SEA-CD70 for Myelodysplastic Syndrome and Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+60 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Seagen, a wholly owned subsidiary of Pfizer
Must not be taking: CYP3A inducers
Disqualifiers: Stem cell transplant, CNS leukemia, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
This trial is testing a new drug, SEA-CD70, alone and with azacitidine, to see if it is safe and works for adults with certain blood cancers that haven't responded to other treatments. The study will determine the best dose and check for side effects. Azacitidine is a treatment that improves survival, reduces the need for transfusions, and lowers the risk of progression to acute myeloid leukemia in patients with higher risk myelodysplastic syndromes.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, for Part G, you cannot use strong or moderate CYP3A inducers (a type of drug that affects how your body processes other medications). It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug SEA-CD70 for treating Myelodysplastic Syndrome and Acute Myeloid Leukemia?
How does the drug SEA-CD70 work differently from other treatments for myelodysplastic syndrome and acute myeloid leukemia?
SEA-CD70 is unique because it targets the CD70/CD27 signaling pathway, which is involved in the growth and survival of leukemia cells. By blocking this pathway, SEA-CD70 can reduce the proliferation of cancer cells and promote their differentiation, offering a novel approach compared to traditional chemotherapy.14678
Eligibility Criteria
This trial is for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Participants must have relapsed after partial remission or shown no response to previous treatments like azacitidine. They should be in good physical condition, with an ECOG performance status of 0-1, and not have other treatment options available.Inclusion Criteria
I had a severe reaction to HMA treatment and had to stop it.
My MDS has returned or is not responding to treatment, and I have no other known beneficial treatment options.
You have an abnormal percentage of immature blood cells in either your bone marrow or peripheral blood.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Part A: Dose escalation to identify the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70 monotherapy in participants with relapsed/refractory MDS
Up to 4 weeks
Dose Expansion
Parts B and C: Evaluate safety and tolerability of SEA-CD70 monotherapy in participants with relapsed/refractory MDS and AML
Up to 2 years
Combination Dose Finding
Part D: Dose-finding and optimization of SEA-CD70 with azacitidine in participants with MDS or MDS/AML
Up to 4 weeks
Combination Dose Expansion
Parts E and F: Evaluate safety and tolerability of SEA-CD70 with azacitidine in participants with MDS or MDS/AML
Up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 4 years
Treatment Details
Interventions
- SEA-CD70 (Monoclonal Antibodies)
Trial OverviewThe study tests SEA-CD70 alone and combined with azacitidine to determine the safe dosage levels and effectiveness against MDS and AML. It's divided into six parts, each aiming to establish safety profiles and dosages for different patient groups within these conditions.
Participant Groups
7Treatment groups
Experimental Treatment
Group I: Part GExperimental Treatment3 Interventions
SEA-CD70 + azacitidine +venetoclax dose-finding/dose optimization in previously untreated and unfit for induction therapy AML
Group II: Part FExperimental Treatment2 Interventions
SEA-CD70 + azacitidine expansion cohort in relapsed/refractory MDS or MDS/AML
Group III: Part EExperimental Treatment2 Interventions
SEA-CD70 + azacitidine expansion cohort in previously untreated higher-risk MDS or MDS/AML
Group IV: Part DExperimental Treatment2 Interventions
SEA-CD70 + azacitidine dose-finding/dose optimization cohorts in relapsed/refractory MDS or MDS/AML, and previously untreated higher-risk MDS or MDS/AML
Group V: Part CExperimental Treatment1 Intervention
SEA-CD70 expansion cohort in relapsed/refractory AML
Group VI: Part BExperimental Treatment1 Intervention
SEA-CD70 expansion cohort in relapsed/refractory (HMA-failure) MDS
Group VII: Part AExperimental Treatment1 Intervention
SEA-CD70 dose escalation cohort in relapsed/refractory (HMA-failure) MDS
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
James Cancer Hospital / Ohio State UniversityColumbus, OH
Medical University of South Carolina/Hollings Cancer CenterCharleston, SC
Colorado Blood Cancer InstituteDenver, CO
City of HopeDuarte, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Seagen, a wholly owned subsidiary of PfizerLead Sponsor
Seagen Inc.Lead Sponsor
References
CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. [2021]Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.
Targeting treatment in AML. [2016]Currently available chemotherapy has probably reached the limits of its potential in treating acute myeloid leukemia (AML). In considering the next steps it is appropriate to exploit on the one hand knowledge of the molecular, immunophenotypic and biological characteristics of the disease and on the other the biology of the patient. The aim is to move towards a more targeted approach. Immunophenotyping has defined an adequate target (CD33) for antibody-directed treatment, although this is not leukemia specific. Monotherapy has produced important response rates in relapsed disease but it is unlikely to displace conventional chemotherapy. Several randomized trials of antibody directed chemotherapy in combination with chemotherapy nearing completion will establish the usefulness of this approach. In most patients a leukemia-specific immunophenotype can be characterized that can be used to monitor treatment. Minimal residual disease (MRD) detection in morphological remission can detect patients at high risk of relapse, as can a limited number of molecular markers. The clinical value of intervening at the time of MRD detection is not clear. Among the increasing molecular abnormalities described in AML, FLT-3 mutations appear the most attractive for therapeutic intervention. Several phase 2 studies have shown limited efficacy, and randomized trials in combination are underway. Other mechanisms that can be specifically targeted include farnesylation, methylation status, and histone deacelylation. Newer knowledge about the immunophenotypic and biological characteristics of the leukemic stem cell population has opened opportunities to develop treatments that exploit characteristics of the leukemic stem cells that differ from the normal stem cell. Some of these initiatives are now discussed.
Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: the significance of the stem-cell glycoprotein CD34 (My10) [2019]A series of 23 monoclonal antibodies reactive with normal lymphoid and myeloid cells at various stages of differentiation were used to characterize 96 adult patients with acute myelocytic leukaemia (AML), concentrating on the possible role the expression of these antigens may have in predicting response to intensive chemotherapy. Only the expression of CD34 (P = 0.008) and HLA-DR (P = 0.035) was significant in predicting response to therapy; patients with leukaemic cells expressing CD34 (My10) had a complete remission (CR) rate of 59% compared to 87% for those with blasts not expressing the antigen. In a multivariate analysis predicting for CR, the expression of CD34, the disease category (de novo AML versus secondary AML [SAML] or a history of antecedent haematological disorder [AHD]), and WBC were significant covariates. Adjusting for disease category and WBC, patients with CD34-positive AML were one-third as likely to enter CR as with those with disease not expressing the antigen (P = 0.066). Comparison of clinical characteristics between the 58 patients whose leukaemia expressed CD34 and the 33 which were CD34-negative found that patients with CD34-positive AML had a higher incidence of SAML and AHD, a lower WBC at diagnosis, and a more frequent incidence of chromosomal abnormalities involving chromosomes 5 and/or 7. Twenty-eight of these patients also had immunophenotyping performed at relapse. Patients who presented with CD34-positive AML, and entered remission, and then relapsed all recurred with CD34-positive leukaemia; there was no case of CD34-positive AML at diagnosis relapsing with CD34-negative disease. In addition, there were patients presenting with CD34-negative AML and then relapsing with CD34-positive AML. These results suggest that intensive cytoreductive therapy is ineffective against CD34-positive AML. Patients who present with CD34-positive AML may require different therapeutic approaches to completely eradicate their disease.
A pilot study of priming with granulocyte macrophage colony-stimulating factor plus all-trans retinoic acid combined with remission induction chemotherapy in patients with acute myeloid leukemia. [2013]Priming with granulocyte macrophage colony-stimulating factor (GM-CSF) plus all-trans retinoic acid (ATRA) during induction chemotherapy may enhance response rates and survival in patients with acute myeloid leukemia (AML) due to the differentiation of human myeloblastic leukemia cells into granulocytes.
Signal transduction in Acute Myeloid Leukemia - Implications for Novel Therapeutic Concepts. [2019]Acute Myeloid Leukemia (AML) is a highly aggressive clonal hematopoietic disorder that has been managed with largely unchanged treatment protocols for the past decades. Although conventional chemotherapy bears the potential to cure some AML patients, the course of the disease is frequently fatal despite treatment highlighting the need for novel therapeutic concepts. Recent progress in genetic technologies significantly furthered our understanding of the molecular events leading to the disease, but these advances have not yet been successfully translated into improved treatment outcomes. Here, we review some of the new promising targets expressed by leukemic blasts, including important signaling pathways involved in AML stem/progenitor cell maintenance and drug resistance. We furthermore discuss novel targeted therapies in pre-clinical and clinical development thereby focusing on new compounds targeting receptor and non-receptor tyrosine kinases, farnesyltransferase proteins, and epigenetic modifiers.
Prognostic value of immunophenotyping in acute myeloid leukemia. Australian Leukaemia Study Group. [2021]The diagnostic and prognostic value of immunophenotyping with 18 murine monoclonal antibodies (MoAbs) to a variety of leukocyte differentiation antigens was assessed in 168 adults aged 15 to 60 years with acute myeloid leukemia (AML). Patients were entered on the multicentre Australian Leukaemia Study Group M4 protocol, and were randomized to receive either standard or high-dose Ara-C together with daunorubicin and etoposide as induction chemotherapy, followed by standard consolidation and maintenance therapy. Diagnostic bone marrow aspirate (152 cases) or peripheral blood samples (16) were analyzed by indirect immunofluorescence and flow cytometry. MoAbs used were directed at myeloid (CD11b, CD13, CD14, CD15, CD33, CD41), lymphoid (CD2, CD3, CD7, CD9, CD10, CD19), or stem cell (HLA-DR, CD34, c-kit receptor) antigens, as well as the leukocyte integrins CD18 and CD49e, and the transferrin receptor CD71. Of the myeloid markers, CD13 and CD33 were the most useful diagnostically (71% and 79% of cases positive, respectively), with CD11b, CD14, and CD15 less commonly positive. A minority of cases expressed lymphoid antigens, either T cell (CD2 16%, CD3 7%, CD7 28%) or B cell (CD10 2%, CD19 7%). CD34 was detected on 42% and c-kit receptor on 48%. When patients were analyzed for response to treatment, CD2, CD9, and CD14 were significantly associated with complete remission rate: cases expressing these antigens had a poorer response than negative cases. In univariate analysis, CD11b+ cases had shorter periods of remission (relative risk of relapse, 2.33; P = .003) and shorter survival (relative death rate, 1.91; P = .006). In multivariate analysis, adjusting for other prognostic factors, CD9 and CD11b were significantly predictive of shorter survival. No other marker had a significant predictive effect. We conclude that myeloid MoAbs are useful in confirming the diagnosis of AML, but their prognostic value may be limited to CD11b. Lymphoid antigen expression is a consistent phenomenon in a minority of cases of AML, but appears to have little clinical significance.
CD72 is a pan-tumor antigen associated to pediatric acute leukemia. [2023]In the development of novel immunotherapeutic approaches, the step of target identification is a challenging process, because it aims at identifying robust tumor-associated antigens (TAAs) specific for the pathological population and causing no off-target effects. Here we propose CD72 as a novel and robust TAA for pediatric acute leukemias. We provided an outline of CD72 expression assessed by flow cytometry on a variety of cancer cell lines and primary samples, including normal bone marrow (BM) samples and hematopoietic stem and progenitor cells. We analyzed CD 72 expression on a cohort of 495 pathological pediatric BM aspirates, including: 215 B-cell precursor acute lymphoblastic leukemias (BCP-ALL), 156 acute myeloid leukemias (AMLs), 88 T-lineage ALLs or lymphoblastic lymphomas with BM infiltration, 13 B-lineage lymphoblastic lymphomas with BM infiltration, 9 myelodysplastic syndromes with increased blasts (5%-9% blasts on BM: MDS-IB1) and 14 non-hematopoietic solid tumors infiltrating BM. Results showed that CD72 is highly expressed in almost all BCP-ALL and the majority of AML at diagnosis, including BCP-ALL cases characterized by CD19 loss. These findings support a potential role for advanced diagnostics and novel immunotherapy approaches, providing a pan-ALL and AML target.
A subset of patients with high-risk acute myelogenous leukemia shows improved peripheral blood cell counts when treated with the combination of valproic acid, theophylline and all-trans retinoic acid. [2013]Acute myelogenous leukemia (AML) patients (24 consecutive patients, median age 71 years, 17 high-risk disease) were treated with all-trans retinoic acid, theophylline and valproic acid. Among 22 evaluable patients 9 responded with increased normal peripheral blood cell counts. The responses could be classified as hematological improvement according to response criteria for patients with myelodysplastic syndromes (MDS) for four patients only. The nine patients with increased normal cell counts had a median survival from start of therapy of 147 days compared with 48 days for the other patients. Four patients fulfilling the MDS criteria had a survival ranging from 112 to 644 days. The treatment was associated with decreased in vitro cytokine-dependent AML cell proliferation and increased blood levels of Endocan and angiopoietin-2 both for responders and non-responders. We conclude that the therapy causes disease stabilization for a subset of AML patients.