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Lymphoma Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

Fig.1 Lymphoma signaling pathway. Targeted agents (listed in orange boxes) include those in clinical use (colored in green) and those in preclinical or early phase development (colored in red) for the treatment of lymphoma.

An Introduction to Lymphoma

Lymphoma is blood cancer arising from lymphocytes of the lymphatic system. These cells exist in various organs or tissues such as the lymph nodes, bone marrow, thymus, spleen. During the lymphoma process, lymphocytes often show abnormal change and growth. Currently, Lymphomas have many subtypes, such as the anaplastic large cell lymphoma (ALCL), Hodgkin's lymphomas (HL), non-Hodgkin lymphomas (NHL) and diffuse large B-cell lymphoma (DLBCL). HL and NHL represent the two main subtypes of lymphomas, and about 90% of lymphomas are NHL. In most cases, the cause of the lymphomas is unclear. However, some factors are associated with this cancer including age, genders, weak immune system, immune system disease, infection of a virus, exposure to chemicals and treated for cancer with radiation. Signs and symptoms commonly include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired and sweating at night. To date, the main treatment strategies of this cancer often include chemotherapy, radiation therapy, targeted therapy, and surgery.

1 Main Signaling Pathways in Lymphoma Therapy

1.1 B-cell receptor (BCR) signaling cascade

BCR signaling pathways are divided into chronic active BCR signaling, tonic BCR signaling, and autonomous BCR signaling based on their modes of initiation. This first classical antigen-dependent BCR signaling and its downstream signaling involve in numerous cellular functions, including proliferation, survival, apoptosis and differentiation. This pathway is frequently and aberrantly activated in chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) with low level IgM expression, in a subset of active B-cell-like (ABC) DLBCL bearing CD79B and CARD11 mutations, in mucosa-associated lymphoid tissue lymphoma (MALT) with Hp infection, and in splenic marginal zone lymphoma with hepatitis C virus infection. MALT1/API2 fusion and B-cell lymphoma 10 overexpression, PI3K mutation, phosphatase and tensin homolog (PTEN) gene loss of function are associated with the oncogenesis of MALT and DLBCL. The second BCR pathway, tonic BCR signaling exists in normal B-cell function and is commonly observed in Burkitt lymphoma (BL) that bears some distinctly different genetic abnormality, such as in transcription factor 3 (TCF3) and inhibitor of DNA binding 3(ID3) alterations. Autonomous BCR signaling pathway is the third kind of BCR pathway where the BCR aggregates without external antigen but relies on an interaction between the two neighboring BCRs through CDR3 and FR2 crosslinking.

1.2 Nuclear factor-kappaB (NF-κB) signaling cascade

The NF-κB pathway is one of the most common signaling pathways in normal lymphoid cells and several types of tissues. The constitutively activated NF-κB pathway has been proved involved in oncogenesis of many types of human malignancies including lymphomas. The NF-κB pathway includes canonical and noncanonical pathway, and includes p50, p65 (RelA), RelB, p52, and c-Rel proteins. The constitutively activated canonical and non-canonical NF-κB signaling pathways exist in almost all types of lymphoma. One example, ABC-DLBCL is the type affected by NF-κB through various mechanisms. These oncogenic events can cause a dysregulated upstream chronic active BCR signaling. In addition, other oncogenic events, such as dysregulated upstream of the JAK/STAT pathway, NF-κB target genes alteration, chromosomal translocation, or EBV infection, also can trigger the constitutive activation of the NF-κB pathway in ABCDLBCL, MALT, BL, HL, or other types of lymphoma.

1.3 PI3K/AKT/mTOR signaling cascade

The PI3K/AKT/mTOR signaling pathway is activated following the BCR pathway, the TNFR pathway, or other upstream pathways. This pathway plays a critical role in cell growth, survival, apoptosis, proliferation, metabolism, and motility processes. The aberrant activation of the PI3K/AKT/mTOR pathway can lead to many types of cancer. Commonly, this oncogenic activation is associated with the PIK3CD mutation in DLBCL, loss of function PTEN in GCB-DLBCL, and PIK3CA copy number increasing in mantle cell lymphoma (MCL). Moreover, the overexpression of p-AKT has been acted as an inferior outcome indicator in DLBCL, MCL, and peripheral T-cell lymphoma. Given the critical status of the PI3K/AKT/mTOR pathway in lymphoma, PI3K, AKT, and mTOR are considered as potential targets to design drugs for the treatment of lymphoma patients.

1.4 JAK/STAT signaling cascade

The JAK/STAT pathway is an important signaling pathway as a key mediator of cytokine signaling. The underlying molecular mechanisms of the JAK/STAT pathway dysregulation in lymphoma still remain unclear. But some main aberrations like JAK2 aberration are companied by Jumonji domain-containing protein 2C (JMJD2C) abnormality, loss-of-function mutation of SOCS1, and protein tyrosine phosphatase non-receptor type 2 (PTPN2) deletion may contribute to the oncogenic JAK/STAT signaling in primary mediastinal B-cell lymphoma (PMBL), classical HL, and ABC-DLBCL. Particularly, aberrations of STAT3, STAT5, and JAK2 have been found to be the most common characterization in these malignancies. Thus, targeting the JAK/STAT pathway is an approach to treat hematologic patients with lymphoma. Some inhibitors against JAKs, STATs, or ILs, and other related biomarkers have been developed or are under investigation, which are promising to treat lymphoma via many rational ways such as inducing growth arrest and inhibiting angiogenesis.

1.5 Apoptosis signaling cascade

Apoptosis is a pathway of programmed cell death that is involved in a variety of important biological process including the normal organism development, biological evolution, internal environmental stability, and abnormal cells clearance. This process is regulated by a series of highly conserve molecules, like the BCL2 family, the caspase family, and the tumor suppressor protein p53. The apoptosis pathway can function through at least two distinct but interconnected pathways, the extrinsic and the intrinsic apoptosis pathways. In the pathologic process, the normal apoptosis signaling pathway is interrupted by oncogenic defects and cells grow unchecked, resulting in the oncogenesis of a wild variety of cancer including the lymphoma. Interfering pathologic apoptosis pathway and restoring its normal function by targeting therapeutic targets, such as BCL2, MYC, and p53 are regarded as potential therapy methods.

1.6 PD-1/PD-Ls signaling cascade

PD-1 and PD-Ls are regulated by the immune system to balance its immune function. Upon binding to its ligands, PD-1 transfers co-inhibitory signals, negatively regulating the functions of T and B cells to maintain the immune balance. However, during tumor process, overexpression of PD-Ls in tumor cells and infiltrating cells due to genetic alteration, virus infection, or other intrinsic and extrinsic factors, can activate PD-1 signaling and cause exhaustion of effector T cells after the interaction of PD-1 and PD-Ls. Such an immune escaping signaling is a primary mechanism resulting in oncogenesis, tumor aggression and metastasis. Agents blocking the immune checkpoint path way is a promising approach and showed encouraging efficacy to treat a broad spectrum of malignancies such as the lymphoma including relapsed/refractory cHL, DLBCL, and follicular lymphoma (FL). More and more of the checkpoint inhibitors especially the monoclonal antibodies have been approved and translated into clinical immunotherapy management.

Lymphoma Diagnosis

Lymphoma targeted therapies target specific biomarkers that are key components of oncogenic pathways or other related molecules in cases of mutation, deletion, translocation, and overexpression. These biomarkers can be used for disease diagnosis, rational drugs design, and to predict treatment outcome of patients who may benefit from the pathway-based therapy management.

2.1 Molecular Markers for Lymphoma

The detection of highly recurrent hot spot mutations, such as MYD88 L265P in lymphoplasmacytic lymphoma (LPL) have helped to refine these entities and added markers to the diagnostic repertoire, which can be evaluated using relatively simple, straightforward techniques such as allele-specific PCR or pyrosequencing. BRAF V600E occurs in rare cases of plasma cell myeloma and nodal marginal zone lymphoma that can be used as a biomarker. Pathogenic mutations in lymphoma are not distributed randomly, but can influence certain pathways linked to lymphocyte biology, often leading to similar biological effects despite targeting different genes. In B-NHL, B-cell receptor and TOLL-like signaling, the NF-kB and NOTCH pathways and epigenetic regulators are commonly affected, whereas in T-cell lymphoma, the TCR and the JAK/STAT signaling pathways are frequently targeted. Both B- and T-cell lymphomas show common mutations of tumor suppressor genes such as TP53. In mature B-NHL, aberrant somatic hypermutation can target a variety of genes, including BCL6, PAX5, PIM1, BTG1/2 IRF4 and MYC, as well as the translocated alleles of BCL2 in cases of FL and DLBCL carrying a t(14; 18) translocation. Another frequent target of mutations in NHL are genes involved in epigenetic regulation of gene expression, including TET2, CREBBP, DNMT3A, EZH2 and others.

2.2 Protein Markers for Lymphoma

A variety of therapeutic biomarkers in lymphoma have been identified. BCL2 is encoded by the BCL2 gene located on chromosome 18q21.3. BCL2 is an apoptosis regulator that can suppress apoptotic death by interacting with caspases and other BCL2 family members. BCL2 is the critical molecule in the apoptosis pathway and involved in cell survival, apoptosis, and proliferation. As a nuclear transcription factor, p53 can regulate the expression of numerous target genes involved in physiological cellular functions. As a tumor suppressor protein, p53 functions as an important mediator in the apoptosis pathways under oncogenic stress, DNA damage, and hypoxia. Inactivation and the dysregulation of p53 signaling pathway contribute to oncogenesis of cancers including in lymphomas. Myc protein is encoded by the proto-oncogene Myc, which is a typical pleiotropic transcription factor and is involved in almost every process of cell biology and oncology by regulating thousands of target genes. In aggressive lymphomas, Myc acts as a driver involving in oncogenesis, malignant transformation, and aggressive clinical features. BTK is a member of the Tec family as a cytoplasmic tyrosine kinase and is mainly expressed in B cells and myeloid cells. In addition to its critical function in B lymphocyte development and differentiation, BTK is an indispensable component for BCR signaling. BTK as a therapeutic biomarker can be targeted by its inhibitors to interrupt BCR signaling and NF-kB signaling. Other protein markers include SYK (a cytoplasmic nonreceptor-type tyrosine kinas), PI3Ks, AKT, mTOR, PTEN, STATs, JAKs, Interleukin 6 (IL-6), MYD88, PD-1 and PD-Ls, etc.

3 Targeted Therapy for Lymphoma

The BCR, NF-κB, PI3K/AKT/mTOR, JAK/STAT, apoptosis and PD-1/PD-Ls signaling pathway plays important roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The overexpression of oncogenes and tumor suppressor genes include p-IκBα, PI3K, AKT, mTOR, JAKs, STATs, ILs, BCL2, MYC, and p53 have been used as targets for targeted therapy in lymphoma progress.

We have focused on recently discovered therapeutic targets for lymphoma. Here, we summarize the potential targets and new drugs developed that have been used in recent, ongoing and future clinical trials to try to improve the clinical outcomes of this disease (Table1-25).

3.1 Lymphoma therapy for BCR pathway

Aberrant activation of BCR signaling has been increasingly implicated in oncogenesis of several types of B-cell hematologic malignancies, especially in CLL/SLL and ABC-DLBCL, the inhibitors targeting the BCR pathway provide the patients with B-cell lymphomas an effective option for treatment. Some clinical trials targeting some oncogenic biomarkers in the BCR pathway have been showing promising efficacy to treat the malignant lymphomas with aberrant signaling pathway activation. These BCR pathway inhibitors include Ibrutinib (PCI-32765), BGB-3111, AVL-292 (cc-292), M7583, Acalabrutinib (ACP-196), Fostamatinib (R788) (R406), Cerdulatinib (PRT062070) and Entospletinib (GS-9973).

Table 1 Clinical trials of BTK inhibitor Ibrutinib

Nct id Status Lead sponsor Study first posted
NCT02451111 Active, not recruiting Swiss Group for Clinical Cancer Research 21-May-15
NCT02309580 Recruiting Memorial Sloan Kettering Cancer Center 5-Dec-14
NCT02356458 Active, not recruiting Swiss Group for Clinical Cancer Research 5-Feb-15
NCT02956382 Recruiting Georgetown University 6-Nov-16
NCT02558816 Active, not recruiting Nantes University Hospital 24-Sep-15
NCT03282396 Recruiting M.D. Anderson Cancer Center 13-Sep-17
NCT03323151 Recruiting PrECOG, LLC. 26-Oct-17
NCT04477486 Not yet recruiting AbbVie 20-Jul-20
NCT02689869 Active, not recruiting Ludwig-Maximilians - University of Munich 24-Feb-16
NCT03877055 Active, not recruiting Memorial Sloan Kettering Cancer Center 15-Mar-19
NCT03478514 Recruiting Alliance Foundation Trials, LLC. 27-Mar-18
NCT04234061 Recruiting Peter MacCallum Cancer Centre, Australia 21-Jan-20
NCT04212013 Recruiting Memorial Sloan Kettering Cancer Center 26-Dec-19
NCT03424122 Recruiting Incyte Corporation 6-Feb-18
NCT02623010 Recruiting Rabin Medical Center 7-Dec-15
NCT03710772 Recruiting M.D. Anderson Cancer Center 18-Oct-18
NCT03939182 Recruiting Memorial Sloan Kettering Cancer Center 6-May-19
NCT03295240 Recruiting Memorial Sloan Kettering Cancer Center 27-Sep-17
NCT02542514 Active, not recruiting The Lymphoma Academic Research Organisation 7-Sep-15
NCT02159755 Active, not recruiting National Cancer Institute (NCI) 10-Jun-14
NCT03399513 Recruiting University Hospital Muenster 16-Jan-18
NCT03876028 Recruiting Novartis Pharmaceuticals 15-Mar-19
NCT02736617 Recruiting OHSU Knight Cancer Institute 13-Apr-16
NCT03093831 Recruiting National Cancer Centre, Singapore 28-Mar-17
NCT03198026 Recruiting Sidney Kimmel Cancer Center at Thomas Jefferson University 23-Jun-17
NCT03112174 Recruiting Pharmacyclics LLC. 13-Apr-17
NCT02703272 Recruiting Janssen Research & Development, LLC 9-Mar-16
NCT03581942 Recruiting Memorial Sloan Kettering Cancer Center 10-Jul-18
NCT02446236 Active, not recruiting Hackensack Meridian Health 18-May-15
NCT02947347 Recruiting Pharmacyclics LLC. 27-Oct-16
NCT02760485 Active, not recruiting Incyte Corporation 3-May-16
NCT02315326 Active, not recruiting Memorial Sloan Kettering Cancer Center 11-Dec-14
NCT03703167 Recruiting Memorial Sloan Kettering Cancer Center 11-Oct-18
NCT02207062 Active, not recruiting University of Washington 1-Aug-14
NCT02940301 Recruiting Ohio State University Comprehensive Cancer Center 20-Oct-16
NCT02626884 Active, not recruiting University of Cologne 10-Dec-15
NCT03684694 Recruiting ADC Therapeutics S.A. 26-Sep-18
NCT04061850 Recruiting Samsung Medical Center 20-Aug-19
NCT03770416 Recruiting M.D. Anderson Cancer Center 10-Dec-18
NCT03697512 Recruiting International Extranodal Lymphoma Study Group (IELSG) 5-Oct-18
NCT02692248 Active, not recruiting Grupo Espaol de Linfomas y Transplante Autlogo de Mdula sea 26-Feb-16
NCT01974440 Active, not recruiting Janssen Research & Development, LLC 1-Nov-13
NCT02824029 Recruiting Barbara Ann Karmanos Cancer Institute 6-Jul-16
NCT01776840 Active, not recruiting Janssen Research & Development, LLC 28-Jan-13
NCT02858258 Recruiting Prof. Dr. M. Dreyling (co-chairman) 8-Aug-16
NCT02203526 Recruiting National Cancer Institute (NCI) 30-Jul-14
NCT02670616 Active, not recruiting Samsung Medical Center 2-Feb-16
NCT02077166 Active, not recruiting Pharmacyclics LLC. 4-Mar-14
NCT02443077 Recruiting National Cancer Institute (NCI) 13-May-15
NCT03129828 Recruiting Prof. Dr. Clemens Schmitt 26-Apr-17
NCT03425591 Recruiting Janssen-Cilag Ltd. 7-Feb-18
NCT02682641 Active, not recruiting Grupo Espaol de Linfomas y Transplante Autlogo de Mdula sea 15-Feb-16
NCT03153202 Recruiting Joshua Brody 15-May-17
NCT01849263 Active, not recruiting National Cancer Institute (NCI) 8-May-13
NCT02242097 Active, not recruiting Northwestern University 16-Sep-14
NCT03964090 Recruiting National Cancer Institute (NCI) 28-May-19
NCT02955628 Recruiting Singapore General Hospital 4-Nov-16
NCT03190330 Recruiting Johnson & Johnson Private Limited 16-Jun-17
NCT02756247 Active, not recruiting Memorial Sloan Kettering Cancer Center 29-Apr-16
NCT02954406 Active, not recruiting Millennium Pharmaceuticals, Inc. 3-Nov-16
NCT02427620 Active, not recruiting M.D. Anderson Cancer Center 28-Apr-15
NCT04129710 Recruiting Second Affiliated Hospital, School of Medicine, Zhejiang University 17-Oct-19
NCT03136497 Recruiting Hackensack Meridian Health 2-May-17
NCT04450173 Not yet recruiting Joseph Tuscano 29-Jun-20
NCT04189757 Not yet recruiting M.D. Anderson Cancer Center 6-Dec-19
NCT03220022 Recruiting National Cancer Institute (NCI) 18-Jul-17
NCT02910583 Active, not recruiting Pharmacyclics LLC. 22-Sep-16
NCT01829568 Active, not recruiting National Cancer Institute (NCI) 11-Apr-13
NCT02518555 Active, not recruiting Jennifer Woyach 10-Aug-15
NCT04419389 Not yet recruiting Aprea Therapeutics 5-Jun-20
NCT01880567 Recruiting M.D. Anderson Cancer Center 19-Jun-13
NCT01724346 Active, not recruiting Pharmacyclics LLC. 9-Nov-12
NCT02636322 Active, not recruiting M.D. Anderson Cancer Center 21-Dec-15
NCT04421560 Not yet recruiting Dana-Farber Cancer Institute 9-Jun-20
NCT04066920 Not yet recruiting Deok-Hwan Yang 26-Aug-19
NCT04446962 Not yet recruiting Institut Curie 25-Jun-20
NCT02532257 Active, not recruiting M.D. Anderson Cancer Center 25-Aug-15
NCT02927964 Recruiting Robert Lowsky 7-Oct-16
NCT03223610 Recruiting National Cancer Institute (NCI) 21-Jul-17
NCT01589302 Active, not recruiting Kami Maddocks 1-May-12
NCT02991638 Recruiting The University of Hong Kong 13-Dec-16
NCT02869633 Active, not recruiting Vanderbilt-Ingram Cancer Center 17-Aug-16
NCT02268851 Active, not recruiting Dana-Farber Cancer Institute 20-Oct-14
NCT03734016 Recruiting BeiGene 7-Nov-18
NCT01886859 Active, not recruiting National Cancer Institute (NCI) 26-Jun-13
NCT03949062 Recruiting Ruijin Hospital 14-May-19
NCT01955499 Active, not recruiting National Cancer Institute (NCI) 7-Oct-13
NCT03479268 Recruiting City of Hope Medical Center 27-Mar-18
NCT03440567 Recruiting City of Hope Medical Center 22-Feb-18
NCT02747732 Recruiting Meirav Kedmi MD 22-Apr-16
NCT02733042 Active, not recruiting Celgene 11-Apr-16
NCT03331198 Recruiting Juno Therapeutics, a Subsidiary of Celgene 6-Nov-17
NCT04094051 Recruiting The First Affiliated Hospital with Nanjing Medical University 18-Sep-19
NCT01500733 Active, not recruiting National Heart, Lung, and Blood Institute (NHLBI) 28-Dec-11
NCT02332980 Recruiting Mayo Clinic 7-Jan-15
NCT02436707 Recruiting Canadian Cancer Trials Group 7-May-15
NCT01479842 Active, not recruiting Kami Maddocks 28-Nov-11
NCT02406742 Active, not recruiting Celgene 2-Apr-15
NCT03045328 Active, not recruiting Steven E. Coutre 7-Feb-17
NCT02048813 Active, not recruiting National Cancer Institute (NCI) 29-Jan-14
NCT04116437 Recruiting BeiGene 4-Oct-19
NCT04407845 Recruiting European Georges Pompidou Hospital 29-May-20
NCT03088878 Recruiting University of California, San Diego 23-Mar-17
NCT03128879 Recruiting M.D. Anderson Cancer Center 25-Apr-17
NCT03960840 Recruiting Novartis Pharmaceuticals 23-May-19
NCT04209621 Recruiting National Heart, Lung, and Blood Institute (NHLBI) 24-Dec-19
NCT02514083 Active, not recruiting National Heart, Lung, and Blood Institute (NHLBI) 3-Aug-15
NCT03204188 Recruiting National Heart, Lung, and Blood Institute (NHLBI) 29-Jun-17
NCT03462719 Active, not recruiting Janssen Research & Development, LLC 12-Mar-18
NCT01644253 Active, not recruiting Aptevo Therapeutics 19-Jul-12
NCT02160015 Active, not recruiting National Cancer Institute (NCI) 10-Jun-14
NCT02420912 Active, not recruiting M.D. Anderson Cancer Center 20-Apr-15
NCT03219047 Recruiting M.D. Anderson Cancer Center 17-Jul-17
NCT03422393 Recruiting Michael Choi 5-Feb-18
NCT03701282 Recruiting National Cancer Institute (NCI) 10-Oct-18
NCT02629809 Recruiting M.D. Anderson Cancer Center 14-Dec-15
NCT03310619 Recruiting Celgene 16-Oct-17
NCT03731234 Recruiting Fondazione Italiana Linfomi ONLUS 6-Nov-18
NCT04230304 Not yet recruiting Mayo Clinic 18-Jan-20
NCT02005289 Active, not recruiting Ohio State University Comprehensive Cancer Center 9-Dec-13
NCT04494503 Not yet recruiting Ascentage Pharma Group Inc. 31-Jul-20
NCT02756897 Active, not recruiting M.D. Anderson Cancer Center 29-Apr-16
NCT04155710 Recruiting Iovance Biotherapeutics, Inc. 7-Nov-19
NCT03280160 Active, not recruiting PETHEMA Foundation 12-Sep-17
NCT02007044 Active, not recruiting M.D. Anderson Cancer Center 10-Dec-13
NCT03144674 Active, not recruiting Incyte Corporation 9-May-17
NCT03235544 Recruiting Incyte Corporation 1-Aug-17
NCT03570892 Recruiting Novartis Pharmaceuticals 27-Jun-18
NCT03267186 Recruiting Andrew Rezvani 30-Aug-17
NCT02997761 Recruiting Brian Jonas 20-Dec-16
NCT02388048 Recruiting Gruppo Italiano Malattie EMatologiche dell'Adulto 13-Mar-15
NCT02639910 Active, not recruiting MorphoSys AG 28-Dec-15
NCT04025593 Recruiting Ruijin Hospital 19-Jul-19
NCT03740529 Recruiting Loxo Oncology, Inc. 14-Nov-18
NCT03162536 Recruiting ArQule 22-May-17

According to statistics, a total of 135 Ibrutinib projects targeting lymphoma BTK are currently in clinical stage, of which 75 are recruiting and 60 are not recruiting.

Table 2 Clinical trials of BTK inhibitor BGB-3111

Nct id Status Lead sponsor Study first posted
NCT03846427 Active, not recruiting BeiGene 19-Feb-19
NCT03189524 Active, not recruiting BeiGene 16-Jun-17
NCT03332017 Recruiting BeiGene 6-Nov-17
NCT03206970 Active, not recruiting BeiGene 2-Jul-17
NCT03145064 Active, not recruiting BeiGene 9-May-17
NCT03520920 Active, not recruiting BeiGene 11-May-18
NCT04116437 Recruiting BeiGene 4-Oct-19
NCT04002297 Recruiting BeiGene 28-Jun-19
NCT03206918 Active, not recruiting BeiGene 2-Jul-17
NCT04436107 Not yet recruiting BeiGene 17-Jun-20
NCT03734016 Recruiting BeiGene 7-Nov-18
NCT03336333 Recruiting BeiGene 8-Nov-17
NCT02795182 Active, not recruiting BeiGene 10-Jun-16
NCT03219047 Recruiting M.D. Anderson Cancer Center 17-Jul-17
NCT03740529 Recruiting Loxo Oncology, Inc. 14-Nov-18
NCT02569476 Active, not recruiting BeiGene 6-Oct-15
NCT04172246 Recruiting BeiGene 21-Nov-19
NCT03162536 Recruiting ArQule 22-May-17

According to statistics, a total of 18 BGB-3111 projects targeting lymphoma BTK are currently in clinical stage, of which 9 are recruiting and 9 are not recruiting.

Table 3 Clinical trials of BTK inhibitor M7583

Nct id Status Lead sponsor Study first posted
NCT02825836 Active, not recruiting EMD Serono Research & Development Institute, Inc. 7-Jul-16

According to statistics, a total of 1 M7583 project targeting lymphoma BTK is currently in clinical stage and is not recruiting.

Table 4 Clinical trials of BTK inhibitor Acalabrutinib

Nct id Status Lead sponsor Study first posted
NCT04402138 Not yet recruiting SCRI Development Innovations, LLC 26-May-20
NCT04189757 Not yet recruiting M.D. Anderson Cancer Center 6-Dec-19
NCT03571308 Active, not recruiting University Hospital Southampton NHS Foundation Trust 27-Jun-18
NCT04484012 Not yet recruiting City of Hope Medical Center 23-Jul-20
NCT02213926 Active, not recruiting Acerta Pharma BV 12-Aug-14
NCT02972840 Recruiting Acerta Pharma BV 25-Nov-16
NCT02112526 Active, not recruiting Acerta Pharma BV 14-Apr-14
NCT02180711 Recruiting Acerta Pharma BV 3-Jul-14
NCT03623373 Active, not recruiting Washington University School of Medicine 9-Aug-18
NCT04094142 Recruiting Seoul National University Hospital 18-Sep-19
NCT04462328 Not yet recruiting Washington University School of Medicine 8-Jul-20
NCT03863184 Recruiting Weill Medical College of Cornell University 5-Mar-19
NCT02717624 Recruiting Acerta Pharma BV 24-Mar-16
NCT04257578 Not yet recruiting University of Washington 6-Feb-20
NCT04115631 Recruiting ECOG-ACRIN Cancer Research Group 4-Oct-19
NCT04002947 Recruiting National Cancer Institute (NCI) 1-Jul-19
NCT03946878 Recruiting M.D. Anderson Cancer Center 13-May-19
NCT04404088 Recruiting M.D. Anderson Cancer Center 27-May-20
NCT04189952 Not yet recruiting University of Miami 6-Dec-19
NCT03932331 Recruiting AstraZeneca 30-Apr-19
NCT03516617 Recruiting Mayo Clinic 4-May-18
NCT03788291 Recruiting University of Rochester 27-Dec-18
NCT03736616 Recruiting Swedish Medical Center 9-Nov-18
NCT04169737 Not yet recruiting M.D. Anderson Cancer Center 20-Nov-19
NCT04116437 Recruiting BeiGene 4-Oct-19
NCT03527147 Recruiting Acerta Pharma BV 17-May-18
NCT02337829 Active, not recruiting Acerta Pharma BV 14-Jan-15
NCT02296918 Active, not recruiting Acerta Pharma BV 21-Nov-14
NCT02328014 Active, not recruiting Acerta Pharma BV 31-Dec-14
NCT02362035 Active, not recruiting Acerta Pharma BV 12-Feb-15
NCT02029443 Active, not recruiting Acerta Pharma BV 8-Jan-14
NCT03219047 Recruiting M.D. Anderson Cancer Center 17-Jul-17
NCT03740529 Recruiting Loxo Oncology, Inc. 14-Nov-18
NCT03899337 Not yet recruiting University of Birmingham 2-Apr-19
NCT03162536 Recruiting ArQule 22-May-17

According to statistics, a total of 35 Acalabrutinib projects targeting lymphoma BTK are currently in clinical stage, of which 18 are recruiting and 17 are not recruiting.

Table 5 Clinical trials of SYK inhibitor Cerdulatinib

Nct id Status Lead sponsor Study first posted
NCT01994382 Active, not recruiting Portola Pharmaceuticals 25-Nov-13

According to statistics, a total of 1 Cerdulatinib project targeting lymphoma SYK is currently in clinical stage and is not recruiting.

Table 6 Clinical trials of SYK inhibitor Entospletinib

Nct id Status Lead sponsor Study first posted
NCT03010358 Active, not recruiting OHSU Knight Cancer Institute 5-Jan-17

According to statistics, a total of 1 Entospletinib project targeting lymphoma SYK is currently in clinical stage and is not recruiting.

3.2 Lymphoma therapy for NF-κB pathway

The inhibition of NF-κB pathway can be performed by directly inhibiting NF-κB components or indirectly by inhibiting its upstream pathways. For example, Bortezomib, a proteasome inhibitor targeting p-IκBα is a rational option for treating patients with constitutive NF-κB pathway activities and has shown good efficacy for DLBCL patients in combination with traditional chemotherapy. Another p-IκBα blockade, MLN 4924 has shown obvious anti-tumor activity in mantle cell lymphoma (MCL) and DLBCL.

Table 7 Clinical trials of p-IκBα inhibitor Bortezomib

Nct id Status Lead sponsor Study first posted
NCT02356458 Active, not recruiting Swiss Group for Clinical Cancer Research 5-Feb-15
NCT03016988 Not yet recruiting Tingbo Liu 11-Jan-17
NCT02840539 Recruiting Seoul National University Hospital 21-Jul-16
NCT02613598 Recruiting University of Michigan Rogel Cancer Center 24-Nov-15
NCT00114738 Active, not recruiting National Cancer Institute (NCI) 17-Jun-05
NCT03487133 Recruiting Samsung Medical Center 3-Apr-18
NCT02783625 Recruiting Memorial Sloan Kettering Cancer Center 26-May-16
NCT00863369 Active, not recruiting City of Hope Medical Center 18-Mar-09
NCT04061772 Recruiting Zhejiang Cancer Hospital 20-Aug-19
NCT01805557 Active, not recruiting Fondazione Italiana Linfomi ONLUS 6-Mar-13
NCT03129828 Recruiting Prof. Dr. Clemens Schmitt 26-Apr-17
NCT00477412 Active, not recruiting M.D. Anderson Cancer Center 23-May-07
NCT01216683 Active, not recruiting Eastern Cooperative Oncology Group 7-Oct-10
NCT01965977 Recruiting Samsung Medical Center 18-Oct-13
NCT01695941 Active, not recruiting National Cancer Institute (NCI) 28-Sep-12
NCT01267812 Active, not recruiting City of Hope Medical Center 29-Dec-10
NCT01286272 Active, not recruiting National Cancer Institute (NCI) 31-Jan-11
NCT01415752 Active, not recruiting Eastern Cooperative Oncology Group 12-Aug-11
NCT03335098 Recruiting Seoul National University Hospital 7-Nov-17
NCT01381692 Active, not recruiting National Cancer Institute (NCI) 27-Jun-11
NCT02112916 Active, not recruiting National Cancer Institute (NCI) 14-Apr-14
NCT02211755 Recruiting National Cancer Institute (NCI) 7-Aug-14
NCT04433156 Recruiting Henan Cancer Hospital 16-Jun-20
NCT02371148 Active, not recruiting Fondazione Italiana Linfomi ONLUS 25-Feb-15
NCT03136146 Recruiting M.D. Anderson Cancer Center 2-May-17
NCT03117751 Recruiting St. Jude Children's Research Hospital 18-Apr-17
NCT03616782 Recruiting Ho Sup Lee 6-Aug-18
NCT03590171 Recruiting Charite University, Berlin, Germany 18-Jul-18
NCT04224571 Recruiting Chinese University of Hong Kong 13-Jan-20
NCT02553460 Recruiting St. Jude Children's Research Hospital 17-Sep-15
NCT03390387 Recruiting Federal Research Institute of Pediatric Hematology, Oncology and Immunology 4-Jan-18
NCT03643276 Recruiting Martin Schrappe 22-Aug-18
NCT01959698 Recruiting Roswell Park Cancer Institute 10-Oct-13
NCT00720785 Recruiting National Heart, Lung, and Blood Institute (NHLBI) 23-Jul-08
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT00492050 Active, not recruiting M.D. Anderson Cancer Center 27-Jun-07
NCT03515200 Active, not recruiting St. Jude Children's Research Hospital 3-May-18
NCT02551718 Recruiting University of Washington 16-Sep-15

According to statistics, a total of 38 Bortezomib projects targeting lymphoma p-IκBα are currently in clinical stage, of which 22 are recruiting and 16 are not recruiting.

Table 8 Clinical trials of p-IκBα inhibitor MLN 4924

Nct id Status Lead sponsor Study first posted
NCT03479268 Recruiting City of Hope Medical Center 27-Mar-18
NCT03323034 Recruiting Children's Oncology Group 26-Oct-17
NCT03349281 Recruiting Julio Barredo, MD 21-Nov-17

According to statistics, a total of 3 MLN 4924 projects targeting lymphoma p-IκBαis currently in clinical stage and are recruiting

3.3 Lymphoma therapy for PI3K/AKT/mTOR pathway

Idelalisib (CAL-101, GS-1101), a p110δ-selective inhibitor, is the first FDA-approved PI3K inhibitor in treating relapsed FL and SLL. Clinical trials demonstrated that idelalisib was tolerable and had modest single-agent activity in relapsed or refractory HL. Umbralisib (TGR-1202) and parsaclisib (INCB050465) are also p110δ inhibitors with different chemical structures. A phase 1 trial (NCT02268851) of umbralisib and ibrutinib showed an ORR of 67% (CR 19%) in relapsed or refractory MCL. Duvelisib (IPI-145/INK1197), which is an inhibitor of both p110δ and p110γ, showed efficacy in various types of lymphomas, including DLBCL and MCL, in preclinical studies. Temsirolimus (CCI-779) is a derivative of rapamycin, and is assessed in clinical trial. Everolimus (RAD001) is an oral mTOR inhibitor that has been used as a single agent in relapsed or refractory aggressive and indolent NHLs as well as HL. Other PI3K/AKT/mTOR inhibitors include AMG 319, Acalisib (GS-9820) (CAL-120), Buparlisib (BKM120), SAR 245408 (XL147), Perifosine (KRX-0401), MK-2206, GSK690693, Ridaforolimus (AP23573, MK-8669), Rapamycin (Sirolimus) and AZD2014.

Table 9 Clinical trials of PI3Kδ inhibitor Idelalisib

Nct id Status Lead sponsor Study first posted
NCT03890289 Recruiting Fondazione Italiana Linfomi ONLUS 26-Mar-19
NCT02536300 Recruiting Gilead Sciences 31-Aug-15
NCT03568929 Recruiting Gilead Sciences 26-Jun-18
NCT03576443 Active, not recruiting Nordic Lymphoma Group 3-Jul-18
NCT02332980 Recruiting Mayo Clinic 7-Jan-15
NCT03133221 Recruiting University of Maryland, Baltimore 28-Apr-17
NCT01644253 Active, not recruiting Aptevo Therapeutics 19-Jul-12
NCT02135133 Active, not recruiting Dana-Farber Cancer Institute 9-May-14
NCT04379167 Not yet recruiting Shanghai YingLi Pharmaceutical Co. Ltd. 7-May-20
NCT03151057 Active, not recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 12-May-17
NCT02639910 Active, not recruiting MorphoSys AG 28-Dec-15
NCT03639324 Not yet recruiting Virginia Commonwealth University 21-Aug-18
NCT03283137 Recruiting University of Chicago 14-Sep-17
NCT03757000 Recruiting Shanghai YingLi Pharmaceutical Co. Ltd. 28-Nov-18
NCT03742323 Recruiting PETHEMA Foundation 15-Nov-18
NCT03740529 Recruiting Loxo Oncology, Inc. 14-Nov-18
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19

According to statistics, a total of 17 Idelalisib projects targeting lymphoma PI3Kδ are currently in clinical stage, of which 10 are recruiting and 7 are not recruiting.

Table 10 Clinical trials of PI3Kδ/γ inhibitor Duvelisib

Nct id Status Lead sponsor Study first posted
NCT04331119 Not yet recruiting Washington University School of Medicine 2-Apr-20
NCT02783625 Recruiting Memorial Sloan Kettering Cancer Center 26-May-16
NCT01882803 Active, not recruiting Verastem, Inc. 20-Jun-13
NCT04038359 Recruiting Verastem, Inc. 30-Jul-19
NCT03372057 Recruiting Verastem, Inc. 13-Dec-17
NCT03961672 Recruiting City of Hope Medical Center 23-May-19
NCT03892044 Recruiting Jennifer Woyach 27-Mar-19
NCT02004522 Active, not recruiting Verastem, Inc. 9-Dec-13
NCT04209621 Recruiting National Heart, Lung, and Blood Institute (NHLBI) 24-Dec-19
NCT04342117 Recruiting Verastem, Inc. 10-Apr-20
NCT03534323 Recruiting Dana-Farber Cancer Institute 23-May-18
NCT04379167 Not yet recruiting Shanghai YingLi Pharmaceutical Co. Ltd. 7-May-20
NCT03757000 Recruiting Shanghai YingLi Pharmaceutical Co. Ltd. 28-Nov-18

According to statistics, a total of 13 Duvelisib projects targeting lymphoma PI3Kδ/γ are currently in clinical stage, of which 9 are recruiting and 4 are not recruiting.

Table 11 Clinical trials of PI3Kγ inhibitor Buparlisib

Nct id Status Lead sponsor Study first posted
NCT02756247 Active, not recruiting Memorial Sloan Kettering Cancer Center 29-Apr-16
NCT02049541 Active, not recruiting Kami Maddocks 30-Jan-14

According to statistics, a total of 2 Buparlisib projects targeting lymphoma PI3Kγ are currently in clinical stage, and are not recruiting.

Table 12 Clinical trials of mTOR inhibitor Temsirolimus

Nct id Status Lead sponsor Study first posted
NCT00700258 Recruiting Pfizer 18-Jun-08
NCT01381692 Active, not recruiting National Cancer Institute (NCI) 27-Jun-11
NCT03213678 Recruiting National Cancer Institute (NCI) 11-Jul-17
NCT01075321 Active, not recruiting Mayo Clinic 25-Feb-10
NCT03697408 Recruiting University of Pennsylvania 5-Oct-18
NCT02693535 Recruiting American Society of Clinical Oncology 26-Feb-16
NCT03190174 Recruiting Sarcoma Oncology Research Center, LLC 16-Jun-17
NCT02423915 Active, not recruiting M.D. Anderson Cancer Center 22-Apr-15
NCT03297606 Recruiting Canadian Cancer Trials Group 29-Sep-17
NCT01625351 Active, not recruiting St. Jude Children's Research Hospital 21-Jun-12
NCT00577278 Active, not recruiting City of Hope Medical Center 20-Dec-07
NCT04473911 Not yet recruiting Zachariah Michael DeFilipp 16-Jul-20
NCT02722668 Recruiting Masonic Cancer Center, University of Minnesota 30-Mar-16
NCT03155620 Recruiting National Cancer Institute (NCI) 16-May-17
NCT03018223 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 11-Jan-17
NCT00305682 Active, not recruiting Masonic Cancer Center, University of Minnesota 22-Mar-06
NCT02790515 Recruiting St. Jude Children's Research Hospital 6-Jun-16
NCT03192397 Recruiting Roswell Park Cancer Institute 20-Jun-17
NCT02321501 Recruiting M.D. Anderson Cancer Center 22-Dec-14
NCT02793544 Active, not recruiting Center for International Blood and Marrow Transplant Research 8-Jun-16
NCT03246906 Recruiting Fred Hutchinson Cancer Research Center 11-Aug-17
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT03970096 Recruiting Fred Hutchinson Cancer Research Center 31-May-19
NCT01885689 Active, not recruiting City of Hope Medical Center 25-Jun-13
NCT02551718 Recruiting University of Washington 16-Sep-15
NCT00792948 Active, not recruiting National Cancer Institute (NCI) 18-Nov-08
NCT03670966 Recruiting Fred Hutchinson Cancer Research Center 14-Sep-18
NCT01353625 Active, not recruiting Celgene 13-May-11
NCT03128034 Recruiting Fred Hutchinson Cancer Research Center 25-Apr-17

According to statistics, a total of 29 Temsirolimus projects targeting lymphoma mTOR are currently in clinical stage, of which 18 are recruiting and 11 are not recruiting.

Table 13 Clinical trials of mTOR inhibitor Rapamycin

Nct id Status Lead sponsor Study first posted
NCT01381692 Active, not recruiting National Cancer Institute (NCI) 27-Jun-11
NCT00700258 Recruiting Pfizer 18-Jun-08
NCT03213678 Recruiting National Cancer Institute (NCI) 11-Jul-17
NCT01075321 Active, not recruiting Mayo Clinic 25-Feb-10
NCT03697408 Recruiting University of Pennsylvania 5-Oct-18
NCT03190174 Recruiting Sarcoma Oncology Research Center, LLC 16-Jun-17
NCT02693535 Recruiting American Society of Clinical Oncology 26-Feb-16
NCT02423915 Active, not recruiting M.D. Anderson Cancer Center 22-Apr-15
NCT01625351 Active, not recruiting St. Jude Children's Research Hospital 21-Jun-12
NCT00577278 Active, not recruiting City of Hope Medical Center 20-Dec-07
NCT03297606 Recruiting Canadian Cancer Trials Group 29-Sep-17
NCT02722668 Recruiting Masonic Cancer Center, University of Minnesota 30-Mar-16
NCT04473911 Not yet recruiting Zachariah Michael DeFilipp 16-Jul-20
NCT00305682 Active, not recruiting Masonic Cancer Center, University of Minnesota 22-Mar-06
NCT02321501 Recruiting M.D. Anderson Cancer Center 22-Dec-14
NCT02790515 Recruiting St. Jude Children's Research Hospital 6-Jun-16
NCT02793544 Active, not recruiting Center for International Blood and Marrow Transplant Research 8-Jun-16
NCT03155620 Recruiting National Cancer Institute (NCI) 16-May-17
NCT03018223 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 11-Jan-17
NCT03246906 Recruiting Fred Hutchinson Cancer Research Center 11-Aug-17
NCT03192397 Recruiting Roswell Park Cancer Institute 20-Jun-17
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT03970096 Recruiting Fred Hutchinson Cancer Research Center 31-May-19
NCT01885689 Active, not recruiting City of Hope Medical Center 25-Jun-13
NCT00792948 Active, not recruiting National Cancer Institute (NCI) 18-Nov-08
NCT02551718 Recruiting University of Washington 16-Sep-15
NCT03670966 Recruiting Fred Hutchinson Cancer Research Center 14-Sep-18
NCT01353625 Active, not recruiting Celgene 13-May-11
NCT03128034 Recruiting Fred Hutchinson Cancer Research Center 25-Apr-17

According to statistics, a total of 29 Rapamycin projects targeting lymphoma mTOR are currently in clinical stage, of which 17 are recruiting and 12 are not recruiting.

Table 14 Clinical trials of mTOR inhibitor Everolimus

Nct id Status Lead sponsor Study first posted
NCT03697408 Recruiting University of Pennsylvania 5-Oct-18
NCT01665768 Active, not recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 15-Aug-12
NCT03328104 Recruiting Emory University 1-Nov-17
NCT04305444 Recruiting Zhejiang DTRM Biopharma 12-Mar-20
NCT01075321 Active, not recruiting Mayo Clinic 25-Feb-10
NCT02900716 Recruiting Zhejiang DTRM Biopharma 14-Sep-16
NCT02321501 Recruiting M.D. Anderson Cancer Center 22-Dec-14
NCT03740334 Recruiting Dana-Farber Cancer Institute 14-Nov-18
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT02551718 Recruiting University of Washington 16-Sep-15

According to statistics, a total of 10 Everolimus projects targeting lymphoma mTOR are currently in clinical stage, of which 8 are recruiting and 2 are not recruiting.

Table 15 Clinical trials of mTOR inhibitor AZD2014

Nct id Status Lead sponsor Study first posted
NCT02752204 Active, not recruiting University of Birmingham 26-Apr-16

According to statistics, a total of 1 AZD2014 project targeting lymphoma mTOR is currently in clinical stage and is not recruiting.

3.4 Lymphoma therapy for JAK/STAT pathway

Ruxolitinib (INCB018424) is a JAK1/2 inhibitor approved by the FDA to treat myelofibrosis, which can significantly promote apoptosis in HL and PMBCL and survival in a lymphoma xenograft murine model. A phase 1 study (NCT03681561) of ruxolitinib in combination with nivolumab in relapsed or refractory HL is currently recruiting patients. itacitinib (INCB039110) is another JAK1 inhibitor can selectively inhibit JAK1, which is expected to better treat lymphomas. A phase 1/2 study (NCT03697408) of itacitinib in combination with everolimus in relapsed or refractory HL is evaluating. Additionally, a phase 1/2 trial (NCT02760485) of itacitinib in combination with ibrutinib in subjects with relapsed or refractory DLBCL is also ongoing. Other JAK/STAT inhibitors include Tofacitinib (CP-690550), Pacritinib (SB1518), Pyrimethamine and IONIS-STAT3Rx (ISIS 481464).

Table 16 Clinical trials of JAK1/2 inhibitor Ruxolitinib

Nct id Status Lead sponsor Study first posted
NCT02613598 Recruiting University of Michigan Rogel Cancer Center 24-Nov-15
NCT03681561 Recruiting Veronika Bachanova 24-Sep-18
NCT02974647 Recruiting Memorial Sloan Kettering Cancer Center 28-Nov-16
NCT01431209 Active, not recruiting University of Nebraska 9-Sep-11
NCT03117751 Recruiting St. Jude Children's Research Hospital 18-Apr-17
NCT03613428 Not yet recruiting Sichuan University 3-Aug-18
NCT02723994 Recruiting Incyte Corporation 31-Mar-16
NCT03571321 Recruiting University of Chicago 27-Jun-18
NCT01712659 Recruiting National Cancer Institute (NCI) 23-Oct-12
NCT02494882 Active, not recruiting Memorial Sloan Kettering Cancer Center 10-Jul-15
NCT02420717 Active, not recruiting M.D. Anderson Cancer Center 20-Apr-15
NCT03515200 Active, not recruiting St. Jude Children's Research Hospital 3-May-18
NCT01319981 Active, not recruiting M.D. Anderson Cancer Center 22-Mar-11
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT02587598 Active, not recruiting Incyte Corporation 27-Oct-15
NCT02551718 Recruiting University of Washington 16-Sep-15

According to statistics, a total of 16 Ruxolitinib projects targeting lymphoma JAK1/2 are currently in clinical stage, of which 9 are recruiting and 7 are not recruiting.

Table 17 Clinical trials of JAK1 inhibitor itacitinib

Nct id Status Lead sponsor Study first posted
NCT02760485 Active, not recruiting Incyte Corporation 3-May-16
NCT03697408 Recruiting University of Pennsylvania 5-Oct-18
NCT03755414 Recruiting Washington University School of Medicine 28-Nov-18
NCT03320642 Recruiting Incyte Corporation 25-Oct-17

According to statistics, a total of 4 itacitinib projects targeting lymphoma JAK1 are currently in clinical stage, of which 3 are recruiting and 1 is not recruiting.

Table 18 Clinical trials of JAK3 inhibitor Tofacitinib

Nct id Status Lead sponsor Study first posted
NCT03598959 Not yet recruiting Sichuan University 26-Jul-18

According to statistics, a total of 1 Tofacitinib project targeting lymphoma JAK3 is currently in clinical stage and is not recruiting.

Table 19 Clinical trials of JAK2 inhibitor Pacritinib

Nct id Status Lead sponsor Study first posted
NCT03601819 Recruiting University of Michigan Rogel Cancer Center 26-Jul-18

According to statistics, a total of 1 Pacritinib project targeting lymphoma JAK2 is currently in clinical stage and is recruiting.

Table 20 Clinical trials of STAT3 inhibitor Pyrimethamine

Nct id Status Lead sponsor Study first posted
NCT01066663 Recruiting Dana-Farber Cancer Institute 10-Feb-10

According to statistics, a total of 1 Pyrimethamine project targeting lymphoma STAT3 is currently in clinical stage and is recruiting.

3.5 Lymphoma therapy for PD-1/PD-Ls pathway

Nivolumab and pembrolizumab were approved to treat relapsed or refractory HL by the FDA. A variety of clinical trials are assessed the outcome of nivolumab in different lymphoma. Nivolumab combinations with other targeted agents such as lenalidomide in relapsed or refractory lymphoma (NCT03015896), rituximab in FL (NCT03245021), cabiralizumab in PTCL (NCT03927105), and in combination with chemotherapy, such as rituximab, gemcitabine, and oxaliplatin (R-GemOx) in elderly lymphoma patients (NCT03366272), R-CHOP (NCT03704714), and rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) (NCT03749018) in aggressive NHLs are ongoing. Pembrolizumab, a humanized mAb of PD-1 is investigated in clinical trials for relapsed or refractory HL, transformed DLBCL, relapsed or refractory CLL, relapsed or refractory PMBCL, relapsed or refractory gray-zone lymphoma and PCNSL and B-NHLs treatment. Pembrolizumab in combination with other targeted agents, such as umbralisib (NCT03283137), lenalidomide (NCT02875067), mogamulizumab (NCT03309878), rituximab (NCT03401853), pralatrexate (NCT03598998), CAR-T (tisagenlecleucel, NCT03630159), and radiation (NCT03210662 and NCT03385226), are ongoing. Other PD-1/PD-Ls inhibitors include MEDI0680 (AMP-514), Pidilizumab (CT-011), Durvalumab (MEDI4736), Avelumab (MSB0010718C) and Atezolizumab (MPDL3280A) (RG7446).

Table 21 Clinical trials of PD-1 inhibitor Nivolumab

Nct id Status Lead sponsor Study first posted
NCT03586999 Recruiting University of Colorado, Denver 16-Jul-18
NCT03337919 Recruiting University College, London 9-Nov-17
NCT03436862 Recruiting SCRI Development Innovations, LLC 19-Feb-18
NCT03569696 Recruiting Meirav Kedmi MD 26-Jun-18
NCT03920631 Recruiting Ahmed Galal, MD 19-Apr-19
NCT02038946 Active, not recruiting Bristol-Myers Squibb 17-Jan-14
NCT04091490 Not yet recruiting State Budgetary Healthcare Institution, Ministry of Health of Russia 16-Sep-19
NCT04230330 Recruiting National Cancer Centre, Singapore 18-Jan-20
NCT03245021 Recruiting Dr. Eliza Hawkes 10-Aug-17
NCT04431635 Recruiting Big Ten Cancer Research Consortium 16-Jun-20
NCT03927105 Active, not recruiting Ryan Wilcox 25-Apr-19
NCT02857426 Active, not recruiting Bristol-Myers Squibb 5-Aug-16
NCT03681561 Recruiting Veronika Bachanova 24-Sep-18
NCT03480334 Recruiting University of Cologne 29-Mar-18
NCT02572167 Active, not recruiting Seattle Genetics, Inc. 8-Oct-15
NCT02940301 Recruiting Ohio State University Comprehensive Cancer Center 20-Oct-16
NCT03770416 Recruiting M.D. Anderson Cancer Center 10-Dec-18
NCT03502733 Recruiting National Cancer Institute (NCI) 19-Apr-18
NCT03580408 Recruiting The Lymphoma Academic Research Organisation 9-Jul-18
NCT03703050 Recruiting Gustave Roussy, Cancer Campus, Grand Paris 11-Oct-18
NCT03843294 Recruiting Catherine Bollard 18-Feb-19
NCT03366272 Recruiting University Hospital, Saarland 8-Dec-17
NCT03004833 Active, not recruiting University of Cologne 29-Dec-16
NCT03033914 Recruiting Memorial Sloan Kettering Cancer Center 27-Jan-17
NCT03200977 Recruiting Bristol-Myers Squibb 27-Jun-17
NCT01896999 Recruiting National Cancer Institute (NCI) 11-Jul-13
NCT03585465 Recruiting Centre Oscar Lambret 13-Jul-18
NCT03798314 Recruiting Mayo Clinic 9-Jan-19
NCT03311958 Recruiting Fox Chase Cancer Center 17-Oct-17
NCT03121677 Recruiting Washington University School of Medicine 20-Apr-17
NCT03305445 Recruiting Icahn School of Medicine at Mount Sinai 10-Oct-17
NCT03484819 Recruiting National Cancer Institute (NCI) 2-Apr-18
NCT03739619 Active, not recruiting Emory University 14-Nov-18
NCT03057795 Recruiting City of Hope Medical Center 20-Feb-17
NCT02973113 Active, not recruiting Baylor College of Medicine 25-Nov-16
NCT03016871 Recruiting City of Hope Medical Center 11-Jan-17
NCT04134325 Recruiting UNC Lineberger Comprehensive Cancer Center 22-Oct-19
NCT02758717 Active, not recruiting Academic and Community Cancer Research United 2-May-16
NCT03884998 Recruiting City of Hope Medical Center 21-Mar-19
NCT02581631 Active, not recruiting Bristol-Myers Squibb 21-Oct-15
NCT03620578 Recruiting Stichting Hemato-Oncologie voor Volwassenen Nederland 8-Aug-18
NCT03892044 Recruiting Jennifer Woyach 27-Mar-19
NCT03233347 Recruiting Academic and Community Cancer Research United 28-Jul-17
NCT03015896 Recruiting Kami Maddocks 10-Jan-17
NCT03061188 Active, not recruiting Northwestern University 23-Feb-17
NCT03038672 Recruiting National Cancer Institute (NCI) 1-Feb-17
NCT02408861 Recruiting National Cancer Institute (NCI) 6-Apr-15
NCT02978625 Recruiting National Cancer Institute (NCI) 1-Dec-16
NCT03712202 Recruiting City of Hope Medical Center 19-Oct-18
NCT03749018 Recruiting Kami Maddocks 21-Nov-18
NCT03907488 Recruiting National Cancer Institute (NCI) 9-Apr-19
NCT03646123 Recruiting Seattle Genetics, Inc. 24-Aug-18
NCT01703949 Recruiting University of Washington 11-Oct-12
NCT03138499 Active, not recruiting Bristol-Myers Squibb 3-May-17
NCT02181738 Active, not recruiting Bristol-Myers Squibb 4-Jul-14
NCT03704714 Recruiting Northwestern University 15-Oct-18
NCT02927769 Recruiting Bristol-Myers Squibb 7-Oct-16
NCT04022980 Recruiting Steven Park, MD 17-Jul-19
NCT02420912 Active, not recruiting M.D. Anderson Cancer Center 20-Apr-15
NCT04401774 Recruiting Memorial Sloan Kettering Cancer Center 26-May-20
NCT03161613 Recruiting Bristol-Myers Squibb 22-May-17
NCT01592370 Active, not recruiting Bristol-Myers Squibb 7-May-12
NCT03229278 Active, not recruiting Rutgers, The State University of New Jersey 25-Jul-17
NCT02922764 Recruiting Rgenix, Inc. 4-Oct-16
NCT01716806 Recruiting Seattle Genetics, Inc. 30-Oct-12
NCT02681302 Recruiting Hackensack Meridian Health 12-Feb-16
NCT04439214 Active, not recruiting National Cancer Institute (NCI) 19-Jun-20
NCT02393625 Active, not recruiting Novartis Pharmaceuticals 19-Mar-15
NCT03258567 Recruiting National Cancer Institute (NCI) 23-Aug-17
NCT04419441 Recruiting Ospedale Maggiore Di Trieste 5-Jun-20
NCT04205409 Recruiting University of Washington 19-Dec-19
NCT02702492 Recruiting Karyopharm Therapeutics Inc 8-Mar-16
NCT02304458 Active, not recruiting National Cancer Institute (NCI) 2-Dec-14
NCT01822509 Active, not recruiting National Cancer Institute (NCI) 2-Apr-13
NCT04052659 Recruiting Peking University 12-Aug-19
NCT03530683 Recruiting Trillium Therapeutics Inc. 21-May-18
NCT02879695 Recruiting National Cancer Institute (NCI) 26-Aug-16
NCT02693535 Recruiting American Society of Clinical Oncology 26-Feb-16
NCT02327078 Active, not recruiting Incyte Corporation 30-Dec-14
NCT03544723 Recruiting MultiVir, Inc. 4-Jun-18
NCT03190174 Recruiting Sarcoma Oncology Research Center, LLC 16-Jun-17
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15
NCT03297606 Recruiting Canadian Cancer Trials Group 29-Sep-17
NCT03841110 Recruiting Fate Therapeutics 15-Feb-19
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19
NCT02663518 Recruiting Trillium Therapeutics Inc. 26-Jan-16

According to statistics, a total of 86 Nivolumab projects targeting lymphoma PD-1 are currently in clinical stage, of which 65 are recruiting and 21 are not recruiting.

Table 22 Clinical trials of PD-1 inhibitor pembrolizumab

Nct id Status Lead sponsor Study first posted
NCT04317066 Recruiting Merck Sharp & Dohme Corp. 20-Mar-20
NCT03728972 Recruiting Memorial Sloan Kettering Cancer Center 2-Nov-18
NCT03021057 Recruiting The University of Hong Kong 13-Jan-17
NCT03873025 Not yet recruiting University College, London 13-Mar-19
NCT04417166 Not yet recruiting International Extranodal Lymphoma Study Group (IELSG) 4-Jun-20
NCT03179917 Recruiting Memorial Sloan Kettering Cancer Center 7-Jun-17
NCT03630159 Recruiting Novartis Pharmaceuticals 14-Aug-18
NCT03331731 Not yet recruiting Peter MacCallum Cancer Centre, Australia 6-Nov-17
NCT02684292 Active, not recruiting Merck Sharp & Dohme Corp. 17-Feb-16
NCT03983668 Recruiting Umar Farooq 12-Jun-19
NCT03618550 Recruiting Memorial Sloan Kettering Cancer Center 7-Aug-18
NCT02453594 Active, not recruiting Merck Sharp & Dohme Corp. 25-May-15
NCT03010176 Recruiting Merck Sharp & Dohme Corp. 4-Jan-17
NCT02650999 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 8-Jan-16
NCT03407144 Recruiting Merck Sharp & Dohme Corp. 23-Jan-18
NCT03586024 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 13-Jul-18
NCT02362997 Recruiting Dana-Farber Cancer Institute 13-Feb-15
NCT02576990 Active, not recruiting Merck Sharp & Dohme Corp. 15-Oct-15
NCT03990961 Recruiting University of Chicago 19-Jun-19
NCT03249792 Recruiting Merck Sharp & Dohme Corp. 15-Aug-17
NCT02535247 Recruiting Fox Chase Cancer Center 28-Aug-15
NCT03179930 Recruiting Memorial Sloan Kettering Cancer Center 7-Jun-17
NCT02677155 Recruiting Oslo University Hospital 9-Feb-16
NCT04268277 Not yet recruiting University of Ulm 13-Feb-20
NCT03605589 Recruiting Children's Hospital Medical Center, Cincinnati 30-Jul-18
NCT03331341 Recruiting University of Washington 6-Nov-17
NCT03153202 Recruiting Joshua Brody 15-May-17
NCT03385226 Recruiting University College, London 28-Dec-17
NCT03401853 Recruiting University of Washington 17-Jan-18
NCT03255018 Recruiting National Cancer Institute (NCI) 21-Aug-17
NCT02446457 Recruiting M.D. Anderson Cancer Center 18-May-15
NCT03934814 Recruiting I-Mab Biopharma Co. Ltd. 2-May-19
NCT03340766 Recruiting Amgen 14-Nov-17
NCT03226249 Active, not recruiting Northwestern University 21-Jul-17
NCT03283137 Recruiting University of Chicago 14-Sep-17
NCT03316573 Recruiting Dana-Farber Cancer Institute 20-Oct-17
NCT04421560 Not yet recruiting Dana-Farber Cancer Institute 9-Jun-20
NCT03309878 Recruiting National Cancer Institute (NCI) 16-Oct-17
NCT02332668 Recruiting Merck Sharp & Dohme Corp. 7-Jan-15
NCT04134325 Recruiting UNC Lineberger Comprehensive Cancer Center 22-Oct-19
NCT03077828 Recruiting Northwestern University 13-Mar-17
NCT03598998 Recruiting City of Hope Medical Center 26-Jul-18
NCT03995147 Recruiting University of Chicago 21-Jun-19
NCT03035331 Recruiting Mayo Clinic 30-Jan-17
NCT03349450 Recruiting Sunnybrook Health Sciences Centre 21-Nov-17
NCT03210662 Recruiting M.D. Anderson Cancer Center 7-Jul-17
NCT04118868 Not yet recruiting All  
NCT03150329 Recruiting City of Hope Medical Center 12-May-17
NCT02332980 Recruiting Mayo Clinic 7-Jan-15
NCT03445858 Recruiting Children's Hospital Medical Center, Cincinnati 26-Feb-18
NCT03240211 Recruiting Owen A, O'Connor, M.D., Ph.D. 7-Aug-17
NCT03789097 Recruiting Icahn School of Medicine at Mount Sinai 28-Dec-18
NCT03498612 Recruiting University of Washington 13-Apr-18
NCT03204188 Recruiting National Heart, Lung, and Blood Institute (NHLBI) 29-Jun-17
NCT03884556 Recruiting Tizona Therapeutics, Inc 21-Mar-19
NCT03598608 Recruiting Merck Sharp & Dohme Corp. 26-Jul-18
NCT02783300 Recruiting GlaxoSmithKline 26-May-16
NCT03278782 Active, not recruiting M.D. Anderson Cancer Center 12-Sep-17
NCT03229278 Active, not recruiting Rutgers, The State University of New Jersey 25-Jul-17
NCT03236935 Recruiting Jorge G. Darcourt 2-Aug-17
NCT02981914 Recruiting University of Chicago 5-Dec-16
NCT02922764 Recruiting Rgenix, Inc. 4-Oct-16
NCT03719105 Recruiting New York Medical College 25-Oct-18
NCT04254107 Recruiting Seattle Genetics, Inc. 5-Feb-20
NCT03013218 Recruiting ALX Oncology Inc. 6-Jan-17
NCT02362035 Active, not recruiting Acerta Pharma BV 12-Feb-15
NCT04419441 Recruiting Ospedale Maggiore Di Trieste 5-Jun-20
NCT02595866 Recruiting National Cancer Institute (NCI) 4-Nov-15
NCT03287817 Recruiting Autolus Limited 19-Sep-17
NCT02935257 Active, not recruiting University College, London 17-Oct-16
NCT04187872 Recruiting University of Florida 5-Dec-19
NCT03329950 Recruiting Celldex Therapeutics 6-Nov-17
NCT04052659 Recruiting Peking University 12-Aug-19
NCT02376699 Recruiting Seattle Genetics, Inc. 3-Mar-15
NCT03286114 Recruiting University of Michigan Rogel Cancer Center 18-Sep-17
NCT03160079 Recruiting Matthew Wieduwilt, M.D., Ph.D. 19-May-17
NCT02693535 Recruiting American Society of Clinical Oncology 26-Feb-16
NCT03512405 Recruiting City of Hope Medical Center 30-Apr-18
NCT03012620 Recruiting UNICANCER 6-Jan-17
NCT03544723 Recruiting MultiVir, Inc. 4-Jun-18
NCT02178722 Active, not recruiting Incyte Corporation 1-Jul-14
NCT03454451 Recruiting Corvus Pharmaceuticals, Inc. 6-Mar-18
NCT03695471 Recruiting Mayo Clinic 4-Oct-18
NCT03063632 Active, not recruiting National Cancer Institute (NCI) 24-Feb-17
NCT03820596 Recruiting Huiqiang Huang 29-Jan-19
NCT03841110 Recruiting Fate Therapeutics 15-Feb-19
NCT03058289 Recruiting Intensity Therapeutics, Inc. 20-Feb-17
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19

According to statistics, a total of 88 pembrolizumab projects targeting lymphoma PD-1 are currently in clinical stage, of which 70 are recruiting and 18 are not recruiting.

Table 23 Clinical trials of PD-L1 inhibitor Durvalumab

Nct id Status Lead sponsor Study first posted
NCT03054532 Not yet recruiting Singapore General Hospital 15-Feb-17
NCT04462328 Not yet recruiting Washington University School of Medicine 8-Jul-20
NCT03003520 Active, not recruiting Celgene 28-Dec-16
NCT03685344 Active, not recruiting ADC Therapeutics S.A. 26-Sep-18
NCT02733042 Active, not recruiting Celgene 11-Apr-16
NCT03161223 Recruiting Columbia University 19-May-17
NCT03610061 Recruiting Austin Health 1-Aug-18
NCT02706405 Recruiting Fred Hutchinson Cancer Research Center 11-Mar-16
NCT03011814 Recruiting City of Hope Medical Center 5-Jan-17
NCT02793466 Recruiting Children's Hospital Los Angeles 8-Jun-16
NCT03310619 Recruiting Celgene 16-Oct-17
NCT03323398 Recruiting ModernaTX, Inc. 27-Oct-17
NCT03739931 Recruiting ModernaTX, Inc. 14-Nov-18
NCT02643303 Recruiting Ludwig Institute for Cancer Research 31-Dec-15
NCT03544723 Recruiting MultiVir, Inc. 4-Jun-18
NCT03878524 Recruiting OHSU Knight Cancer Institute 18-Mar-19

According to statistics, a total of 16 Durvalumab projects targeting lymphoma PD-L1 are currently in clinical stage, of which 11 are recruiting and 5 are not recruiting.

Table 24 Clinical trials of PD-L1 inhibitor Avelumab

Nct id Status Lead sponsor Study first posted
NCT03046953 Recruiting University of Birmingham 8-Feb-17
NCT03617666 Recruiting University College, London 6-Aug-18
NCT03439501 Active, not recruiting Samsung Medical Center 20-Feb-18
NCT03244176 Recruiting Austin Health 9-Aug-17
NCT03451825 Active, not recruiting EMD Serono Research & Development Institute, Inc. 2-Mar-18
NCT03440567 Recruiting City of Hope Medical Center 22-Feb-18
NCT03636503 Recruiting Dana-Farber Cancer Institute 17-Aug-18
NCT03905135 Recruiting National Cancer Institute (NCI) 5-Apr-19

According to statistics, a total of 8 Avelumab projects targeting lymphoma PD-L1 are currently in clinical stage, of which 6 are recruiting and 2 are not recruiting.

Table 25 Clinical trials of PD-L1 inhibitor Atezolizumab

Nct id Status Lead sponsor Study first posted
NCT03850028 Recruiting University Medical Center Groningen 21-Feb-19
NCT02631577 Active, not recruiting Hoffmann-La Roche 16-Dec-15
NCT03892525 Recruiting The Lymphoma Academic Research Organisation 27-Mar-19
NCT03276468 Recruiting The Lymphoma Academic Research Organisation 8-Sep-17
NCT02926833 Active, not recruiting Kite, A Gilead Company 6-Oct-16
NCT03533283 Recruiting Hoffmann-La Roche 23-May-18
NCT02500407 Recruiting Genentech, Inc. 16-Jul-15
NCT04167137 Recruiting Synlogic 18-Nov-19
NCT03422523 Recruiting University Hospital Southampton NHS Foundation Trust 5-Feb-18
NCT03321643 Recruiting National Cancer Institute (NCI) 26-Oct-17
NCT03357224 Active, not recruiting European Organisation for Research and Treatment of Cancer - EORTC 29-Nov-17
NCT02594384 Active, not recruiting AI Therapeutics, Inc. 3-Nov-15
NCT03046953 Recruiting University of Birmingham 8-Feb-17
NCT02846623 Recruiting M.D. Anderson Cancer Center 27-Jul-16
NCT03463057 Recruiting Stichting Hemato-Oncologie voor Volwassenen Nederland 13-Mar-18
NCT03544723 Recruiting MultiVir, Inc. 4-Jun-18
NCT03841110 Recruiting Fate Therapeutics 15-Feb-19
NCT03003520 Active, not recruiting Celgene 28-Dec-16

According to statistics, a total of 18 Atezolizumab projects targeting lymphoma PD-L1 are currently in clinical stage, of which 13 are recruiting and 5 are not recruiting.

References

  1. Wang, L.; et al. Advances in targeted therapy for malignant lymphoma. Signal transduction and targeted therapy. 2020, 5(1): 1-46.
  2. Sun, R.; et al. Diagnostic and predictive biomarkers for lymphoma diagnosis and treatment in the era of precision medicine. Modern Pathology. 2016, 29(10): 1118-1142.
  3. Montes-Mojarro, I. A.; et al. Molecular diagnosis of lymphoma: a case-based practical approach. Diagnostic Histopathology. 2019, 25(6): 229-239.
  4. Sun, R.; et al. Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies. Critical Reviews™ in Oncogenesis. 2017, 22(5-6).
  5. Arita, A.; et al. Signaling pathways in lymphoma: pathogenesis and therapeutic targets. Future oncology. 2013, 9(10): 1549-1571.