Treatment Overview > Agents that Target Disease Pathways

Last update: 07/10/2019

Alphabetical list of targeted agents
for lymphoma OR CLL: 

INTRODUCTION

Index (A to I redone. See Notice)

By Class (new & under development.

 Terms related to targeted drugs in lay language 

NOTICE:

Over a decade we have converted queries of clinical trials.gov into shortcut URLS. This so users of lymphomation can click once to find trials by agent or other criteria, such as lymphoma subtype. Doing this allows us to also count how many people have clicked the link. Bitley converted the URLs to USA.gov short urls for government sites such as for clinicaltrials.gov, NASA, NOA, etc as a way to show the URL was a reliable USA.gov site.

The Trump administration ended it without, as far as I know, opportunity for public comment. See blog.usa.gov for the notice. We will rebuild some of these queries of clinicaltrials.gov, starting with find trials by agent name A to Z. It will take some time.

Meanwhile, we are also developing queries to locate trials by the class of therapy:

Introduction

We hope that the queries of clinicaltrials.gov provided within will aid patients and their treating oncologists to keep up with emerging investigational studies for lymphoma and CLL.  The notion guiding this way to find trials is that how a drug is thought to work is easier to remember than the arcane names and alias for each drug.

Very few people fully, or even partially, understand drug mechanisms of actions. Even scientists in the field have gaps in knowledge, else we would not need to test them.

Very briefly: Cancer starts with mutations in DNA, which are the "recipes" for cell behavior.  In normal cells the cell behavior is regulated so that cell growth and cell death are balanced.  In cancer cells, the mutations can lead to unchecked growth by turning on or off key PATHWAYS: cell division systems, disabling of the break systems, or by suppression of the immune system. 

Agents that bind to and inhibit these systems (or pathways) can cause the malignant cells to stop growing, shrink. or to go away completely. These good effects must then be weighed against the side effects in clinical trials.

Some types of agents bind to normal molecules on the surface of cancer cells.  These molecules may be present on both normal and malignant cells.  Antibodies that bind to these molecules may have direct killing effects and may also serve to enlist the immune system to kill the cells (Rituxan). 

...Stem cells that do not have these targets can then rebuild the normal blood cells killed by this approach to treatment.  The exploitation of normal cell surface drug target (cd20, cd22, cd19, cd30, CD79b) is a major reason for the relatively fast recent progress against blood cell cancers! 

Other agents bind to block pathways within the cells.  When the drug binds to a pathway driving the malignant behavior the cells may become visible to the immune system, or stop dividing, or die.  

The best future drugs will have high specificity -- causing anti-cancer effects primarily to the tumor cells with fewer off target effects. Because all treatment have side effects and financial toxicity, the ideal future treatments (in my view) will help patients to become free of the disease and of the need for continued treatment - will help patients to live longer with better quality of life.

  (Karl Schwartz, advocate)

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FIND TRIALS BY CLASS OF AGENT for Lymphoma or CLL

Please note that how a drug, or class of drug, is thought to work does not mean it is proven to provide clinical benefit, which is defined as helping the patients to live longer or better.   

Blood cells are inherently sensitive to chemotherapy and radiation, thus, these remain very effective agents in the treatment of blood-cell cancers. These generally work by damaging the DNA of rapidly dividing cells causing the cells to kill themselves (a cell process called apoptosis).

All Agents & Protocols by Phase of Lymphoma or CLL Study

Phase 1 (safety & dose finding)  http://bit.ly/2G3Pt2Q 694
 Phase 2 (activity & safety)  http://bit.ly/2XZEt0k  787
Phase 3 (compare to a standard of care) http://bit.ly/30oso2v 149

DIRECTED TO CELL-SURFACE MOLECULES / IMMUNOTHERAPY

Antibody-drug conjugates studies http://bit.ly/2J4Dq5M  30
 as of June 28, 2019:  3 of 30 in phase 3
Typically given by vein on a fixed schedule
Binding molecule on surface of tumor cell type, releasing toxin.
Examples: Polatuzumab Vedotin (binding to CD79b) Brentuximab Vedotin (binding cd30)

Bi-specific antibodies studies http://bit.ly/2KrnbCY 18
 as of June 28, 2019: 3 of 18 in phase 3
Antibody-directed immunotherapy
Typically given by vein on fixed schedule
Binding 2 molecules on surface of lymphocytes)
Example: Blinatumomab binding CD19 on b-cells and CD3 on T-cells (a t-cell engager)

Monoclonal antibodies studies http://bit.ly/2Y323WN 153
 as of June 28, 2019:  13 of 153 in phase 3
Antibody-directed Immunotherapy
Typically given by vein on a fixed schedule.
Binding to molecules on the surface of lymphocytes such as cd20, or cd19
Example: Rituxan

Radioimmunotherapy studies http://bit.ly/2N1crxu 6
 as of June 28, 2019:  3 of 6 in phase 3
Antibody-directed Immunotherapy with radiotherapy
Given by vein on fixed schedule - about 1 week.
Antibody-radiation conjugate, binding molecule on surface of b-cell exposing bound and nearby cells to radiation)
Example: Zevalin

DIRECTED TO INTERNAL CELL PATHWAYS

BCL-2 inhibitors studies http://bit.ly/2YbuJwS  76
 as of June 28, 2019: 10 of 76 in phase 3
Pathway-directed
Given by mouth; variable schedule
Binding to internal pathway of b-cells involved in prolonged tumor persistence
Examples: Venetoclax

BTK inhibitors studies  http://bit.ly/31Pdxzq 47
as of June 28, 2019: 2 of 47 in phase 3
Pathway-directed
Given by mouth; usually until progression or unacceptable toxicity
Binding to internal pathway of b-cells involved in b-cell receptor (BCR)
Examples: Ibrutinib, Acalabrutinib

ITK inhibitors studies http://bit.ly/2RuzY8j 1
 New: as of June 28, 2019:  0 of 1 in phase 3
Pathway-directed
Given by mouth until progression or unacceptable toxicity
Binding toTCR signaling through ITK, which is expressed in a variety of T cell lymphomas including PTCL, CTCL, ALCL, and in a subgroup of T lymphoblastic leukemia/lymphoma. Example:  CG-806

PI3k inhibitors studies  http://bit.ly/31Pdxzq 32
as of June 28, 2019: 2 of 32 in phase 3
Pathway-directed
Given by mouth or by vein (depending on type); usually until progression or unacceptable toxicity
Binding to internal PI3K pathway having a role in cell metabolism, growth, migration, survival and angiogenesis.
Examples: Copanlisib, Umbralisib, Parsaclisib 

DIRECTED TO EPIGENETIC PATHWAYS

Epigenetic Or Histone Deacetylase OR HDAC  http://bit.ly/2Xi8CbR  29
 as of June 30, 2019: 4 of 29 in phase 3
Binding to internal pathway that control gene expression, such as by activating tumor suppressor genes.
Examples: Romidepsin, Abexinostat, Vorinostat

IMMUNOTHERAPIES

Immune modulating studies http://bit.ly/32g2PlT 155
 as of June 28, 2019: 13 of 153 in phase 3
Variety of agents and mechanisms of actions that modify the immune system to fight cancer  
Examples: Lenalidomide, UTOMILUMAB, Umbralisib ...

Immunotherapy excluding CAR T studies http://bit.ly/2Y5Nvpq 64
 as of June 28, 2019 8 of 64 in phase 3.
Wide range of agents and mechanisms of actions that induce the immune system to fight cancer    

CAR T-cell studies http://bit.ly/2Ihqxq9   119
 as of June 28, 2019:  5 of 119 in phase 3
Programmed T-cell immunotherapy
Given by vein -  typically a 1 time infusion.  
The engineered T-cells are modified to bind to molecules on the surface of lymphocytes.  Can require bridge treatment to allow time to harvest and modify the cells
Examples: Tisagenlecleucel, YESCARTA, YTB323 (rapid production CAR T-cells)

IMMUNE CHECKPOINT INHIBITORS

PD-1/L checkpoint inhibitor studies http://bit.ly/2IXDQem 38
 as of June 28, 2019:  2 of 38 in phase 3
Antibody-directed Immunotherapy / immune modulation
Given by vein on fixed but typically long term schedule.
Binding to receptors on the tumor and t-cells that inhibit immune activation of t-cells against tumor cells.  Particularly active in Hodgkin lymphoma.
Examples: Atezolizumab,  Pembrolizumab

CD47 checkpoint inhibitor studies  http://bit.ly/2JcwWlu  4 of 7 phase 3

CANCER VACCINES

Vaccine studies  http://bit.ly/31NtUwt  26
 as of June 28, 2019:  0 of 26 in phase 3
Immunotherapy
Typically given under the skin as an injection of a tumor-specific antigen.  The objective is to promote or amplify the immune system recognition of the tumor as not belonging in order to prevent relapse while in remission from standard therapies.

More classes of agents to be added soon.

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Also see:

About Targeted Drugs

7 Reasons to Consider Trials based on our unique clinical circumstances

Since choosing a trial is complicated, we believe it's important also to consult specialists.  To assist we provide:

Trial Talk - specialists to consult about trials

 Study drug name ¹ / alternate name 
(short name for target or mechanism) ²
Find Trials ³ 

1  links to background articles
2  mechanism or target
3  lists clinical trials for agent

REDONE (A-H)

ABT-199 venetoclax (activates apoptosis - programmed cell death - through bcl2 pathway)  http://bit.ly/2KchVmK | Full prescribing info for CLL 76

Abexinostat  (oral, pan HDAC inhibitor / epigenetic -  activating or quieting genes to induce tumor cell death) http://bit.ly/2K8yXlD 4

Acalabrutinib (ACP-196) (inhibits btk / B-cell receptor pathway - an overactive pathway in b-cell lymphomas) http://bit.ly/2KHQhgT  23

ADCT-301 (anti-CD25-PBD antibody-drug conjugate)  NCI Drug Dictionary http://bit.ly/2F3aw4R 1

Adcetris  / SGN-35 / brentuximab vedotin  (antibody-drug conjugate: anti-cd30 + antitubulin - more selective delivery of a toxin to cancer cells)   http://bit.ly/31sk8zA

ADCT-301  (interleukin-15-based superagonist, induces memory CD8) http://bit.ly/2wV8TSd 3

Adcetris Ofatumumab /  Arzerra cd20 antibody approved for CLL http://bit.ly/2X4Dmw1 5

Atezolizumab (immune checkpoint antibody - pd-1 pathway) http://bit.ly/2IBbnLg 15

Azacitidine (epigenetic) http://bit.ly/2wM7yxg 15

Belinostat PXD101 (epigenetic - recently approved for t-cell lymphoma) http://bit.ly/2KgQ8RV 1

BET protein inhibitor -  BET family regulate the transcription of growth-promoting genes) http://bit.ly/31sH69V 1

Betalutin  (Lu-tetraxetan-tetulomab) radioimmunotherapy antibody targeting cd37 http://bit.ly/2IDK3vF 3

Bendamustine / Treanda (cytotoxic) http://bit.ly/2XIhBze 60

PI3K inhibitor class of agents - BCR pathway) http://bit.ly/2KhjGyO 10

Blinatumomab (BiTe) cd3 cd19 bi-specific antibody http://bit.ly/2F8pyq1 41

Brentuximab Vedotin (anti-cd30 antibody-drug conjugate) http://bit.ly/2RezIu5 50

CC-122  (immune-modulating, pleiotropic pathway modifier) http://bit.ly/31sUPxw 2

CART T-cell therapy (Chimeric antigen receptor adoptive immunotherapy)  http://bit.ly/2Ihqxq9   119

Cerdulatinib (Syk\Jak Inhibitor / PRT062070)  http://bit.ly/2KkdztB 1

Cirmtuzumab (Anti-ROR1 Mab) http://bit.ly/2IeFXLB 1

Copanlisib / BAY 80-6946 (PI3Kα/β inhibitor given by vein) http://bit.ly/2KOQgYk 14

CPI-613 (targets mitochondrial metabolism) http://bit.ly/2WEGla2 1

CUDC-907 (dual inhibitor of PI3K and HDAC) http://bit.ly/2wNwXXp 1

Daratumumab  (anti-cd38) http://bit.ly/2L09r1r 4

Duvelisib / IPI-145 (PI3K)-delta / PI3K-gamma) http://bit.ly/2x0gaAu 6

Entospletinib (SYK inhibitor in BCR pathway)  http://bit.ly/2MXKczG 1

EZH2 inhibitors (epigenetic pathway that contributes to abnormal growth) http://bit.ly/2MTam6u 2

EPZ-6438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) http://bit.ly/2Y7xxuQ 5

Hu5F9-G4 (5F9) humanized antibody targeting CD47, a don�t eat me signal http://bit.ly/2WOxRlM 2

HMPL-689 (PI3K delta inhibitor)  http://bit.ly/2Y4oJ9q  2

Ibrutinib (inhibits b-cell receptor / btk pathway) http://bit.ly/2N2oHO0 109

Idasanutlin (p53 tumor suppressor gene activator) http://bit.ly/2XmS8OJ 1

Idelalisib (PI3K kinase inhibitor / b-cell receptor pathway)  http://bit.ly/2x3EKR3  12

INCB050465 / Parsaclisib  oral (PI3Ks inhibitor - same class as Idelalisib)  http://bit.ly/2J1Nv3o 6

Inotuzumab Ozogamicin (cd20 antibody-drug conjugate) http://bit.ly/2x5B4hv 19

Ipilimumab anti-CTL-A (MXD-010)  (Immune checkpoint blockade) CTL-A t-reg http://bit.ly/2ZJjQ67 12

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TODO:

	JNJ-64052781 (Humanized CD19 x CD3 Dual-Affinity Re-Targeting Protein)  Find Trials  | NCI Drug Dictionary
	Lirilumab (NK-cell agonist) Find Trials | Report
	Lenalidomide / Revlimid (immune modulation and direct activity)  Find trials  Our topic
	MEDI-551 (humanized cd19 antibody) Find trials
	MEDI-570 (anti-ICOS antibody for t-cell lymphoma) Find Trials
	Mogamulizumab / POTELIGEO� anti-CCR4 antibody, approved in Japan for CCR4-positive adult T-cell leukemia-lymphoma. Find trials
	Monalizumab (CD94/NKG2A checkpoint mab) for| CLL OR lymphoma Find Trials
	MOR00208 /XmAb5574)  (cd19 antibody) Find Trials
	MEDI-570 (Anti-ICOS Monoclonal Antibody) for Peripheral T-cell Lymphoma Follicular Variant or Angioimmunoblastic T-cell Lymphoma  Study of Interest
	MLN9708 (Ixazomib, GATA-3 inhibitor) for Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas Trial of interest
	MT-3724 (CD20-specific Engineered Toxin Body ) Find Trials - NCI Drug Dictionary http://bit.ly/2iXLewi
	Obinutuzumab / GA-101 (next gen cd20 antibody)  Find trials
	Palbociclib (oral, reversible, selective, small-molecule inhibitor of cyclin-dependent kinases (CDK) -- of interest for MCL)  Find Trials
	PD1/L antibodies (removes block on immune system - immune checkpoint blockade)  Find trials | Open trials only - Atezolizumab  / MPDL3280A (pd-1 pathway) Find Trials   NCI Drug Dictionary http://bit.ly/2vZJdRz - Nivolumab (immune checkpoint blockade) in  Lymphoma Trial of Interest - Pembrolizumab / CT-011) / BMS-936558  | Lambrolizumab (Merck)   NCI Drug Dictionary http://bit.ly/2eWHQOa
	PF-05082566 (immunotherapy - anti-4-1BB agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137) Find Trials  | Report
	Polatuzumab Vedotin (cd22 drug-antibody conjugate) Find trials  Polatuzumab Vedotin With cd20 antibody With Bendamustine in Relapsed or Refractory Follicular DLBC Lymphoma Trial of interest
	Pomalidomide  (Lenalidomide derived - Immune modulating) Find trials
	PNT2258 (first-in-class DNAi -- BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide )  Find trials
	REGN197 (CD20xCD3 bispecific antibody) - Find Trials  Regeneron [ REGN1979 - CD20xCD3 bispecific antibody] 8 in 10 complete responses in relapsed or refractory follicular lymphoma trial | FierceBiotech http://bit.ly/2LL5DiV
	Romidepsin  (FDA approved, HDAC inhibitor) Find trials   Romidepsin + Pralatrexate (novel chemo)  in Relapsed/Refractory Lymphoid Malignancies - PTCL only for expansion phase Trial of interest
	RP6530 (dual PI3K inhibitor) Find trials
	RXDX-106 Oral Immunomodulatory Tyrosine Kinase Inhibitor - Find trials
	SAR 245409 oral pan-inhibitor of PI3K Find trials
	Selinexor  /KPT-330 (activates tumor suppress gene  Find trials |  Safety report | Report NCI Drug Dictionary http://bit.ly/2x5nKvE
	TAK659  (Syk inhibitor) Find Trials
	Tazemetostat /  EZH2 inhibitors (inhibits an epigenetic pathway that contributes to abnormal growth)   Find Trials
	TGR-1202 (PI3k Delta Inhibitor) Find Trials TGR-1202 + Ibrutinib in Patients With Select B-Cell lymphoma http://1.usa.gov/1zvYgmu TGR-1202 (PI3K Delta Inhibitor) With Brentuximab Vedotin for Hodgkin's Lymphoma Patients� Trial of interest
	TRU-016 (cd37 antibody) Find trials
	Ublituximab (next gen cd20 antibody) Find Trials
	Umbralisib  (next gen PI3Kδ Inhibitor)  Find Trials Shows Early Promise in CLL and Lymphoma http://bit.ly/2GOQSbt
	Utomilumab (immune adjuvant) Find trials Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer  http://bit.ly/2Ejlrbh
	varlilumab   (cd27 immune modulating )  Find Trials
	Veltuzumab / Immu-106 / Ha20  (next gen cd20 antibody)  Find trials
	Venetoclax | ABT-199  / (activates apoptosis - programmed cell death - through bcl2 pathway)  Findtrials Full prescribing info for CLL
	Vidaza � / 5-Azacytidine (epigenetic - activating or shutting off genes) Find trials
	YM155 (Survivin inhibitor)  Find Trials >
	Zevalin � /(Ibritumomab tiuxetan)  (anti-CD20 + Yttrium 90 ) cd20 Find trials

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Terms related to targeted therapies

The purpose is to introduce terms used for targeted therapies for lymphoma

Cancer is caused by genetic abnormalities or defects in genes called mutations. Genes are recipes that our cells follow to make cellular proteins.  These proteins lead to signals within the cell that determine (or drive) the cell behavior.  ... The signals involve many parts of the cell called molecular pathways.  (Analogy: the electrical system in an automobile is similar to a pathway; distinct from the fuel system. Mutations in key genes (oncogenes) can cause the affected cell to divide too rapidly and/or to persist too long This so-called malignant behavior, can lead to the accumulation of the cancer cells called tumors.

An effective targeted drug is one that binds to a molecule of tumor cells leading to stopping the growth or tumor cell death.  For this reason targeted therapy is sometimes called molecular or precision medicine.  The molecule or target that the drug binds to can be external or internal.  An external target is typically a receptor that is on the surface of the cell that's unique to the type of cell or tumor cell, such as cd20 in b-lymphocytes.  An internal target is typically a molecule inside the cell that is involved in a signaling pathway that is overactive because of a mutation in the gene. The best targeted drugs have good specificity and affinity.  Specificity means the target is unique to the tumor cell.  Affinity means how well the drug binds and remains bound to the target.  A drug with high specificity will have less off-target effects (side effects).  A drug with high affinity is more likely to be active against the disease.

Limitations and considerations

That a study drug is  targeted does not mean it will prove to be effective or safe for a given type of lymphoma or cancer when tested in clinical trials. 

Important questions for patients, and consideration for referring physicians:

1) Is the targeted agent first-in-class (never before tested in humans), or
has a similar agent proven effective in clinical tests in patients with your type of lymphoma?  

2) Is there is a companion diagnostic test to help determine if the target exists based on your tumor sample.

	The molecular target might vary leading to good or poor binding.
	The internal pathway might not be driving the malignancy, or the tumor cells might adapt leading to a limited activity against the behavior of the cells. Or, the external receptor might not be related to cell growth or survival.
	The targeted agent might have off-target effects (binding to similar molecules on normal cells) leading to toxicity.
	The targeted agent might not be safe or tolerable at a dose needed to have anti-cancer effects. Note:  When testing targeted drugs that have been approved in other types of cancer, the clinically active and safe dose will be based on prior clinical experience.  Therefore the recommended dose and risks will be better understood and can be monitored for with more assurance.

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Other terms (coming soon)

Genes have different names, such as BRAF.  Oncogenes are genes that can lead to cancer when mutated.  The changes/  rearrangements / mutations to genes can take place in different portions of the gene (codon, exon), leading to activation of different pathways. 

Most targeted drugs inhibit the pathway ... do not correct the gene mutation.

The changes to genes leading to cancer are almost always acquired (somatic), not inherited (germline).

	codon
	exon
	phosphorylation
	cellular signal transduction
	Recurrent mutations in exon NUMBER of GENE NAME (eg. BRAF)
	wild type MUTATION NAME (BRAF).
	GENE NAME rearrangements (mutations) fuse the kinase domain NAME with a partner gene which leads to constitutive activation of the NAMED pathway

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Further reading? What is a gene mutation and how do mutations occur? - Genetics Home Reference http://1.usa.gov/1E8ACZP