Tagraxofusp for Leukemia Maintenance Post-Transplant
Recruiting in Palo Alto (17 mi)
Overseen byKaren Ballen
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Karen Ballen, MD
Must not be taking: Prednisone, others
Disqualifiers: Active malignancy, CNS disease, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?In this study, tagraxofusp (Tag) is given to patients with CD 123+ myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) after allogeneic stem cell transplant (HCT) to help prevent relapse. Patients will receive up to about 9 cycles of treatment with Tag and have a bone marrow biopsy after cycle 4 and about 1 year after HCT.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received any disease-related therapy, including radiation or investigational agents, within 14 days of starting the study.
What data supports the effectiveness of the drug Tagraxofusp for leukemia maintenance post-transplant?
Tagraxofusp, a drug that combines diphtheria toxin with interleukin-3, has shown promising results in treating certain blood cancers by targeting specific receptors on cancer cells. Studies have demonstrated its ability to kill leukemia cells and prolong survival in animal models, suggesting potential effectiveness in similar human conditions.
12345What safety data exists for Tagraxofusp in humans?
Tagraxofusp has been shown to have a manageable safety profile in humans, with common side effects including mild liver enzyme changes, 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.
12567How is the drug Tagraxofusp unique for leukemia maintenance post-transplant?
Tagraxofusp is unique because it combines a diphtheria toxin with interleukin-3, specifically targeting leukemia cells that overexpress the interleukin-3 receptor, which is not a common approach in standard leukemia treatments. This targeted mechanism allows it to kill leukemia cells while sparing normal cells, offering a novel strategy for patients who may not respond well to traditional chemotherapy.
12358Eligibility Criteria
Adults aged 18-75 with CD123+ myelofibrosis, chronic myelomonocytic leukemia, or acute myeloid leukemia who've had a stem cell transplant within the last 60-120 days. They should be in remission post-transplant and have good organ function. Participants must agree to use contraception and adhere to lifestyle guidelines.Inclusion Criteria
Patient meets the 2016 WHO diagnostic criteria for MF, is CD 123+, and has an IPSS/DIPSS/DIPSS-plus intermediate-1 with anemia (Hb < 10g/dl), splenomegaly (> 12 cm), leukocytosis (WBC > 25K) intermediate-2 or high-risk disease pre transplant, or Patient has a 2016 WHO-defined diagnosis of CMML pre transplant and is CD123+, or Patient has 2016 WHO-defined CMML-1 and CMML-2 pre transplant and is CD 123+, or Patient has CD 123+ AML in morphologic remission pre transplant, Receipt of first allogeneic stem cell transplant (related, unrelated, haploidentical or cord blood) 60-120 days prior to study registration, Patient is in morphologic remission post-HCT and at the time of study registration, Provision of signed and dated informed consent form, Stated willingness to comply with all study procedures and availability for the duration of the study, For females and males of reproductive potential: agreement to use adequate contraception for at least one month prior to screening, during study participation and for an additional one week after the end of study drug administration. Other (non-study) medications may require participants to use adequate contraception for longer, For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. Other (non-study) medications may require participants to use adequate contraception for longer, Agreement to adhere to Lifestyle Considerations throughout study duration
I can take care of myself and am up and about more than half of my waking hours.
Patient has a life expectancy of >6 months
+2 more
Exclusion Criteria
I do not have serious heart problems like uncontrolled heart failure or recent heart attack.
I have a history of cancer, but it's not one that would affect this study's results.
I do not have any severe illnesses or social situations that would stop me from following the study's requirements.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive tagraxofusp starting between 60 and 120 days following HCT, with up to 9 cycles of treatment. Tag is given by IV on days 1-3 of cycles 1-4 and days 1-2 of subsequent cycles.
9 cycles (each cycle is 28 days)
Inpatient for cycle 1, outpatient for subsequent cycles with 4-hour observation post-infusion
Follow-up
Participants are monitored for safety and effectiveness after treatment, including regular blood checks and bone marrow biopsies after cycle 4 and about 1 year after HCT.
2 years after HCT
Participant Groups
The trial is testing Tagraxofusp as a maintenance therapy after allogeneic stem cell transplant for patients with certain blood cancers. It aims to prevent cancer relapse over up to nine treatment cycles, including bone marrow biopsies after cycle four and around one year post-transplant.
1Treatment groups
Experimental Treatment
Group I: Tagraxofusp (escalating doses)Experimental Treatment1 Intervention
IV tagraxofusp on days 1-3 of cycles 1-4 and days 1-2 of additional cycles for up to 9 cycles (some participants could receive more if considered in their best interest)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Danyelle ColeyCharlottesville, VA
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Who Is Running the Clinical Trial?
Karen Ballen, MDLead Sponsor
References
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.
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 human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression. [2021]Leukemic blasts from patients with acute myeloid leukemia (AML) frequently express high levels of the interleukin-3 receptor alpha chain (IL-3Ralpha). In the present study, we have explored the sensitivity of primary leukemic blasts obtained from 34 patients with AML to a diphtheria toxin (DT) composed of the catalytic and translocation domains of DT (DT388) fused to IL-3 (DT388IL-3) and to DT388 fused to a variant IL-3 with increased binding affinity (DT388IL-3[K116W]). On a molar basis, DT388IL-3[K116W] was significantly more active than DT388IL-3 in mediating leukemic cell killing. The rate of cell killing induced by the 2 DT/IL-3 fusion proteins was significantly correlated with the level of IL-3Ralpha/IL-3Rbeta expressed on leukemic blasts. These observations support a potential use of DT388IL-3[K116W] in the treatment of refractory AMLs and provide a simple biochemical parameter for the selection of eligible patients.
High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein. [2019]Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant AML. We prepared DT(388)IL3 composed of human interleukin-3 (IL3) fused to the catalytic and translocation domain of diphtheria toxin (DT(388)) and assessed its activity on patient AML blasts. The number and affinity of IL3 receptors in circulating blasts was measured using a radiolabeled IL3 agonist (SC-65461). Ninety-two percent of patients' blasts had both high and low affinity IL3 receptors. DT(388)IL3 cytotoxicity (>1 log cell kill) was seen in nine of 25 samples (36%). There was a significant correlation between DT(388)IL3 log cell kill and blast high affinity IL3 receptor density (P=0.0044). These results show that specific high affinity IL3 binding is one factor important in the sensitivity of patients' leukemic blasts to DT(388)IL3.
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.
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.
Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. [2019]DT(388)IL3 fusion protein containing the catalytic and translocation domains of diphtheria toxin fused to human interleukin 3 was administered in an inter-patient dose escalation trial by 15 min i.v. infusions every other day for up to 6 doses to patients with chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS). The maximal tolerated dose was >12.5 microg/kg/dose. Transient grade 3 transaminasemia and grade 2 fevers, chills, hypoalbuminemia, and hypotension occurred. Peak DT(388)IL3 levels correlated with dose and day of administration but not antibody titer. Anti-DT(388)IL3 antibodies developed in most patients between day 15 and 30. Of 40 evaluable AML patients, 1 had a CR (8 months) and 1 had PR (3 months). Of 5 MDS patients, 1 had a PR (4 months). Because of the prolonged infusion schedule, many patients failed to receive six doses. DT(388)IL3 produces remissions in patients with relapsed/refractory AML and MDS with minimal toxicities, and alternate schedules of administration are needed to enhance the response rate.
Variant diphtheria toxin-interleukin-3 fusion proteins with increased receptor affinity have enhanced cytotoxicity against acute myeloid leukemia progenitors. [2022]A fusion protein linking a truncated form of diphtheria toxin (DT(388)) to human interleukin-3 (DT(388)IL3) kills malignant progenitors from some patients with acute myeloid leukemia (AML) while sparing normal progenitors. This study evaluated two variants of DT(388)IL3 with increased affinity for the IL-3 receptor (IL-3R) for their cytotoxicity to AML progenitors and determined the ability of quantitative reverse transcription-PCR assessment of expression of the IL-3R subunits to predict the effectiveness of wild-type DT(388)IL3 and its variants. Both the IL-3 deletion variant (Delta125-133) and the amino acid substitution variant (K116W) showed enhanced toxicity against AML colony-forming cells (AML-CFC; but not normal CFC) compared with wild-type DT(388)IL3 with the K116W variant achieving >90% AML-CFC kill with 17 of 23 patient samples. This variant was also more effective against AML cells engrafting in nonobese diabetic severe combined immunodeficient mice. There was a significant correlation between the expression of the alpha and, particularly, the common beta subunit of the IL-3R on AML blasts detected by quantitative reverse transcription-PCR and AML-CFC kill. Thus, the combined use of IL-3R expression to select patients most likely to respond to DT(388)IL3 and the improved cytotoxicity of the K116W DT(388)IL3 variant against leukemic progenitors may enhance the clinical usefulness of these fusion proteins.