New Clinical Trial: A Phase 1 Open Label Study of ACP-196 in Patients with Waldenstrom’s MacroglobulinemiaPosted: October 20, 2014
The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with diffuse large B-cell lymphoma. The study sponsor is Acerta Pharma BV, and the principal investigator at Weill Cornell is Dr. Richard Furman. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at email@example.com.
- Men and women age 18 and older with a confirmed diagnosis of Waldenstrom’s Macroglobulinemia
- Previously treated with at least one prior therapy
- Cannot have received prior therapy with a BTK inhibitor
- Must be disease free from a former malignancy for at least two years
- Detailed eligibility reviewed when you contact the study team.
This clinical trial is for men and woman with a form of cancer called Waldenstrom’s Macroglobulinemia (WM) who have relapsed or not responded to at least one prior therapy. Inhibition of Bruton’s tyrosine kinase (BTK) has been established as an effective means for treating WM. ACP-196 is an oral, novel inhibitor of BTK with increased specificity for the target and fewer drug interactions than other BTK inhibitors being studied. Subjects will receive different doses ACP-196 (depending upon when they enter the trial) in order to determine the side effects and effective dose of ACP-196.
Subjects will be assigned to one of two treatment groups:
Cohort 1: ACP-196 100 mg twice a day (BID) for 28 days
Cohort 2: ACP-196 200 mg once a day (QD) for 28 days
New Clinical Trial: Efficacy of ACP-196 in Patients with Relapsed or Refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma (DLBCL)Posted: September 30, 2014
The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with diffuse large B-cell lymphoma. The study sponsor is Acerta Pharma BV, and the principal investigator at Weill Cornell is Dr. Jia Ruan. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at firstname.lastname@example.org.
- Men and women greater than or equal to 18 years of age
- Confirmed de novo ABC DLBCL, and subjects must have archival tissue available for central pathology review
- Recurrence of disease after a complete response or progressive disease at the completion of the treatment regimen preceding entry to the study
- Detailed eligibility will be reviewed when you contact the study team
The purpose of this study is to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of ACP-196 in treating subjects relapsed or refractory de novo ABC diffuse large B-cell lymphoma (DLBCL).
Clinical Studies have shown that targeting the B-cell receptor (BCR) signaling pathway by inhibiting Bruton tyrosine kinase (Btk) produces significant clinical benefit in patients with non-Hodgkin lymphoma. Acerta Pharma BV has developed a novel second generation Btk inhibitor, ACP-196, that achieves significant oral bioavailability and potency.
This study is a multi-center, open-label, randomized, parallel group study. No placebo will be administered during this study. Twenty subjects, 10 refractory and 10 relapsed, will be enrolled and will take 100 mg of ACP-196 twice per day.
Treatment will occur for 5 cycles with a 30 day follow-up period following the last dose. Treatment with ACP-196 may be continued for more than 28 days until disease progression or an unacceptable drug-related toxicity occurs. Subjects with disease progression will be removed from the study. All subjects who discontinue study drug will have a safety follow-up visit 30 (±7) days after the last dose of study drug unless they have started another cancer therapy within that time frame.
DLBCLs are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability, thus generating a diverse set of clones of cells encoding high affinity antibodies. The GC phenotype poses a significant risk in the malignant transformation to B cells, with epigenetic regulatory complexes playing a critical role in lymphomagenesis. During a symposium session at the recent American Association for Cancer Research, the Melnick Lab, reported how the deregulation of histone methyltransferases causes the malignant transformation of B-cells.
EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GC, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCL in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes.
Epigenetic heterogeneity is associated with unfavorable outcomes in B-cell lymphoma. This suggests that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that allows for a more complete response to chemotherapy treatment. These DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for first line treatment of patients with DLBCL. However, further research will be required to confirm this targeted therapy approach for clinical use in patients.
Diffuse large B cell lymphoma (DLBCL) is a common aggressive lymphoma that represents 30-40% of newly diagnosed cases of non-Hodgkin lymphoma, but accounts for up to 80% of lymphoma-related deaths. Although R-CHOP remains the standard first line therapy, it has more recently been associated with a frequent lack of response in DLBCL patients. This lack of response has enforced the necessity for finding alternate therapeutic targets.
At the 2014 meeting of the American Association for Cancer Research researchers from Weill Cornell Medical College reported on their recent findings. In a late breaking abstract the Shaknovich Lab reported on the potential of the IL10 receptor as a new biomarker and therapeutic target in DLBCL. The hypothesis is that DLBCL is dependent on the feed-forward autostimulatory loop that begins from the autocrine IL10 secretion and stimulation of overexpressed receptors leading to cell proliferation and that blocking the receptor would lead to cell death.
The research team of postdoctoral fellow Wendy Beguelin and research associate Seema Sawh determined that blocking IL10R results in specific inhibition of signaling through JAK1/2 and loss of phosphorylation at STAT3Y705 immediately after treatment. The inhibition of signaling through MAPK and phosphorylation of STAT3S727 came at a later time in treatment. The inhibition of signaling was sustained for days with only one drug treatment leading to induction of apoptosis. Anti-IL10R treatment resulted in significant downregulation of IL10 and IL10RA transcription, leading to interruption of IL10-IL10R autostimulatory loop.
IL10R is a novel therapeutic target in DLBCL that allows for easy detection and targeting. Shaknovich Lab is planning further animal studies and hopes to develop therapeutic antibody for clinical use in patients.
Although conventional chemotherapy is primarily aimed at tumor cells, we now know of the importance of neighborhood cells, included within the tumor mass. These include endothelial cells and pericytes that form blood vessels, macrophages that mediate inflammation, and fibroblasts and extracellular matrix proteins that build matrix and scar tissues. The interaction between the tumor cells and their neighborhood is collectively known as the tumor microenvironment. Given the importance of the tumor microenvironment in maintaining tumor growth and developing resistance to conventional chemotherapy, novel strategies that target the microenvironment are under active investigation. Clinical researchers led by, Dr. Jia Ruan, have recently published 2 important studies on developing novel therapeutic strategies that target lymphoma angiogenesis (blood vessel formation) and lymphangiogenesis (lymphatic vessel formation) within the tumor microenvironment.
The first study was published in the leading hematology journal Blood in collaboration with Dr. Leandro Cerchietti, a lymphoma biologist, and Dr. Katherine Hajjar, a vascular biology expert, both at Weill Cornell Medical College. The study found that pericytes, the vascular accessory cells surrounding the endothelial cells, are important players in lymphoma tumor angiogenesis, and represent potentially novel therapeutic targets for anti-lymphoma therapy. Specifically, the Weill Cornell lymphoma researchers treated human diffuse large B-cell lymphoma (DLBCL) growing in mouse models with an oral drug called imatinib. This incapacitated a critical cell surface receptor within the pericytes, namely platelet-derived growth factor receptor β (PDGFRβ), which is important for the survival of the pericytes and its communication with the endothelial cells. As a result, lymphoma-associated microvascular blood vessel formation was reduced due to programmed-cell death of both pericytes and endothelial cells. This ultimately translated into therapeutic effect of lymphoma growth impairment. This study provided proof of principal that targeting non-tumor vascular cells within the lymphoma microenvironment can result in significant inhibition of lymphoma growth, providing the basis for more refined consideration of anti-angiogenesis as a treatment strategy for lymphoma patients.
The second study published in Cancer Research, in collaboration with Dr. Lijun Xia, a glycoprotein and vascular biology expert at the Oklahoma Research Foundation. The researchers found that 1) lymphatic vessels, which form the vascular network known as lymphangiogenesis, contributed to the growth and spreading of lymphomas in an experimental model of mantle cell lymphoma (MCL), and 2) treatment with the immunomodulatory drug lenalidomide potently inhibited the growth and spreading of MCL by disabling tumor lymphangiogenesis. Mechanistically the researchers demonstrated that treatment with lenalidomide reduced the number of MCL-associated macrophages and their production of a growth factor important for the formation of lymphatic vessels, namely vascular endothelial growth factor-C (VEGF-C). This is the first study to address the potential importance of lymphangiogenesis in lymphoma growth, and provided a novel perspective of the mechanisms of action of lenalidomide in lymphoma therapy. This pre-clinical study synergizes with our recent clinical data displaying high response rates and durable remissions with the biologic combination of lenalidomide + rituximab in patients with previously untreated MCL.
Both studies open potentially new novel paths to treating lymphoma, exemplifying the Lymphoma Program’s commitment to the bench-to-bedside translational research that brings cutting-edge science to patient care.
1. Blood. 2013 Jun 27:121(26):5192-202. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.
2. Cancer Res. 2013 Dec 15:73(24):7254-64. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma.
Despite improvements in care for patients with diffuse large B-cell lymphoma (DLBCL), roughly one-third of patients do not respond to initial therapy or relapse within the first 2-3 years after treatment. Unfortunately, our current understanding of the molecular mechanisms of relapse is extremely poor.
During the recent 2013 American Society of Hematology meeting, we reported for the first time that there exist at least two distinct scenarios of DLBCL relapse. In the first scenario, the tumor cells at diagnosis are almost genetically identical to tumor cells at relapse. Both tumors harbor the same set of mutations with the relapsed tumor possessing a few additional mutations, suggesting that the relapsed tumor evolved continuously from the tumor present at diagnosis. We termed this scenario “linear” mode. In the second scenario, the tumors at diagnosis and relapse carry different mutations, suggesting that an early divergent event occurred and that the tumors developed in parallel. Therefore, we named this scenario the “divergent” mode. Moreover, we observed that tumors with higher genetic heterogeneity at diagnosis were more likely to relapse through the divergent mode. This may provide a foundation for evaluation of different treatment strategies for different relapse modes.
Currently, we are expanding our study to investigate the role of epigenetics, particularly DNA methylation, in DLBCL relapse. For more research information on DLBCL, and relapsed DLBCL, please visit our websites at the Elemento Lab and the Melnick lab.