A phase Ib, open-label, multicenter study of urelumab (BMS-663513) in combination with rituximab in subjects with relapsed/refractory B-cell malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3108-TPS3108 ◽  
Author(s):  
Holbrook Edwin Kohrt ◽  
John E. Godwin ◽  
Izidore S. Lossos ◽  
Michael E. Williams ◽  
John Timmerman ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Combined Treatment ◽  
Single Agent ◽  
Costimulatory Molecule ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
B Cell Malignancies ◽  
Phase Ib

TPS3108 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.

scholarly journals Suppressing Synthesis of the Long Isoform of the Prolactin Receptor Is a Targeted Strategy to Prevent and Treat B Cell Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1135-1135
Author(s):  
Adeleh Taghi Khani ◽  
Anil Kumar ◽  
Kelly Radecki ◽  
Sung June Lee ◽  
Mary Lorenson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Nk Cells ◽  
Malignant Transformation ◽  
Nk Cell ◽  
B Cell Lymphoma ◽  
B Cell Malignancies ◽  
Autoreactive B Cells ◽  
Cell Numbers ◽  
Bcl2 Expression

Abstract Rationale B cell malignancies, including leukemia and lymphoma, are high-risk lymphoid neoplasms. B cell malignancies predispose to autoimmune diseases including systemic lupus erythematosus (SLE) which increase the risk of developing these malignancies by >5-fold. Increased prolactin (PRL) expression is known to exacerbate SLE and promote the survival of autoreactive B cells. Furthermore, PRL induces expression of the protooncogenes, MYC and BCL2, in lymphoid tissues. However, whether PRL drives the initiation and maintenance of B cell malignancies was not known. Results We first tested our hypothesis that PRL, specifically signaling through the pro-proliferative and anti-apoptotic long isoform (LF) of the PRL receptor (PRLR), drives the progression of SLE to B cell malignancies. To this end, we knocked down the LF PRLR in MRL-lpr mice predisposed to developing SLE using a splice-modulating oligomer (SMO) that blocks splicing to produce the LF PRLR without affecting the short isoforms. LF PRLR knockdown reduced splenic and circulating B cell numbers in MRL-lpr SLE mice (Fig.1a). Consistent with reduced B cell numbers, BCL2 expression in B cells of SLE mice was suppressed after LF PRLR knockdown, although MYC was unaltered (Fig.1b). By sequencing the immunoglobulin heavy chains (IGH), we compared the composition of the splenic B cell repertoire between control- and LF PRLR SMO-treated SLE mice. Control oligomer treated SLE mice accumulated splenic B cells with long complementary determining region 3 (CDR3) and B cells with non-functional IGH, characteristics of autoreactive B cells. Treatment with the LF PRLR SMO reduced both. We then measured the expression of enzymes known to induce malignant transformation of B cells, namely recombination activating genes 1/2 (RAG1/2) and activation-induced cytidine deaminase (AID), in B cells of SLE mice in controls versus LF PRLR knockdown. Importantly, LF PRLR knockdown significantly reduced RAG1 (Fig.1c) and AID expression in splenic B cells of SLE mice (Fig.1d,e). Our findings thus underscore a causal role for LF PRLR signaling in promoting of malignant transformation of B cells in SLE. Because PRL induces the expression of BCL2 and MYC in lymphocytes, we next determined whether LF PRLR promotes the survival of overt B cell malignancies that overexpress MYC and BCL2, including diffuse large B cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL). We observed that B-lymphoblasts expressed significantly higher levels of PRL and the LF PRLR as compared to normal B cells (Fig.1f). We also found that higher expression of PRL at diagnosis predicts poor clinical outcome in DLBCL patients (P=0.0244), and that patients with MYC/BCL2-overexpressing ALLs with a poor prognosis had significantly higher expression of the LF PRLR compared to their MYC lowBCL2 low counterparts (P<0.0001). These observations suggested that LF PRLR may modulate MYC and BCL2 expression. Knockdown of the LF PRLR using the LF PRLR SMO in MYC/BCL2-driven human B cell malignancies killed lymphoblasts and reduced MYC and BCL2 protein levels (Fig.1g). Because we previously showed that MYC-driven lymphoid malignancies are sensitive to natural killer (NK) cell-mediated immune clearance, we also examined whether LF PRLR knockdown synergized with NK cells in killing DLBCL. We found that LF PRLR knockdown enhanced NK cell-mediated killing of B-lymphoblasts (Fig.1h). Of note, no reductions were observed in NK cell viability or MYC levels within NK cells upon LF PRLR knockdown, suggesting that LF PRLR selectively kills B-lymphoblasts without negatively impacting NK homeostasis. Conclusion Our studies identify the specific knockdown of LF PRLR as a potentially safe and targeted strategy to prevent the onset of B cell malignancies in SLE patients and to treat flagrant DLBCL and B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Phase 1 Study of Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) Plus Rituximab In Japanese Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2872-2872 ◽  
Author(s):  
Kiyohiko Hatake ◽  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Kota Tokushige ◽  
Chiho Ono ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Study Drug ◽  
B Cell Lymphoma ◽  
Japanese Patients ◽  
Clinical Activity ◽  
Inotuzumab Ozogamicin

Abstract Abstract 2872 Background: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. Inotuzumab ozogamicin targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose of inotuzumab ozogamicin administered as a single agent was previously determined to be 1.8 mg/m2 administered intravenously every 28 days, and clinical activity was shown in both non-Japanese and Japanese patients with relapsed or refractory B-cell NHL. Safety and efficacy data in non-Japanese patients with relapsed or refractory B-cell NHL treated with inotuzumab ozogamicin given in combination with rituximab was previously reported. Objectives: To assess safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin in combination with rituximab in Japanese patients with relapsed or refractory B-cell NHL. Methods: Patients were eligible if they had both CD20 and CD22-positive B-cell NHL, which had not responded to or progressed after 1 or 2 therapies. At least 1 prior regimen had to contain rituximab, and patients could not have progressed under treatment or within 6 months of start of rituximab-containing therapy. Patients received 375 mg/m2 of rituximab on Day 1 followed by 1.8 mg/m2 of inotuzumab ozogamicin on Day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression or intolerable toxicity. Adverse events (AEs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0 in patients who received at least 1 dose of the study drug. Objective response rate (ORR) was evaluated according to the International Response Criteria for NHL. Results: Ten patients were enrolled and treated with 1.8 mg/m2 of inotuzumab ozogamicin in combination with rituximab for a median of 4 cycles. Median age was 60.5 (range 46 – 74), 50% were male, and 50% each had 1 and 2 prior chemotherapy regimens. Six patients were diagnosed as having follicular lymphoma (FL), 2 patients as mantle cell lymphoma (MCL), 1 patient each as diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma. Grade 3 or 4 treatment-emergent AEs reported in >20% of the patients were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). AEs resulting in treatment discontinuation were neutropenia (30%) and hyperbilirubinemia (20%). No serious AEs were observed. An ORR of 80% (95% CI, 44 – 98%) was observed in the 10 patients treated. Five out of 6 patients with FL and 1 patient with MALT lymphoma achieved a complete response (CR). One out of 2 patients with MCL achieved unconfirmed CR (CRu), and 1 patient with FL attained partial response (PR). Progression-free survival (PFS) rate at 52 weeks was estimated to be 89% (95% CI, 43 – 98). ORR was 88% (95% CI, 47 – 100%) in the 8 patients that received at least 2 doses of the study drug and had at least 1 post-baseline tumor assessment (5 FL, 2 MCL, and 1 MALT lymphoma). Results of the pharmacokinetics assessment will be presented at the meeting. Conclusion: The combination of inotuzumab ozogamicin plus rituximab has a safety profile similar to that previously reported for inotuzumab ozogamicin as a single agent, with hematologic AEs being the most frequent toxicities. The preliminary but encouraging evidence of clinical activity in Japanese patients with relapsed or refractory B-cell NHL warrants continued clinical development of this combination. Disclosures: Tokushige: Pfizer Japan Inc.: Employment. Ono:Pfizer Japan Inc.: Employment. Vandendries:Pfizer Inc.: Employment, Equity Ownership.

Spleen Tyrosine Kinase (Syk) Inhibitors Block B Cell Receptor Signaling and Survival In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3604-3604
Author(s):  
Julia Hoellenriegel ◽  
Greg Coffey ◽  
Uma Sinha ◽  
Anjali Pandey ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Cell Viability ◽  
B Cell ◽  
Cell Activation ◽  
Kinase Inhibitor ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
Syk Inhibitor

Abstract Abstract 3604 B cell antigen receptor (BCR) signaling is increasingly recognized as a key factor promoting clonal expansion in various B cell malignancies, such as diffuse large B cell lymphoma and CLL. Engagement of the BCR receptor activates Syk, which leads to a number of downstream events that promote cell survival and growth. Therefore, inhibition of Syk represents a novel therapeutic approach in CLL. Another Syk inhibitor (fostamatinib disodium/R788) has clinical activity in patients with CLL (Blood 115: 2570, 2010). R788 is a relatively selective Syk inhibitor, but also displays activity against Flt3, Jak, and Lck. In this study we tested two highly selective Syk inhibitors (P142-76 and P505-15) and a multi-kinase inhibitor (P420-89) for their efficacy to antagonize BCR-related CLL cell activation and survival responses. We found that BCR crosslinking with anti-IgM significantly increased CLL cell viability compared to controls, and this pro-survival effect of BCR triggering was abrogated by treatment with the Syk inhibitors P142-76 and P505-15. Figure A shows contour plots that depict CLL cell viability in a representative case, treated with anti-IgM in the presence or absence of the Syk inhibitors. The mean relative CLL cell viability at 48 hours was decreased to 78% ± 4% (P142-76), 62% ± 5% (P505-15) or 50% ± 4.5% (P420-89) of controls (means ± SEM, n=19). Additionally, we found that the inhibitors induce apoptosis in CLL cells in co-culture with nurselike cells (NLC), indicating that Syk inhibition antagonizes microenvironment-derived survival signals which may or may not be related to the BCR. For example, P505-15 significantly reduced CLL cell viability in NLC co-cultures from 84.4% ± 5% to 46% ± 8% at 48 hours (mean ± SEM, n=6,*P< 0.05, summarized in Fig. B). The chemokines CXCL12 and CXCL13 regulate migration and homing of CLL cells within the CLL microenvironment, and CLL cell responsiveness to these chemokines is modulated by BCR signaling. Therefore, we evaluated the effects of the Syk inhibitors on CLL cell chemotaxis towards these chemokines. P505-15 decreased chemotaxis toward CXCL12 and CXCL13 to levels that were 49.5% ± 5% or 32.8% ± 6% of respective controls. In response to BCR crosslinking, CLL cells secrete the chemokines CCL3 and CCL4, which foster interactions between CLL cells and the leukemia microenvironment. This was almost completely abrogated by inhibiting Syk. For example, preincubation with P505-15 significantly reduced CCL3 supernatant levels from 8400 pg/mL ± 1166 pg/mL to 2263 pg/mL ± 744 pg/mL (mean ± SEM, n=5, *P< 0.05). This inhibition of CCL3/4 secretion by CLL cells could also be demonstrated in CLL co-cultures with NLC. Finally, we found that P505-15 blocked BCR-induced activation of the p44/42 MAP kinase, using anti-phospho-MAPK (ERK1/2) antibodies. In summary, our findings demonstrate that specific Syk inhibitors are highly effective in disrupting BCR-derived survival and cell migration-related responses in CLL cells. These data support the clinical development of these new, promising agents in patients with CLL and other selected B cell malignancies. Disclosures: Coffey: Portola Pharmaceuticals: Employment. Sinha:Portola Pharmaceuticals: Employment. Pandey:Portola Pharmaceuticals: Employment.

Antitumor Effect Of Sepantronium Bromide (YM155), a Survivin Suppressant, In Combination With Bendamustine and Rituximab In Diffuse Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3073-3073
Author(s):  
Naoki Kaneko ◽  
Keisuke Mitsuoka ◽  
Nobuaki Amino ◽  
Kentaro Yamanaka ◽  
Aya Kita ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Triple Combination ◽  
Large B Cell Lymphoma ◽  
M Phase ◽  
Large B Cell

Abstract Background Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with rituximab (RTX, an anti-CD20 antibody) based regimen, but a subset of patients still fail to achieve complete or durable responses and are not eligible for high-dose chemotherapy followed by autologous stem cell transplant. Therefore novel effective therapies with less toxicity for relapsed or refractory DLBCL patients are needed. Bendamustine (BEN) is a bifunctional alkylating agent for the treatment of multiple hematological tumors, including indolent and RTX-resistant NHL, and the combination of BEN with RTX showed clinical activity in patients with relapsed or refractory DLBCL in the Phase II study 1. Sepantronium bromide (YM155), a survivin suppressant, shows potent antitumor activities against a wide range of cancer cells, and NHL including DLBCL is one of the most sensitive tumor types to YM155. YM155 showed clinical activity when combined with RTX in patients with relapsed DLBCL 2. In the present study, we evaluated therapeutic potential of YM155, in combination with BEN or BEN and RTX using DLBCL models. Results The combination of YM155 with BEN decreased cell viability to a greater extent than either single agent alone in DB, SU-DHL-8, and WSU-DLCL2 human DLBCL cell lines. Bliss additivism analysis revealed that the combined effects were synergistic. In addition The combination of YM155 with BEN induced a greater sub-G1 population, indicative of apoptosis, than either agent alone. The percentages of sub-G1 population induced by YM155, bendamustine, and combination of both were 5.9%, 6.5%, and 27% in DB cells; 19%, 32%, and 58% in SU-DHL-8 cells; and 46%, 30%, and 71% in WSU-DLCL2 cells, respectively. BEN induced γ-histone 2AX (γ-H2AX), a marker of DNA damage and phosphorylation of ATM substrates including p53, and check point kinase-2 (Chk2) which leads to phosphorylation of cdc2. Further BEN induced G2/M arrest associated with the increase of survivin. The combination of YM155 with BEN inhibited phosphorylation of p53, chk2, and cdc2 and accumulation of survivin at G2/M phase, and induced greater DNA damage and cleaved PARP than either single agent alone. In human DLBCL DB xenografts, 7-day continuous s.c. infusion of YM155 at 1 mg/kg/day enhanced antitumor activity of BEN at 50 mg/kg (i.v.) and induced complete regressions in 6 out of 8 mice without affecting body weight. Further, in an activated B-cell-like (ABC)-DLBCL disseminated xenograft model, the combination of YM155 with BEN and RTX significantly prolonged survival associated with the decrease in the FLT-PET signals in lymph node compare with either the combination of BEN with RTX and YM155 with RTX. Conclusions Our data indicates that YM155 enhances the antitumor activity of BEN against DLBCL models through inhibition of DNA damage responses as well as survivin accumulation at the G2/M phase. Further, triple combination of YM155 with BEN and RTX showed survival benefit in comparison with either BEN-RTX combination or YM155-RTX combination, supporting the further clinical investigation of this triple combination for the treatment of relapsed or refractory DLBCL. Reference: 1. Ohmachi et al. J Clin Oncol. 2013 Jun 10;31(17):2103-9 2. Papadopoulos et al. American Society of Hematology Annual meeting Abstract No. 2731. 2012. Disclosures: No relevant conflicts of interest to declare.

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Results of the Part I Cohort of the STORM Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2727-2727 ◽  
Author(s):  
Mathias Witzens-Harig ◽  
Ulrich Keller ◽  
Andreas Viardot ◽  
Christian Buske ◽  
Anne Crombé ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Mtor Inhibitor ◽  
Cell Lymphoma ◽  
Central Venous Access ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Salvage Regimen

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the mTOR inhibitor Temsirolimus from 25, 50, 75 and 100 mg were predefined. Results. Here we report on the preliminary results of part I of this clinical trial. 15 patients were included - 8 patients in the 25 mg cohort and 7 patients in the 50 mg cohort. Median age was 70 (range 49-76) years and median number of prior regimen was 1. Two DLTs (one venous thrombosis in the 25 mg cohort, one esophagus infection in the 50 mg cohort) were observed. The most frequent non-hematologic side effects were nausea (9 pts, 60%), epistaxis (7 pts, 47%), fatigue (6 pts, 40%), increased ALT (6 pts, 40%) and increased creatinine (6 pts, 40%). Frequent grade 3/4 events (n>2) in both cohorts (25mg|50mg) included leukopenia (11 pts, 73% - with a mean duration of 4.4 days | 6.7 days ), thrombocytopenia (11 pts, 73% - with a mean duration of 4.6 days | 11.9 days), lymphopenia (6pts, 40%), anemia (5 pts, 33%), neutropenia (3 pts, 20%), renal failure (3 pts, 20%) and infections (4 pts, 27%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. All but one evaluable patient responded (10/11 pts, 91%), with two CRs and one CRu (27%). Four patients could not be evaluated for response at the time of this report. After a median follow up of 12 (range 5-22) months, no relapse has been documented so far (1 pt lost to follow up). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Recruitment into part II is ongoing and updated results will be presented. Disclosures Witzens-Harig: Pfizer: Honoraria, Research Funding; Roche: Honoraria. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Viardot:Roche: Honoraria; CTI: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Ho:Sanofi: Research Funding. Hess:Janssen, Roche, Celgene, Novartis: Consultancy; Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding.

Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8065-8065 ◽  
Author(s):  
Trishna Goswami ◽  
Andres Forero ◽  
Mehdi Hamadani ◽  
Anne Sonet ◽  
Gregor Verhoef ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
B Cell ◽  
Transmembrane Protein ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Antibody Targeting

8065 Background: Novel B-cell targeting agents, including monoclonal antibodies such as rituximab, are among recent advances in treatment of B-cell malignancies. New approaches are needed for patients progressing after rituximab-based therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a B-cell restricted transmembrane protein with enhanced affinity and antibody-dependent cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, or multiple myeloma received single agent MEDI-551 at dosages ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Six pts had grade 3 toxicities including tumor lysis syndrome, infusion reaction, thrombocytopenia, and neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts recovered. Three partial responses (PR) and 2 complete responses (CR) were seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further study and showed no MTD reached at the highest dose studied. Anti-tumor activity is suggested by the responses achieved across dose levels. Phase II is currently enrolling subjects. This study is funded by MedImmune, LLC. [Table: see text]

scholarly journals Immunomodulatory Drugs for the Treatment of B Cell Malignancies

2021 ◽  
Vol 22 (16) ◽  
pp. 8572
Author(s):  
Nikolaos Ioannou ◽  
Khushi Jain ◽  
Alan G. Ramsay
Keyword(s):  
Combination Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Immune Recognition ◽  
Immunomodulatory Drugs ◽  
B Cell Malignancies ◽  
Cellular Compartments

Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL.

Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1066-1066
Author(s):  
Seth Andrew Wander ◽  
Dejan Juric ◽  
Jeffrey G. Supko ◽  
Douglas Scott Micalizzi ◽  
Laura Spring ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Neutrophil Count ◽  
Clinical Benefit ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Single Agent ◽  
Metastatic Breast ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Phase Ib

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .

The Novel Triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO) Induces Apoptosis of Human Diffuse Large B-Cell Lymphoma Cells (DLCL) through a Peroxisome Proliferator-Activated Receptor γ (PPARγ) Independent Pathway Which Is Enhanced by NFκB Inhibition.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2425-2425
Author(s):  
Denise Ray ◽  
Kimberly Morse ◽  
Shannon Hilchey ◽  
Tatiana Garcia ◽  
Raymond Felgar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
B Cell ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Phenotype ◽  
Clinical Activity ◽  
Peroxisome Proliferator

Abstract Ligands for the transcription factor PPARγ are emerging as a new class of anti-tumor agents. Herein we report that the synthetic triterpenoid CDDO, a PPARγ ligand that induces PPARγ transcriptional activity in human DLCL OCI-Ly-19 cells, also induces cell death in human DLCL of both germinal center (OCI-Ly19) and activated B-cell phenotype (OCI-Ly10), cells which express the PPARγ protein. This effect of CDDO appears to be independent of PPARγ stimulated pathways since the functional antagonist of PPARγ, GW9662, which completely inhibits CDDO induced PPARγ transcriptional activity was unable to prevent CDDO induced cell death. Similar findings were seen using the additional PPARγ antagonists T0070907 and BADGE. CDDO induces cell death by inhibiting cell proliferation and inducing apoptosis as shown by Annexin-V and propidium iodide staining. As we have previously shown that PPARγ ligands inhibit NF-κB activity in B lymphocytes (J. Immunol2005; 174(7): 4060–9), we next examined the effect of CDDO on NF-κB in DLCL cells. Surprisingly, exposure of Ly19 cells to CDDO resulted in a dose-, and time-dependent increase in the activity of both the p50 and p65 subunits of NF-κB as determined by ELISA, by direct visualization of the nuclear translocation of p65 using indirect immunofluorescence assays, and by EMSA. The nuclear translocation of both the p50 and p65 NF-κB subunits was also confirmed by performing immunoblot analyses using nuclear fractions of CDDO-treated Ly19 cells. NF-κB activation was also observed in Ly10 cells exposed to CDDO. Follow-up experiments revealed that the activation of NF-κB in Ly19 cells by CDDO was due to proteolysis of inhibitory IκBα molecules. To determine whether the CDDO-induced NF-κB activation was a pro- survival mechanism, Ly19 and Ly10 cells were pre-treated with the NF-κB inhibitors SN50, helenalin or BAY 11-7082 and then exposed to CDDO for 24 hrs. In all cases, the NF-κB inhibitors significantly enhanced CDDO induced cell death suggesting that NF-κB activation is an anti-apoptotic mechanism elicited to protect the cell against CDDO cytotoxicity. Collectively, these studies suggest that; (a) CDDO (which will shortly be entering clinical trials for patients with acute myeloid leukemia) as a single agent may have significant clinical activity in patients with DLCL and; (b) the combination of CDDO with pharmacological inhibitors of NF-κB would be a rationale combination of novel agents to test in the context of clinical trials for patients with DLCL.

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