scholarly journals Ibrutinib plus obinutuzumab as frontline therapy for chronic lymphocytic leukemia is associated with a lower rate of infusion-related reactions and with sustained remissions after ibrutinib discontinuation: a single-arm, open-label, phase 1b/2 clinical trial NCT0231576

2021 ◽  
Author(s):  
Januario E. Castro ◽  
Paula A. Lengerke-Diaz ◽  
Juliana Velez-Lujan ◽  
Michale Y. Choi ◽  
Eider F. Moreno-Cortes ◽  
...  
Keyword(s):  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Continuous Administration ◽  
Open Label Phase ◽  
Phase 1B ◽  
Treatment Safety ◽  
Anti Cd20

Abstract Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials.

scholarly journals Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 133 (26) ◽  
pp. 2765-2775 ◽  
Author(s):  
Ian W. Flinn ◽  
John G. Gribben ◽  
Martin J. S. Dyer ◽  
William Wierda ◽  
Michael B. Maris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Standard Dose ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8556-TPS8556 ◽  
Author(s):  
Saad Zafar Usmani ◽  
Evangelos Terpos ◽  
Wojt Janowski ◽  
Hang Quach ◽  
Sarah West ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Open Label

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

Analysis of Minimal Residual Disease (MRD) from the Phase 2 Multicenter Study of Subcutaneous (SC) Alemtuzumab Combined with Fludarabine for Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3111-3111 ◽  
Author(s):  
Christopher Flowers ◽  
Hilary Rosenthal ◽  
Jennifer Brown ◽  
Wendy Stock ◽  
Harvey Katzen ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Residual Disease ◽  
Pearson Correlation ◽  
Single Agent ◽  
Complete Response ◽  
Salvage Chemotherapy ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Color Flow ◽  
Prior Therapy

Abstract Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath®) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al J Clin Oncol2005;23:2971–2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al Blood2006;108: abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis. Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 were administered on a 28-day cycle for 4 cycles. Pts with <CR after 4 cycles were eligible to receive 2 additional cycles up to a total of 6 cycles. Responses were assessed based on the 1996 NCI Working Group Criteria. MRD was measured in the BM and PB at baseline, interim analysis, end of treatment, and 2 and 9 months following treatment. Four-color flow cytometry assays (CD5+/CD19+/CD38+/CD20[dim], CD5+/CD19+/CD43+/CD79b[dim], CD5+/CD19+/CD81+/CD22[dim]) were used to evaluate 200,000 to 1,000,000 events per sample, with lower limits of detection (LLD) ranging from 0.005% to 0.01% of leukocytes. Results: The study completed enrollment with 56 pts (median age 62 years, range 37–86; 54% Rai stage III/IV; median 3 prior lines of therapy, range 1–14) receiving at least 1 dose of study treatment; 28 pts (50%) completed 4 or more cycles of therapy and were evaluable for response; of these, 17 (30%) pts completed 5 or more cycles and 11 (20%) completed 6 cycles of therapy. MRD evaluation of the BM was available in 17 pts. The ORR among 28 evaluable pts was 64%, with CR in 6 pts (21%). Four of 6 pts in CR achieved MRD(-) in both BM and PB, which was maintained at last evaluation in all 4 pts. In addition, 9 pts with PR showed no evidence of disease in PB and/or BM below LLD, with 4 of these pts having undetectable disease in BM. The correlation between MRD(-) in the PB and BM was 0.63 and between MRD(-) by 4-color flow and CD5+/CD19+ <1% in the BM was 0.67 (Pearson correlation). Conclusion: After treatment with SC alemtuzumab and IV fludarabine, 64% of pts responded, with 8 of 17 evaluable pts achieving molecular undetectable disease in the BM, suggesting that MRD(-) remissions can be attained in a portion of heavily pretreated pts with CLL. Four-color flow cytometry of the BM is necessary to monitor MRD after an alemtuzumab regimen.

Ad-ISF35-Transduced Autologous Cells In Combination with Fludarabine, Cyclophosphamide, Rituximab (FCR) Induces Complete and Partial Responses In a Phase 1b Study for Patients with Fludarabine-Refractory and/or Del(17p)/p53-Defective Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 168-168
Author(s):  
Januario E. Castro ◽  
Lee Schwartzberg ◽  
Javier Pinilla-Ibarz ◽  
Johanna Melo-Cardenas ◽  
Juan S. Barajas-Gamboa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cytotoxic Activity ◽  
Residual Disease ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
Phase 1B

Abstract Abstract 168FN2 CLL cells with del(17p) typically have loss of functional p53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40 ligand (CD154) are induced to express pro-apoptotic factors to overcome resistance to the cytotoxic activity of p53-dependent drugs, such as fludarabine. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine-refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted. Autologous CLL cells transduced ex vivo with a replication-defective adenovirus vector encoding a membrane-stable, re-engineered form of CD154 (Ad-ISF35) are administered, followed by standard courses of FCR. Subjects with fludarabine-refractory and/or del(17p) CLL received three IV doses (one dose every two weeks) of 3×108autologous Ad-ISF35-transduced CLL cells. Two weeks following the third dose of Ad-ISF35-transduced cells, subjects receive up to six monthly cycles of FCR. Study endpoints include analysis of safety and efficacy. Nine (9) subjects have been enrolled and treated on study. Median age was 63 (range 48–70). All subjects were del(17p) (range 14–96%), and included treatment naïve (n=4) and previously treated (n=5) subjects. The number of prior treatments range from 0–5, including three subjects that previously received fludarabine-containing regimens. The overall response rate was 67% with 56% of subjects achieving a complete response (CR), including 3 CRu pending bone marrow assessment. Two subjects with a marked percentage del(17p) (range 63–66%) continue to have an ongoing complete response (CR) after a median follow up of >2 years, and no detectable minimal residual disease (MRD) in one subject. Three subjects that showed disease progression were treated with either alemtuzumab (1 subject) or ofatumumab plus high dose methylprednisolone therapy followed by allogeneic stem cell transplant (2 subjects). We observed clinical responses not only after FCR but also after infusion of Ad-ISF35-transduced cell. These ISF35-specific responses included reductions in absolute lymphocyte counts in all subjects (decrease from baseline 4–89%), and decreased lymphadenopathy (>50% reduction) in 78% of the subjects (decrease from baseline 19–100%). Infusion of Ad-ISF35-transduced cells plus FCR has been well-tolerated. The primary non-hematologic adverse events have been flu-like symptoms following infusion of Ad-ISF35 transduced cells. This includes transient grade I/II fever (89%), fatigue (56%) and chills (56%). The primary hematologic adverse events have been cytopenias following FCR treatment, including grade III/IV neutropenia (33%) and anemia (22%). Grade I/II hypophosphatemia (56%) following ISF35 has been observed and this might be related to increased serum cytokine levels following Ad-ISF35-transduced cell administration. Correlative studies on CLL cells obtained before and after infusions of Ad-ISF35-transduced CLL cells demonstrated that CLL cells prior to treatment were refractory to the cytoxic effects of P53-dependent drugs (e.g. F-ara-A). However, the CLL cells obtained after treatment with Ad-ISF35-transduced CLL had increases of p73, p21 and Bid and became sensitive in vitro to the cytotoxic activity of F-ara-A. We also observed up-regulation of costimulatory molecules (CD80, CD86, CD54) and death receptors (CD95). The majority of subjects developed antibodies against adenovirus with neutralizing activity. However, they did not developed antibodies against human CD154. Subjects also showed increases in TNFα, IL-6 and IL12 after infusion of Ad-ISF35 transduced cells. In conclusion, the combination of Ad-ISF35 transduced CLL cells plus FCR appears to be well-tolerated and highly effective in CLL patients with fludarabine-refractory disease and/or del(17p). The CR rate that we have observed in this high-risk CLL population is higher than those reported in the literature and makes our results very encouraging. Correlative data suggest that Ad-ISF35 promotes upregulation of costimulatory and death receptor molecules as well as pro-apoptotic proteins that may overcome resistance to FCR in vivo. These encouraging data suggest the combination of Ad-ISF35 plus chemoimmunotherapy could offer an effective treatment option for patients who otherwise would be resistant to standard forms of therapy. Disclosures: Cantwell: Memgen, LLC: Employment, Patents & Royalties.

scholarly journals Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440)

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Stephan Stilgenbauer ◽  
Franck Morschhauser ◽  
Clemens-Martin Wendtner ◽  
Guillaume Cartron ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Dose Finding ◽  
First Line ◽  
Open Label ◽  
Open Label Phase ◽  
Phase 1B ◽  
Grade 3

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100–400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3–4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3–4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

scholarly journals The Type II Glycoengineered Humanized Anti-CD20 Monoclonal Antibody MIL62 Combined with Lenalidomide in Chinese Patients with Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma: Results of a Multicenter, Single-Arm, Phase 1b/2 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1351-1351
Author(s):  
Yuankai Shi ◽  
Yan Qin ◽  
Yongping Song ◽  
Keshu Zhou ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Partial Response ◽  
Follicular Lymphoma ◽  
Marginal Zone ◽  
Objective Response ◽  
Complete Response ◽  
Marginal Zone Lymphoma ◽  
Type Ii ◽  
Open Label ◽  
Phase 1B ◽  
Anti Cd20

Abstract Background: A novel glycoengineered type II anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Lenalidomide combined with anti-CD20 antibody is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin lymphoma. This open-label, multicenter, phase 1b/2 trial (ClinicalTrials.gov, identifier NCT04110301) aims to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL). Methods: Eligible patients included those who had histopathological confirmed CD20 positive MZL or FL of WHO grades 1-3a and had received one to four prior systemic regimens (with at least one rituximab-containing therapy). Patients received oral lenalidomide (15-20 mg; 28-day cycles; days 2-22) plus intravenously infused MIL62 as induction therapy (1000 mg; eight 28-day cycles; cycle 1: day 1, 15; cycle 2-8: day 1) for 8 cycles, maintenance therapy with lenalidomide (10 mg) once a day, and on Days 2-22 plus MIL62 (1000 mg) every 8 weeks on day 1 for 4 cycles. The primary endpoint was objective response rate, defined as a complete response or partial response assessed by investigator per Lugano 2014 criteria every 12 weeks. The secondary endpoints were duration of response, pharmacokinetics, and safety. Adverse events (AEs) were graded by CTCAE criteria version 5.0. Results: From November 29 th, 2019 to December 22 th, 2020，54 patients enrolled from 11 centers in China received at least one dose of either MIL62 or lenalidomide. Median age was 50.0 (range: 28 to 85) years. A total of 51 patients (94.4%) had FL, and 3 patients (5.6%) had MZL. The median number of prior therapies was 1.0 (range: 1 to 4) and 20 (37%) patients were refractory to rituximab. Overall, 23 patients (42.6%) were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index 2 (FLIPI-2). The median treatment time of MIL62 and lenalidomide was 28.6 (range: 0.1-53.7) weeks and 27.9 (range: 2.0-56.6) weeks, respectively. At the data cut-off date (June 30 th, 2021), the median follow-up time was 8.4 (range: 5.8-9.1) months. Overall, 42 (84.0%) of 50 assessable patients had an objective response, including 8 (16.0%) with complete response and 34 (68.0%) with partial response (Table 1). Especially, among 20 patients refractory to rituximab, 16 (80.0%) patients had an objective response, including 3 (15.0%) with complete response and 13 (65.0%) with partial response. The 9-month remission rate and 12-month progression-free survival rate were 80.2% (95%CI 58.1-91.4) and 71.2% (95%CI 50.6-84.4), respectively. Among 54 safety-evaluable patients, all experienced at least one treatment-emergent adverse event (TEAE). Most common treatment-related adverse event (TRAEs) occurring in ≥10% of patients were neutropenia (85.2%), leukopenia (72.2%), thrombocytopenia (57.4%), infusion-related reactions (16.7%), lymphopenia (27.8%), increases in alanine/aspartate aminotransferase (14.8%/13%). Grade 3 or above TEAEs were observed in 40 (74.1%) patients, among which related to MIL62 in 35 (64.8%) patients, including neutropenia in 25 (46.3%) patients, leukopenia in 10 (18.5%) patients, thrombocytopenia in 9 (16.7%) patients, lymphopenia in 4 (7.4%) and herpes zoster, infusion related reaction, tumor lysis syndrome and abdominal pain in 1 (1.9%) patient, respectively. Severe adverse events (SAEs) were observed in 13 (24.1%) patients, and MIL62- and lenalidomide-related SAEs occurred in 8(14.8%) and 8(14.8%) patients, respectively. Conclusion: MIL62 combined with lenalidomide showed promising efficacy in previously treated patients with relapsed or refractory FL and MZL, including those with early relapse, and has a manageable safety profile. A multi-center, randomized, open-label, phase III trial of MIL62 plus lenalidomide versus lenalidomide in rituximab refractory FL patients is ongoing (NCT04834024). Keywords: MIL62; type II anti-CD20 monoclonal antibody; recurrent/refractory follicular lymphoma; recurrent/refractory marginal zone lymphoma Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS534-TPS534 ◽  
Author(s):  
Andrea Necchi ◽  
Luigi Mariani ◽  
Andrea Anichini ◽  
Antonella Messina ◽  
Patrizia Giannatempo ◽  
...  
Keyword(s):  
Ct Scan ◽  
Immune Cell ◽  
Residual Disease ◽  
Systemic Disease ◽  
Single Agent ◽  
Pathologic Complete Response ◽  
Study Drug ◽  
Standard Of Care ◽  
Complete Response ◽  
Open Label

TPS534 Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM (MK-3475) is the standard-of-care for second-line metastatic UC and is being evaluated as single-agent neoadjuvant therapy for MIUBC (NCT02736266). EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in metastatic UC. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T4a N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence), regardless of cisplatin eligibility, will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, 18FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed on TURB specimen (Dako, clone 22C3), relying on the combined positivity score (CPS, 10% cutoff). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H1 is pT0≥20% and H0 pT0≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pT0 will be required in the first stage, and ≥13 pT0 in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). Radiologic findings from mpMRI will be associated with pathologic response (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.

scholarly journals A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

2021 ◽  
Author(s):  
Alexey V. Danilov ◽  
Stephen E. Spurgeon ◽  
Tanya Siddiqi ◽  
Anne-Marie Quinson ◽  
Daniela Maier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Residual Disease ◽  
Transmembrane Protein ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib

SummaryBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.

scholarly journals Safety and Efficacy of a Combination of Venetoclax (GDC-0199/ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 494-494 ◽  
Author(s):  
Ian W. Flinn ◽  
Mark Brunvand ◽  
Michael Y. Choi ◽  
Martin J.S. Dyer ◽  
John Gribben ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Research Funding ◽  
Disease Burden ◽  
Single Agent ◽  
Safety Data ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Study Participation ◽  
Clinical Hold ◽  
Phase 1B

Abstract Introduction Treatment of patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with the combination of venetoclax (VEN), an oral, selective Bcl-2 inhibitor, and rituximab yielded an ORR of 84% (Roberts et al. Haematologica 2015). Treatment of such pts with VEN in combination with obinutuzumab (Gazyva®, Gazyvaro™, G), a Type II, glycoengineered anti-CD20 antibody, may yield even better treatment outcomes. We present preliminary efficacy and updated safety data from an ongoing phase 1b study (NCT01685892) evaluating this combination in R/R or treatment-naïve (TN) pts with CLL in alternate treatment schedules. Methods Pts with CLL with an ECOG PS ≤1 and adequate organ function are enrolled in a study with a 3+3 design and cohorts ranging from 100 to 600 mg/day of VEN. Pts are assigned to one of two dosing schedules, starting treatment with either VEN (Schedule A) or G (Schedule B). Both schedules include tumor lysis syndrome (TLS) risk mitigation based on disease burden at screening, which includes a gradual VEN ramp-up to the assigned cohort dose. Six cycles of combination therapy will be given and then pts with R/R disease continue single-agent VEN until disease progression; TN pts will receive single-agent VEN for an additional 6 months. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination therapy in Schedule A or the first 35 days of combination therapy in Schedule B, and focus on TLS, infusion related reactions, and cytopenias. Based on a safety review of data from this trial, the 600 mg cohort will not be explored. Response is first assessed before Cycle 4 according to 2008 International Workshop on CLL guidelines. Results As of April 20, 2015, 32 pts (26 R/R and 6 TN) have been enrolled. Four R/R pts were unenrolled after a sponsor-initiated clinical hold secondary to TLS events in other VEN studies. Patient characteristics include a median age 62.5 (range, 45-80) years, and 62.5% male pts. TLS risk was assessed in 28 pts following protocol modifications adopted after a Sponsor-initiated clinical hold; 96.4% were at medium or high risk for TLS. The highest VEN dose administered in this study was 400 mg/day (administered to 11 R/R and 6 TN pts). Median time on study was 5.5 (range, 0.1-19.6) mo. for all pts and 2.8 (range, 0.9-2.8) mo. for TN pts. Among pts exposed to VEN, dose interruptions were observed in 17/27 (63%) pts. A summary of AEs is presented in Figure 1. Laboratory TLS was observed in 4/32 (12.5%) pts and all were able to continue study treatment after resolution of electrolyte changes; no cases of clinical TLS occurred. One pt with R/R disease in cohort 1 discontinued study participation following disease progression (the pt completed 6 cycles of combination treatment). A second pt with R/R disease in cohort 1 died secondary to acute respiratory failure; Richter's transformation also was suspected in this pt but not confirmed. Twenty pts with R/R disease and 6 TN pts remain on the study. At least 1 response evaluation has been performed in 17 pts with R/R disease. The overall response rate (ORR) by investigator assessment was 100%; 4/17 (23.5%) pts achieved complete response/complete response with incomplete bone marrow recovery (CR/CRi). Among the 13 (76.5%) pts with PRs after 3 cycles of therapy, 3 have improved to CR/CRi at assessments 28 days after completing C6D1. Full MRD data will be available in the near future but early analyses suggest some patients may achieve MRD negative status by Cycle 4. Conclusion These preliminary data suggest that VEN + G can be safely administered in pts with CLL with no difference in tolerability between R/R and TN subgroups. AEs appear to be manageable and no pt has discontinued study participation secondary to cytopenia, the most frequently observed AE. Data suggests that the TLS prophylaxis measures are effective even in patients with a higher disease burden. An expansion phase is planned using a 400 mg per day dose of VEN in R/R and TN pts following a review of safety data assessing potential differences between dosing schedules. The preliminary efficacy data suggest this regimen may be an important option in patients with CLL; a phase 3 study evaluating VEN+G is ongoing. Disclosures Flinn: Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Brunvand:Celgene: Speakers Bureau; Millenium: Speakers Bureau. Choi:Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Dyer:Roche Pharmaceuticals: Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead: Research Funding. Gribben:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria; Roche/Genentech: Honoraria; Pharmacyclics: Honoraria. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding. Jones:Acerta Pharma BV: Research Funding. Li:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Vosganian:Genentech, Inc.: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

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