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A Study of AK117 in Combination With Azacitidine in Patients With Myelodysplastic Syndromes
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of AK117 or placebo, combined with azacitidine in patients with newly diagnosed higher-risk myelodysplastic syndromes (HR-MDS).
Call 214-648-5005
studyfinder@utsouthwestern.edu, Michael.McCane@UTSouthwestern.edu
Yazan Madanat
ALL
18 Years to old
PHASE2
NCT06196203
STU-2024-1100
Inclusion Criteria:
* Age ≥ 18 years old at the time of enrolment.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.
* Expected life expectancy ≥ 3 months.
* Newly diagnosed HR-MDS, according to the 2016 World Health Organization (WHO) classification with the presence of \< 20% blasts in bone marrow or peripheral blood; Overall IPSS-R score ≥ 3.5.
* Ability to undergo the study-required bone marrow sample collection procedures.
* Suitable venous access for the study-required blood sampling (i.e., including PK and immunogenicity).
* Female patients of childbearing age must have negative serum pregnancy test results before randomization or per region-specific guidance documented in the informed consent and a negative urine pregnancy test on the day of first dose prior to dosing.
* Female patients of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 180 days after the last dose of the study treatment.
* Unsterilized male patients having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until 180 days after the last dose of study treatment.
Exclusion Criteria:
* MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
* Prior treatment with Cluster of Differentiation (CD) 47 or Signal-regulatory protein alpha (SIRPα)-targeting agents.
* Concurrently participating in another interventional clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
* Patients who previously diagnosed with another malignancy and have any evidence of residual disease.
* Known allergy to any component of any study drug; known history of severe hypersensitivity to other monoclonal antibodies.
* Patients with any psychiatric or social factor which the investigator deems may interfere with the patient's ability to comply with the requirements of the study.
* Patients with current hypertension with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.
* Patients with known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders.
* Patients who are breastfeeding or plans to breastfeed during the study.
* Other conditions where the investigator considers the patient inappropriate for enrollment. DRUG: AK117, DRUG: Placebo, DRUG: Azacitidine
Higher-risk Myelodysplastic Syndromes, Leukemia, Other
UT Southwestern
Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome
This phase III trial compares hematopoietic (stem) cell transplantation (HCT) using mismatched related donors (haploidentical \[haplo\]) versus matched unrelated donors (MUD) in treating children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome (MDS). HCT is considered standard of care treatment for patients with high-risk acute leukemia and MDS. In HCT, patients are given very high doses of chemotherapy and/or radiation therapy, which is intended to kill cancer cells that may be resistant to more standard doses of chemotherapy; unfortunately, this also destroys the normal cells in the bone marrow, including stem cells. After the treatment, patients must have a healthy supply of stem cells reintroduced or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. The healthy stem cells may come from the blood or bone marrow of a related or unrelated donor. If patients do not have a matched related donor, doctors do not know what the next best donor choice is. This trial may help researchers understand whether a haplo related donor or a MUD HCT for children with acute leukemia or MDS is better or if there is no difference at all.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Victor Aquino
ALL
6 Months to 21 Years old
PHASE3
NCT05457556
STU-2024-0214
Inclusion Criteria:
* PATIENT INCLUSION CRITERIA FOR ENROLLMENT:
* 6 months to \< 22 years at enrollment
* Diagnosed with ALL, AML, or MDS or mixed phenotype acute leukemia (MPAL) for which an allogeneic hematopoietic stem cell transplant is indicated. Complete Remission (CR) status will not be confirmed at the time of enrollment. CR as defined in these sections is required to proceed with the actual HCT treatment plan
* Has not received a prior allogeneic hematopoietic stem cell transplant
* Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available for stem cell donation
* Has an eligible haploidentical related family donor based on at least intermediate resolution HLA typing
* Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high resolution HLA typing are eligible for randomization to Arm A or Arm B.
* Patients who do not have an eligible MUD donor are eligible for enrollment to Arm C
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
* Co-Enrollment on other trials
* Patients will not be excluded from enrollment on this study if already enrolled on other protocols for treatment of high risk and/or relapsed ALL, AML, MPAL and MDS. This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD Trial, as well as local institutional trials. We will collect information on all co-enrollments
* Patients will not be excluded from enrollment on this study if receiving immunotherapy prior to transplant as a way to achieve remission and bridge to transplant. This includes chimeric antigen receptor (CAR) T cell therapy and other immunotherapies
* PATIENT INCLUSION CRITERIA TO PROCEED TO HCT:
* Karnofsky Index or Lansky Play-Performance Scale \>= 60 on pre-transplant evaluation. Karnofsky scores must be used for patients \>= 16 years of age and Lansky scores for patients =\< 16 years of age (within 4 weeks of starting therapy)
* A serum creatinine based on age/gender as follows:
6 months to \< 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female)
• to \< 2 years: 0.6 mg/dL (Male); 0.6 mg/dL (Female)
• to \< 6 years: 0.8 mg/dL (Male); 0.8 mg/dL (Female) 6 to \< 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to \< 13 years: 1.2 mg/dL (Male); 1.2 mg/dL (Female) 13 to \< 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) \>= 16 years: 1.7 mg/dL (Male); 1.4 mg/dL (Female) * OR * A 24 hour urine Creatinine clearance \>= 60 mL/min/1.73 m\^2 * OR * A glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) * Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility * Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase \[AST\] or serum glutamate pyruvate transaminase (SGPT) aminotransferase \[ALT\] \< 5 x upper limit of normal (ULN) for age * Total bilirubin \< 2.5 mg/dL, unless attributable to Gilbert's Syndrome * Shortening fraction of \>= 27% by echocardiogram or radionuclide scan (MUGA) * OR * Ejection fraction of \>= 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care * Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and corrected carbon monoxide diffusing capability (DLCO) must all be \>= 50% of predicted by pulmonary function tests (PFTs). * For children who are unable to perform for PFTs (e.g., due to age or developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen (O2) saturation (Sat) \> 92% on room air by pulse oximetry, not on supplemental O2 at rest, and not on supplemental O2 at rest * MPAL in first complete remission (CR1) for whom transplant is indicated. Examples include those patients who are poorly responsive to ALL therapy (end of induction failure( IF-MPAL) to ALL induction (see IF-MPAL note below), end of induction MRD ≥ 5% or end-of-consolidation MRD \> 0.01%), as well as patients treated with AML therapy * IF-MPAL: additional criterion for Induction failure for MPAL ONLY as per ALL1732: * An increasing number of circulating leukemia cells on 3 or more consecutive CBCs obtained at daily or longer intervals following day 8 of Induction therapy and prior to day 29 with confirmation by flow cytometry OR development of new sites of extramedullary disease, or other laboratory or clinical evidence of refractory disease or progression prior to the end of Induction evaluation (note that residual testicular disease at the end of Induction is an exception) * MPAL in \> second complete remission (CR2) * ALL high-risk in CR1 for whom transplant is indicated. Examples include: induction failure, treatment failure as per minimal residual disease by flow cytometry \> 0.01% after consolidation and not eligible for AALL1721 or AALL1721 not available/unwilling to enroll, hypodiploidy (\< 44 chromosomes) with MRD+ \> 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent MRD \> 0.01% after consolidation. * ALL in CR2 for whom transplant is indicated. Examples include: B-cell: early (=\< 36 months from initiation of therapy) bone marrow (BM) relapse, late BM relapse (\>= 36 months) with MRD \>= 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (\< 18 months) isolated extramedullary (IEM), late (\>= 18 months) IEM, end-Block 1 MRD \>= 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time * ALL in \>= third complete remission (CR3) * Patients treated with chimeric antigen receptor T-cells (CART) cells for whom transplant is indicated. Examples include: transplant for consolidation of CART, loss of CART persistence and/or B cell aplasia \< 6 months from infusion or have other evidence (e.g., MRD+) that transplant is indicated to prevent relapse * AML in CR1 for whom transplant is indicated. Examples include those deemed high risk for relapse as described in AAML1831: * FLT3/ITD+ with allelic ratio \> 0.1 without bZIP CEBPA, NPM1 * FLT3/ITD+ with allelic ratio \> 0.1 with concurrent bZIP CEBPA or NPM1 and with evidence of residual AML (MRD \>= 0.05%) at end of Induction * Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD) per cytogenetics, fluorescence in situ hybridization (FISH), next generation sequencing (NGS) results, regardless of favorable genetic markers, MRD status or FLT3/ITD mutation status * AML without favorable or unfavorable cytogenetic or molecular features but with evidence of residual AML (MRD \>= 0.05%) at end of Induction * Presence of a non-ITD FLT3 activating mutation and positive MRD (\>= 0.05%) at end of Induction 1 regardless of presence of favorable genetic markers. * AML in \>= CR2 * MDS with \< 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation * Complete remission (CR) is defined as \< 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation with minimum sustained absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC \> 500 cells/microliter. We will be collecting data from all approaches to MRD evaluation performed including NGS and polymerase chain reaction (PCR). It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR. It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR * DONOR ELIGIBILITY CRITERIA: * Matched Unrelated Donors: Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles (HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of additional alleles is recommended according to National Marrow Donor Program (NMDP) guidelines, but will be at the discretion of local centers * Haploidentical Matched Family Members: * Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1, -DQB1 alleles). The following issues (in no particular order) should be considered in choosing a haploidentical donor: * Absent or low patient donor-specific antibodies (DSA) * Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be \< 2000. Donors with higher levels are not eligible. * If a screening assay against pooled HLA antigens is used, positive results must be followed with specificity testing using a single antigen assay. The MFI must be \< 2000 unless the laboratory has validated higher threshold values for reactivity for HLA antigens (such as HLA-C, -DQ, and -DP), that may be enhanced in concentration on the single antigen assays. Donor anti- recipient antibodies are of unknown clinical significance and do not need to be sent or reported. * Consult with Study Chair for the clinical significance of any recipient anti-donor HLA antibody. * If centers are unable to perform this type of testing, please contact the Study Chair to make arrangements for testing. * If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch, KIR-B, or KIR content criteria can be used according to institutional guidelines. * ABO compatibility (in order of priority): * Compatible or minor ABO incompatibility * Major ABO incompatibility * CMV serostatus: * For a CMV seronegative recipient: the priority is to use a CMV seronegative donor when feasible * For a CMV seropositive recipient: the priority is to use a CMV seropositive donor when feasible * Age: younger donors including siblings/half-siblings, and second degree relatives (aunts, uncles, cousins) are recommended, even if \< 18 years * Size and vascular access appropriate by center standard for peripheral blood stem cell (PBSC) collection if needed * Haploidentical matched family members: screened by center health screens and found to be eligible * Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated donor registries. If the donor does not meet the registry eligibility criteria but an acceptable eligibility waiver is completed and signed per registry guidelines, the donor will be considered eligible for this study * Human immunodeficiency virus (HIV) negative * Not pregnant * MUD donors and post-transplant cyclophosphamide haplo donors should be asked to provide BM. If donors refuse and other donors are not available, PBSC is allowed. TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC * Must give informed consent: * Haploidentical matched family members: Institution standard of care donor consent and Protocol-specific Donor Consent for Optional Studies * Unrelated donors: standard NMDP Unrelated Donor Consent
Exclusion Criteria:
* PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:
* Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL/MPAL with known poor outcomes because of sensitivity to alkylator therapy and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc). Patients with Downs syndrome because of increased toxicity with intensive conditioning regimens.
* Patients with any obvious contraindication to myeloablative HCT at the time of enrollment
* Female patients who are pregnant are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
* PATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:
* Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are excluded. Patients with history of fungal disease during chemotherapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by computed tomography (CT) evaluation
* Patients with active central nervous system (CNS) leukemia or any other active site of extramedullary disease at the time of initiation of the conditioning regimen are not permitted.
* Note: Those with prior history of CNS or extramedullary disease, but with no active disease at the time of pre-transplant workup, are eligible
* Pregnant or breastfeeding females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants PROCEDURE: Biospecimen Collection, PROCEDURE: Bone Marrow Aspiration, DRUG: Busulfan, DRUG: Cyclophosphamide, PROCEDURE: Echocardiography, DRUG: Fludarabine, PROCEDURE: Haploidentical Hematopoietic Cell Transplantation, BIOLOGICAL: Lapine T-Lymphocyte Immune Globulin, PROCEDURE: Lumbar Puncture, PROCEDURE: Matched Unrelated Donor Hematopoietic Cell Transplantation, DRUG: Melphalan, DRUG: Methotrexate, PROCEDURE: Multigated Acquisition Scan, DRUG: Mycophenolate Mofetil, PROCEDURE: Myeloablative Conditioning, OTHER: Quality-of-Life Assessment, OTHER: Questionnaire Administration, BIOLOGICAL: Rituximab, PROCEDURE: T-Cell Depletion Therapy, DRUG: Tacrolimus, DRUG: Thiotepa, RADIATION: Total-Body Irradiation
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Leukemia, Not Otherwise Specified, Leukemia, Other
Children’s Health
The Pediatric Acute Leukemia (PedAL) Screening Trial - A Study to Test Bone Marrow and Blood in Children With Leukemia That Has Come Back After Treatment or Is Difficult to Treat - A Leukemia & Lymphoma Society and Children's Oncology Group Study
This study aims to use clinical and biological characteristics of acute leukemias to screen for patient eligibility for available pediatric leukemia sub-trials. Testing bone marrow and blood from patients with leukemia that has come back after treatment or is difficult to treat may provide information about the patient's leukemia that is important when deciding how to best treat it, and may help doctors find better ways to diagnose and treat leukemia in children, adolescents, and young adults.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Kathleen Ludwig
ALL
up to 22 Years old
PHASE1
NCT04726241
STU-2022-0170
Inclusion Criteria:
* Patients must be less than 22 years of age at the time of study enrollment
* Patient must have one of the following at the time of study enrollment:
* Patient has known or suspected relapsed/refractory (including primary refractory) AML as defined in protocol
* This includes isolated myeloid sarcoma
* Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome (ML-DS)
* Patient has known or suspected relapsed ALL as defined in protocol that meets one of the following criteria:
* Second or greater B-ALL medullary relapse, excluding KMT2Ar
* Any first or greater B-ALL medullary relapse involving KMT2Ar
* Any first or greater T-ALL medullary relapse with or without KMT2Ar
* Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL) as defined in protocol
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML)
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS) or treatment-related myelodysplastic syndrome (t-MDS)
* Note: Relapsed/refractory disease includes stable disease, progressive disease, and disease relapse.
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
* Note: Relapsed/refractory disease includes stable disease, progressive disease, and disease relapse.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met PROCEDURE: Biospecimen Collection
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia Post Cytotoxic Therapy, Juvenile Myelomonocytic Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic Syndrome Post Cytotoxic Therapy, Myeloid Leukemia Associated With Down Syndrome, Leukemia, Other, Myeloid and Monocytic Leukemia
Children’s Health
A Study of ASTX030 (Cedazuridine in Combination With Azacitidine) in MDS, CMML, or AML
Study ASTX030-01 is designed to move efficiently from Phase 1 to Phase 3. Phase 1 consists of an open-label Dose Escalation Stage (Stage A) using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine (only one study drug will be escalated at a time) followed by a Dose Expansion Stage (Stage B). Phase 2 is a randomized, open-label, crossover study to compare oral ASTX030 to subcutaneous (SC) azacitidine. Phase 3 is a randomized open-label crossover study comparing the final oral ASTX030 dose to SC azacitidine. The duration of this phase 1-3 study is approximately 7 years.
Call 214-648-5005
studyfinder@utsouthwestern.edu, donglan.xia@utsouthwestern.edu
Yazan Madanat
ALL
18 Years and over
PHASE2
NCT04256317
STU-2023-0235
Inclusion Criteria:
Phase 2:
• Has Confirmed MDS, CMML, MDS/MPN or AML diagnosis who are candidates to receive and benefit from single agent azacitidine and as applicable according to local country approvals and/or local institution standard practice. Phase 3:
• Has confirmed MDS or CMML and is a candidate to receive and benefit from single agent azacitidine as applicable according to local country approvals and/or local institution standard practice: a) French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and CMML or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Participants with adequate organ function.
• For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
• Participants with no major surgery within 3 weeks before first study treatment.
• Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
• Participants with projected life expectancy of at least 12 weeks.
Exclusion Criteria:
Phase 2 and 3:
• Has an active uncontrolled gastric or duodenal ulcer.
• Has poor medical risk because of other conditions.
• Has known human immunodeficiency virus (HIV) infection.
• Is known to be positive for Hepatitis B or C infection.
• Has a life-threatening illness.
• Has a history of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected or adequately treated and controlled with other modalities; and any early stage malignancy for which no definitive therapy is required.
• Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
• Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
• Has been treated with any investigational drug or therapy within 2 weeks, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant adverse events from previous treatment with investigational drug or therapy.
• Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
DRUG: Azacitidine, DRUG: ASTX030 (cedazuridine + azacitidine), DRUG: Azacitidine, DRUG: ASTX030 (cedazuridine + azacitidine), DRUG: Cedazuridine
Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myelodysplastic Syndrome/Neoplasm, Chronic Myelomonocytic Leukemia, Leukemia, Other, Myeloid and Monocytic Leukemia
ASTX030, Myeloid Neoplasm, Hematologic Disease, Leukemia, Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), Vidaza™, Azacitadine, Azacitadine and cedazuridine drug combination
UT Southwestern
Tagraxofusp in Pediatric Patients With Relapsed or Refractory CD123 Expressing Hematologic Malignancies
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.
Call 214-648-5005
studyfinder@utsouthwestern.edu, amira.davis@childrens.com
Tamra Slone
All
1 Year to 21 Years old
Phase 1
NCT05476770
STU-2022-1157
Inclusion Criteria:
Age
• Patients must be ≥ 1 and ≤21 years of age at the time of study enrollment. Diagnosis
• Relapsed and/or refractory hematologic malignancy (including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, mixed phenotype acute leukemia, acute undifferentiated leukemia, blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, and non-Hodgkin lymphoma).
• Tumor cells must demonstrate surface expression of CD123 at the time of enrollment by flow cytometry or immunohistochemistry, as defined by the local institution. Disease Status: Monotherapy, Part 1
• Second or greater relapse; or
• Refractory after 2 or more chemotherapy cycles; or
• First relapse after primary chemotherapy-refractory disease; or
• BPDCN in first relapse or refractory after 1 or more chemotherapy cycles Combination therapy, Part 2
• First or greater relapse; or
• Refractory after 2 or more chemotherapy cycles; or
• BPDCN in first relapse or refractory after 1 or more chemotherapy cycles For relapsed/refractory leukemia, patients must have:
• >5% blasts in the bone marrow aspirate by morphology or flow cytometry
• Patients with 1% - 5% blasts are eligible for Part 2, Cohort C (only), if A single bone marrow sample with flow cytometry and at least one other test (e.g. karyotype, FISH, PCR, or NGS) shows ≥ 1% leukemic blasts and/or flow cytometry demonstrates a stable or rising level of disease on two serial bone marrows. For relapsed/refractory non-Hodgkin or Hodgkin lymphoma, patients must have:
• Histologic verification of relapse
• Measurable disease documented by radiographic criteria or bone marrow
• Patients in Part 1 may have sites of non-CNS extramedullary disease, but no CNS disease. Patients in Part 2 may have CNS disease and/or other non-CNS extramedullary disease. No cranial irradiation is allowed during the protocol therapy.
• Patients with Down syndrome are eligible. Performance Level
• Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age (See Appendix I for Performance Scales). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Prior Therapy
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy, defined as resolution of all such toxicities to ≤ Grade 2 or lower per the inclusion/exclusion criteria. Myelosuppressive chemotherapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 14 day must have elapsed since the completion of myelosuppressive therapy. However, individuals may receive any of the following medications within 14 days without a "wash-out period":
• Hydroxyurea: Hydroxyurea can be initiated and/or continued for up to 24 hours prior to the start of protocol therapy.
• "Maintenance-style" therapy: therapy including vincristine (dosed a maximum of one-time weekly), oral 6-mercaptopurine, oral methotrexate (dosed a maximum of one-time weekly), intrathecal therapy (dosed a maximum of one-time weekly) and/or dexamethasone (dosed at ≤3 mg/m2/dose twice daily) or prednisone (dosed at ≤20 mg/m2/dose twice daily) can be continued for up to 24 hours prior to entering the study.
• Hematopoietic stem cell transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are at least 100 days post-transplant at the time of enrollment.
• Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with granulocyte colony stimulating factor (GCSF) or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
• Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
• Monoclonal antibodies: Maximum of 3 half-lives of the antibody or 21 days (whichever is shorter) must have elapsed after the last dose of monoclonal antibody.
• Immunotherapy: At least 30 days from last infusion of chimeric antigen receptor T cell (CART) therapy or tumor vaccine.
• XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to any extramedullary site other than CNS chloromas; ≥ 90 days must have elapsed if prior TBI or craniospinal XRT.
• Patients that have received other non-tagraxofusp CD123 targeting agents are eligible. Patients that have previously received tagraxofusp are not eligible. Organ Function Requirements Adequate Bone Marrow Function Defined as:
• Patients should not be known to be refractory to red blood cell or platelet transfusions.
• Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be ≥20,000/mm3 to initiate therapy (may receive platelet transfusions). Adequate Renal Function Defined as:
• Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below: Maximum Serum Creatinine (mg/dL):
• 1 to < 2 years old - Male: 0.6, Female: 0.6
• 2 to < 6 years old - Male:0.8, Female: 0.8
• 6 to < 10 years old - Male: 1, Female: 1
• 10 to < 13 years old - Male: 1.2, Female: 1.2
• 13 to < 16 years old - Male: 1.5, Female: 1.4
• ≥ 16 years old - Male: 1.7, Female: 1.4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. Adequate Liver Function Defined as:
• Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x institutional upper limit of normal for age
• SGPT (ALT) and SGOT (AST) must be less than 3x institutional upper limit of normal.
• Serum albumin ≥3.2 g/dL (albumin infusion independent). Adequate Cardiac Function Defined as:
• Shortening fraction of ≥27% by echocardiogram, or
• Ejection fraction of ≥ 50% by gated radionuclide study/echocardiogram. Adequate Pulmonary Function Defined as:
• Pulse oximetry > 94% on room air (> 90% if at high altitude)
• No evidence of dyspnea at rest and no exercise intolerance. Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for 12 weeks after the last dose of tagraxofusp. Exclusion Criteria Disease Status:
• Patients with CNS disease are not eligible for Part 1.
• Patients with isolated CNS disease are not eligible for Part 1 or Part 2.
• Patients with isolated non-CNS disease are eligible for Part 1 and Part 2. Concomitant Medications
• Corticosteroids - Patients receiving corticosteroids for disease control who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
• Investigational Drugs - Patients who are currently receiving another investigational drug are not eligible. The definition of "investigational" for use in this protocol means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
• Anti-cancer Agents - Patients who are currently receiving or may receive while on therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible [except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of study treatment (day 1 therapy).
• Anti-GVHD or agents to prevent organ rejection post-transplant - Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. At least 4 weeks must have elapsed after the last dose of GVHD meds. Infection Criteria - Patients are excluded if they have:
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
• A positive fungal culture within 30 days of study enrollment.
• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.
• Patients will be excluded if they have a known allergy to any of the drugs used in the study.
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
• Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.
Drug: Tagraxofusp, Drug: Fludarabine, Drug: Cytarabine, Drug: Dexamethasone, Drug: Vincristine, Drug: Azacitidine, Drug: Methotrexate, Drug: Cytarabine IT, Drug: Hydrocortisone
Hematologic Malignancy, AML, ALL, BPDCN, MDS, Lymphoblastic Lymphoma, Lymphoma, B-cell, Lymphoma, T-Cell, Hodgkin Lymphoma, Mixed Phenotype Acute Leukemia, Acute Undifferentiated Leukemia, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Leukemia, Other, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma
Children’s Health