Tagraxofusp for Blood Cancers
Recruiting in Palo Alto (17 mi)
+30 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Must not be taking: Corticosteroids, Investigational drugs, Anti-cancer agents
Disqualifiers: CNS disease, Active infection, DNA fragility, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Tagraxofusp is a protein-drug conjugate consisting of a diphtheria toxin redirected to target CD123 has been approved for treatment in pediatric and adult patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). This trial aims to examine the safety of this novel agent in pediatric patients with relapsed/refractory hematologic malignancies.
The mechanism by which tagraxofusp kills cells is distinct from that of conventional chemotherapy. Tagraxofusp directly targets CD123 that is present on tumor cells, but is expressed at lower or levels or absent on normal hematopoietic stem cells. Tagraxofusp also utilizes a payload that is not cell cycle dependent, making it effective against both highly proliferative tumor cells and also quiescent tumor cells.
The rationale for clinical development of tagraxofusp for pediatric patients with hematologic malignancies is based on the ubiquitous and high expression of CD123 on many of these diseases, as well as the highly potent preclinical activity and robust clinical responsiveness in adults observed to date.
This trial includes two parts: a monotherapy phase and a combination chemotherapy phase. This design will provide further monotherapy safety data and confirm the FDA approved pediatric dose, as well as provide safety data when combined with chemotherapy.
The goal of this study is to improve survival rates in children and young adults with relapsed hematological malignancies, determine the recommended phase 2 dose (RP2D) of tagraxofusp given alone and in combination with chemotherapy, as well as to describe the toxicities, pharmacokinetics, and pharmacodynamic properties of tagraxofusp in pediatric patients.
About 54 children and young adults will participate in this study. Patients with Down syndrome will be included in part 1 of the study.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop all current medications, but some medications can be continued up to 24 hours before starting the trial. These include hydroxyurea and certain 'maintenance-style' therapies like vincristine, oral 6-mercaptopurine, and oral methotrexate. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug Tagraxofusp for blood cancers?
Tagraxofusp has shown significant effectiveness in treating a rare blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN), with many patients able to proceed to further treatment like stem cell transplantation. It has also demonstrated promising results in other blood cancers, including myeloid malignancies, by targeting specific cancer cells and reducing disease presence.
12345Is Tagraxofusp safe for use in humans?
Tagraxofusp has a manageable safety profile with common side effects like elevated liver enzymes, low blood protein levels, swelling, and low platelet counts. The most serious risk is capillary leak syndrome, which can be life-threatening but may be managed with early detection and treatment.
12367What makes the drug Tagraxofusp unique for treating blood cancers?
Tagraxofusp is unique because it is the first FDA-approved drug specifically targeting CD123, a protein overexpressed in certain blood cancers, using a fusion of interleukin-3 and a diphtheria toxin to kill cancer cells. It is particularly effective for blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare cancer with no previous standard treatment.
12378Eligibility Criteria
This trial is for children and young adults aged 1 to 21 with relapsed or refractory hematologic malignancies expressing CD123. Eligible participants include those with various types of leukemia, lymphoma, and myelodysplastic syndrome who have experienced multiple relapses or did not respond to at least two chemotherapy cycles. Patients must have adequate organ function and agree to use contraception if applicable.Inclusion Criteria
I have undergone specific treatments like chemotherapy or stem cell transplant.
My leukemia has returned or is not responding to treatment, and more than 5% of my bone marrow cells are immature blood cells.
My heart, lungs, liver, kidneys, and bone marrow are working well.
+9 more
Exclusion Criteria
I do not have a DNA fragility syndrome.
I do not have allergies to the drugs used in this study or specific infections.
I am not on varying doses of corticosteroids for my condition.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Monotherapy Treatment
Participants receive Tagraxofusp monotherapy to assess safety and confirm the FDA approved pediatric dose
21 days
5 visits (in-person)
Combination Chemotherapy Treatment
Participants receive Tagraxofusp in combination with chemotherapy agents such as Azacitidine, Fludarabine, Cytarabine, and others to assess safety and determine the recommended phase 2 dose
28 days
Multiple visits (in-person) on days 1, 8, 15, and 22
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests Tagraxofusp alone and in combination with other chemotherapies (like Hydrocortisone, Dexamethasone) in pediatric patients. It aims to determine the safe dosage levels, describe side effects, understand how the drug works in the body, and improve survival rates for these cancers.
4Treatment groups
Experimental Treatment
Group I: Part 2 - Cohort CExperimental Treatment5 Interventions
Tagraxofsup -Days 1-5
Azacitidine
-Days 1-5
IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy
* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
CNS2/3 IT Therapy
* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
Group II: Part 2 - Cohort BExperimental Treatment6 Interventions
Tagraxofsup
-Days 8-12
Dexamethasone -Days 1-5
Vincristine
-Days 1, 8, 15, and 22
IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy
* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
CNS2/3 IT Therapy
* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
Group III: Part 2 - Cohort AExperimental Treatment6 Interventions
Tagraxofsup
-Days 4-8
Fludarabine -Days 1-5
Cytarabine
-Days 1-5
IT Therapy (may include methotrexate, cytarabine, or triple IT) CNS1 IT Therapy
* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
CNS2/3 IT Therapy
* Days 1, 8, 15, and 22
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
Group IV: Part 1Experimental Treatment4 Interventions
Tagraxofusp
-Days 1-5
IT Therapy (may include methotrexate, cytarabine, or triple IT)
* Day 1
* Patients may receive additional IT therapy with their end-of-cycle disease re-evaluation at the discretion of the treating investigator
Tagraxofusp is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Elzonris for:
- Blastic plasmacytoid dendritic cell neoplasm (BPDCN)
🇪🇺 Approved in European Union as Elzonris for:
- Blastic plasmacytoid dendritic cell neoplasm (BPDCN)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Rainbow BabiesCleveland, OH
Riley Hospital for ChildrenIndianapolis, IN
University of MiamiMiami, FL
Children's Hospital ColoradoDenver, CO
More Trial Locations
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Who Is Running the Clinical Trial?
Therapeutic Advances in Childhood Leukemia ConsortiumLead Sponsor
References
Tagraxofusp, the first CD123-targeted therapy and first targeted treatment for blastic plasmacytoid dendritic cell neoplasm. [2019]Introduction: CD123 or interleukin 3 receptor alpha is overexpressed in multiple hematologic malignancies. Tagraxofusp is an intravenously administered CD123-directed cytotoxin consisting of the fusion of interleukin-3 with a truncated diphtheria toxin payload and was recently approved by the Food and Drug Administration for the treatment of adults and children aged 2 and older with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Areas Covered: In this review, we discuss the use of tagraxofusp in BPDCN, and active clinical trials involving this agent in several hematologic malignancies are also presented. Tagraxofusp has significant efficacy in patients with BPDCN and manageable safety profile, with the most commonly reported adverse events being asymptomatic elevation of alanine and aspartate aminotransferase levels, hypoalbuminemia, peripheral edema, and thrombocytopenia. The most serious side effect is capillary leak syndrome that can be lethal in some cases but the risk may be mitigated by early recognition and intervention. Expert Opinion: Tagraxofusp has been introduced as a novel treatment of BPDCN, a rare hematologic malignancy, for which no standard therapy previously existed. Many patients treated with this agent were able to be bridged to stem cell transplantation, including older patients. In the future, combinations of tagraxofusp with other targeted agents will be explored.
Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. [2020]Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.
Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm. [2020]Tagraxofusp is a toxin-cytokine fusion protein consisting of engineered diphtheria toxin (DT) and interleukin-3 (IL-3). The IL-3 domain binds to the cluster of differentiation 123 (CD123) and translocates DT into the cytosol, which leads to cell death. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a strong expression of CD123. Historical data show that the prognosis of BPDCN is poor, with a median overall survival of 9 to 13 months. On December 21, 2018, the United States Food and Drug Administration (FDA) approved tagraxofusp for the treatment of adults and children with newly diagnosed or relapsed/refractory BPDCN, becoming the first FDA-approved drug for this disease. In this review, we examine the preclinical studies and phase I/II clinical studies that led to FDA approval of tagraxofusp, focusing on its molecular pharmacology, pharmacokinetics, efficacy and safety profile. We also discuss future directions regarding BPDCN management.
Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice. [2022]The novel fusion protein DT(388)IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT(388)) fused with a Met-His linker to human interleukin 3 (IL-3), was tested for anti-leukemia efficacy in an in vivo model of differentiated human acute myeloid leukemia (AML). Six-week-old female SCID mice were irradiated with 350 cGy, inoculated 24 h later with 20 million (i.v., i.p., or s.c.) TF1 cells transfected with the v-SRC oncogene, and treated i.p., starting 24 h later, with up to five daily injections of saline, DT(388)IL3 (2 microg), DT(388)GMCSF (2 microg), DAB(389)IL2 (2 microg), or cytarabine (80 microg) or two weekly injections of anti-CD33-calicheamicin conjugate (5 microg). Animals were monitored twice daily, and moribund animals killed and necropsied. Control animals had a median disease-free survival (DFS) of 37 days (i.v., n = 45), 35 days (i.p., n = 20), and 21 days (s.c., n = 20), respectively. Only 5/49 (10%) of the DT(388)IL3 treated i.v. inoculated animals died with leukemia. Median DFS with i.v., i.p. and s.c. tumor inoculated animals was prolonged by fusion protein treatment to >120 days, 66 days and 31 days (P
Diphtheria toxin fused to variant interleukin-3 provides enhanced binding to the interleukin-3 receptor and more potent leukemia cell cytotoxicity. [2007]Chemoresistance is a common cause of treatment failure in patients with acute myeloid leukemia (AML). We generated a diphtheria toxin (DT) fusion protein composed of the catalytic and translocation domains of DT (DT388) fused to interleukin-3 (IL-3). IL-3 receptors (IL-3R) are overexpressed on blasts from many AML patients. DT388IL-3 showed cytotoxicity to leukemic blasts in vitro and in vivo and minimal damage to normal tissues in nonhuman primate models. However, only a fraction of patient leukemic samples were sensitive to the agent. To enhance the potency and specificity of the DT388IL-3 molecule, we constructed variants with altered residues in the IL-3 moiety. Two of these variants, DT388IL-3[K116W] and DT388IL-3[Delta125-133], were produced and partially purified from Escherichia coli with excellent yields. They showed enhanced binding to the human IL-3R and greater cytotoxicity to human leukemia cell lines relative to wild-type DT388IL-3. Interestingly, the results support a previously hypothesized model for interaction of the C-terminal residues of IL-3 with a hydrophobic patch on the alpha-subunit of IL-3R. Rational modification of the targeting domain based on structural analysis can produce a fusion toxin with increased ability to kill tumor cells. One or both of these variant fusion proteins merit further development for therapy of chemotherapy refractory AML.
Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. [2022]Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically challenging hematologic malignancy with dismal outcomes. With a median age of ∼70 years, the majority of patients with BPDCN have experienced historically suboptimal responses with intensive chemotherapy regimens. The major scientific breakthrough in this field was the recognition of overexpression of a surface receptor, CD123/interleukin 3 (IL-3) receptor α, in all patients. Importantly, a novel therapeutic agent consisting of a truncated diphtheria toxin (DT) payload fused to recombinant human IL-3 was being developed, one that targeted CD123, initially known as DT-IL-3 (later known as SL401; tagraxofusp; tagraxofusp-erzs [Elzonris]). The identification of this agent, and subsequent clinical trials specifically dedicated to patients with BPDCN (including a pilot study, followed by a larger phase 1/2 multicenter study [90% overall response rate [ORR] in frontline and 67% ORR in relapsed/refractory setting]), in part led to approval of tagraxofusp-erzs on 21 December 2018. Tagraxofusp-erzs was the first agent approved for BPDCN (for patients ages 2 years and older), and importantly, established this drug as the first CD123-targeted agent ever approved. The most notable toxicity of tagraxofusp-erzs is occurrence of the capillary leak syndrome, which occurs frequently at all grades, and has also been observed to be life-threatening, appropriately leading to a US Food and Drug Administration "black box" warning in the package insert. The preclinical and clinical aspects of drug development of tagraxofusp-erzs as monotherapy leading to drug approval are reviewed herein, with discussion of future directions of this novel agent, including consideration for rational combinations in BPDCN and beyond.
Tagraxofusp for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A Brief Report on Emerging Data. [2020]Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, for which conventional chemotherapy has poor outcomes. CD123, the α-subunit of interleukin (IL)-3 receptor, is constantly overexpressed at the surface of tumoral cells. Tagraxofusp (or SL-401) is a recombinant cytotoxin which consists of human interleukin-3 fused to a truncated diphtheria toxin. It is currently the only novel therapy with a prospective evaluation of efficacy and safety in the treatment of BPDCN and is also the only one to achieve FDA approval. In this short review, the results of tagraxofusp are summarized and perspectives of its use in BPDCN and in other malignancies are discussed. The safety profile is also summarized, since capillary leak syndrome is the main toxic effect of the drug, along with more common toxicities including an increase in transaminases and thrombocytopenia.
Tagraxofusp in myeloid malignancies. [2023]Tagraxofusp (or SL-401) is a recombinant molecule composed of human interleukin-3 that binds CD123 on neoplastic cells fused to a truncated diphtheria toxin (DT). Tagraxofusp's most significant success has come from studies involving patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive disease that is usually refractory to conventional chemotherapy. Tagraxofusp had an acceptable safety profile and high efficacy in early phase I/II studies on patients with BPDCN. Another phase II study confirmed the good response rates, resulting in Food and Drugs Administration and European Medicine Agency approval of tagraxofusp for the treatment of BPDCN. Considering its high efficacy and its manageable safety profile, tagraxofusp has been suddenly explored in other myeloid malignancies with high expression of cell surface CD123, both in monotherapy or combination strategies. The triplet tagraxofusp-azacytidine-venetoclax appears to be of particular interest among these combinations. Furthermore, combination strategies may be used to overcome tagraxofusp resistance. The downregulation of DPH1 (diphthamide biosynthesis 1), the enzyme responsible for the conversion of histidine 715 on eEF2 to diphthamide, which is then the direct target of ADP ribosylation DT, is typically associated with this resistance phenomenon. It has been discovered that azacitidine can reverse DHP1 expression and restore sensitivity to tagraxofusp. In conclusion, the success of tagraxofusp in BPDCN paved the way for its application even in other CD123-positive malignancies. Nowadays, several ongoing trials are exploring the use of tagraxofusp in different myeloid neoplasms. This review aims to summarize the actual role of tagraxofusp in BPDCN and other CD123-positive myeloid malignancies.