression as a prognostic indicator and suggests that the different clinical results may be due to the distinct molecular biology of the ZAP70-low versus the ZAP70-high CLL samples. © 2014 International Society for Advancement of Cytometry
    Cytometry Part A 09/2014; 85A(9). DOI:10.1002/cyto.a.22485 · 3.07 Impact Factor
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    ABSTRACT: Background Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. Methods In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. Findings From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. Interpretation Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. Funding Janssen.
    The Lancet Oncology 08/2014; 15(9). DOI:10.1016/S1470-2045(14)70311-0 · 24.73 Impact Factor
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    ABSTRACT: Background Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab plus bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. Patients and Methods Patients (n=60) were randomized (1:1) to receive rituximab (375 mg/m2 IV weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg IV days 3 and 15). Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); rituximab/bevacizumab patients also received bevacizumab 10 mg/kg IV every 2 weeks for 16 doses. Results After a median followup of 34 months, progression free survival (PFS) was improved in patients receiving rituximab/bevacizumab compared to patients who received rituximab alone (median 20·7 vs. 10·4 months respectively; HR 0·40 (95% CI: 0·20, 0·80); p=0·007). Overall survival was also improved numerically (73% versus 53% at 4 years), but did not reach statistical significance (HR 0·40 (95% CI: 0·15, 1·05); p=0·055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). Conclusions The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.
    Clinical lymphoma, myeloma & leukemia 08/2014; 14(4). DOI:10.1016/j.clml.2014.02.010 · 1.93 Impact Factor
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    ABSTRACT: CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic. Patients with relapsed or refractory follicular non-Hodgkin lymphoma (FL), mantle cell lymphoma (MCL), or Waldenström's macroglobulinaemia (WM) received otlertuzumab at 20 mg/kg administered intravenously once a week for up to 8 weeks followed by 4 monthly doses. Sixteen patients were treated; median age was 62·5 years (range, 41–81), and median number of prior regimens was 4 (range, 1–7). Twelve patients were refractory to prior treatment, 5 were refractory to rituximab. The mean terminal half-life was 9·5 days. Lymph node reduction of ≥50% by computerized tomography scan measurements was seen in 3 of 12 patients, including one FL patient who had a partial response. One WM patient had a minor response. The most frequent adverse events were neutropenia, fatigue, nausea, thrombocytopenia, diarrhoea, and peripheral oedema; most were grade 1/2. Otlertuzumab treatment appears to have been well tolerated by the patients in this study. Clinical activity was observed in this small heterogeneous cohort of highly refractory, heavily pretreated B-cell non-Hodgkin lymphoma patients. These data suggest that further clinical investigation in non-Hodgkin lymphoma is warranted.
    British Journal of Haematology 08/2014; DOI:10.1111/bjh.13099 · 4.96 Impact Factor
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    ABSTRACT: Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.
    British Journal of Haematology 08/2014; 167(4). DOI:10.1111/bjh.13061 · 4.96 Impact Factor
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    ABSTRACT: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n = 287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n = 195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.
    Journal of Clinical Oncology 05/2014; 32(17). DOI:10.1200/JCO.2012.43.9273 · 17.88 Impact Factor
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    ABSTRACT: Abstract This Phase 2 study assessed safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m(2) weekly for 4 weeks. Grade 3/4/5 AEs were reported in 11/1/1 patients, respectively. Serious AEs were reported by 11/50 patients, and 3 discontinued due to AEs. One patient died from aspiration pneumonia due to possibly drug-related nausea and vomiting. Investigator-assessed response rate was 30% (15/50), including 4 CRs, 3 CRus, and 8 PRs. Investigator-assessed median PFS was 38.3 weeks. Ocaratuzumab's pharmacokinetic profile was similar to that reported for rituximab. Lymphocyte subset analysis showed significant, selective reduction of B-cells during and after ocaratuzumab treatment. Ocaratuzumab at this dose and schedule is active and well tolerated in patients with previously treated FL with low affinity FcγRIIIa genotypes. The study protocol and informed consent were approved by the institutional review boards for each participating institution. ClinTrials registry number: NCT00354926.
    Leukemia & lymphoma 04/2014; 56(1). DOI:10.3109/10428194.2014.911859 · 2.61 Impact Factor
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    ABSTRACT: Idelalisib, an oral inhibitor of PI3Kδ, was evaluated in a 48-week phase I study (50-350 mg qd or bid) enrolling 40 patients with relapsed/refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (52-83) and received median of 4 prior therapies (1-14); 17/40 (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and ALT or AST elevations (60/20). Nine (25%) patients discontinued therapy due to AEs. ORR was 16/40 (40%), with CR in 2/40 (5%) patients. Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This study is registered at Clinicaltrials.gov, identifier: NCT00710528.
    Blood 03/2014; 123(22). DOI:10.1182/blood-2013-11-537555 · 9.78 Impact Factor
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    ABSTRACT: Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n=19; 30%) enrolled into an extension study. Adverse events occurring in 20% or more patients (AEs, total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These studies are registered at clinicaltrials.gov, Identifiers: NCT00710528 and NCT01090414.
    Blood 03/2014; 123(22). DOI:10.1182/blood-2013-11-538546 · 9.78 Impact Factor
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    ABSTRACT: In a Phase 1 trial, idelalisib (GS 1101, CAL 101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory CLL and multiple adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutation (24%). Patients were treated at 6 dose levels of oral idelalisib, ranging from 50 350 mg once or twice daily, and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemo- and cytokines. The most commonly observed Grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%) and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The ORR was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis. The median PFS for all patients was 15.8 months; the median OS was not reached. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These studies are registered at ClinicalTrials.gov, Identifiers: NCT00710528 and NCT01090414.
    Blood 03/2014; 123(22). DOI:10.1182/blood-2013-11-535047 · 9.78 Impact Factor

Publication Stats

7k Citations
1,126.27 Total Impact Points

Institutions

  • 2007–2015
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
  • 2000–2014
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1998–2005
    • The Ohio State University
      • Division of Hospital Medicine
      Columbus, Ohio, United States
  • 1996–2002
    • Johns Hopkins Medicine
      • Division of Hematologic Malignancies
      Baltimore, Maryland, United States
  • 1998–2001
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States