Uproleselan With Pre-Transplant Conditioning in Hematopoietic Stem Cell Transplantation for AML

NCT05569512 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 22-063
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 5

Brief Summary

This research study is studying a new drug, uproleselan, to see if it is safe and effective in decreasing relapse after stem cell transplant and improving leukemia-free survival in pediatric patients with acute myeloid leukemia (AML). The name of the study drugs involved in this study are:

• Uproleselan
• Busulfan
• Clofarabine
• Fludarabine
• Tacrolimus
• Methotrexate
• Mycophenolate Mofetil

Conditions

Acute Myeloid Leukemia; Pediatric Cancer

Keywords

Acute Myeloid Leukemia; Pediatric Cancer

Outcome Measures

Primary Outcomes (3)

• Recommend Phase 2 Dose

  Dose recommended by study team based on maximum tolerated dose (MTD). Highest dose level at or below the maximally administered dose where ≤1 out of 6 patients experienced a Dose Limiting Toxicity (DLT)

  Day -8 pre- transplant through post-transplant Day +30

• Dose Limiting Toxicity (DLT) Phase 1

  All observed toxicities will be summarized using frequencies, proportions, and 95% confidence intervals by type (organ affected or laboratory determination), severity (by CTCAEv5.0), attribution, and expectedness. Only the maximum grade for each type of toxicity will be tabulated for each patient.

  Transplant Day 0 through post-transplant Day +30

• Dose Limiting Toxicity (DLT) Phase 2

  All observed toxicities will be summarized using frequencies, proportions, and 95% confidence intervals by type (organ affected or laboratory determination), severity (by CTCAEv5.0), attribution, and expectedness. Only the maximum grade for each type of toxicity will be tabulated for each patient.

  Transplant Day 0 through post-transplant Day +30

Secondary Outcomes (5)

• Uproleselan Pharmacokinetics

  Day -8 pre-transplant to day -4 pre- transplant

• 12-month Leukemia-Free Survival (LFS)

  12 months

• Overall Survival (OS)

  Date of transplant (Day 0) to 2 years post stem cell transplant

• Relapse Rate at the RP2D

  Up to 2 years

• Number of Patients with Severe Oral or Gastrointestinal Mucositis

  Between day 0 and post-transplant day 14

Study Arms (1)

Uproleselan with pre-transplant conditioning

EXPERIMENTAL

Participants will receive IV uproleselan on day -8 prior to stem cell transplant. Uproleselan will be administered IV twice daily from day -7 through day -2. Participants will also receive a standard pre-transplant conditioning regimen with fludarabine, clofarabine and busulfan. Each of these 3 drugs will be administered IV once daily from day -7 through day -4.

Drug: Uproleselan; Drug: Fludarabine; Drug: Clofarabine; Drug: Busulfan

Interventions

Uproleselan DRUG

Administered by intravenous infusion

Uproleselan with pre-transplant conditioning

Fludarabine DRUG

Administered by intravenous infusion

Also known as: Fludara

Uproleselan with pre-transplant conditioning

Clofarabine DRUG

Administered by intravenous infusion

Also known as: Clolar

Uproleselan with pre-transplant conditioning

Busulfan DRUG

Administered by intravenous infusion

Also known as: Busulfex, Myleran

Uproleselan with pre-transplant conditioning

Eligibility Criteria

• Age: 12 Months - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age ≥12 months and ≤ 39 years
• The minimum and maximum number of subjects enrolled on the study are 20 and 28, respectively. In order to ensure at least 70% of the population are under the age of 18 years of age, the number of subjects \>=18 years old will be limited as follows:
• At least 7 of the first 10 subjects must be under 18 years old
• At least 7 of the second 10 subjects must be under 18 years old
• At least 6 of the last 8 subjects enrolled must be under 18 years old
• Lansky/Karnofsky performance status ≥70% (see Appendix A)
• Weight ≥10 kg
• Acute myeloid leukemia that arises de novo or is secondary to:
• cytotoxic chemoradiotherapy
• myelodysplastic syndrome
• a leukemia predisposition syndrome or inherited marrow failure syndrome other than ones associated with transplant-related morbidity and mortality. A predisposition resulting from a germline RUNX1 mutation is example of an eligible disorder. Fanconi Anemia and Dyskeratosis Congenita are examples of ineligible disorders.
• Disease status: Multidimensional flow cytometry (MDF) to assess disease status for eligibility will be performed centrally by Hematologics.
• In a first or second complete remission (defined as marrow with ≤1% leukemic blasts by MDF and no evidence of extramedullary disease) with minimal residual disease (MRD, defined as marrow with ≥0.05% leukemic blasts by MDF) after at least 2 cycles of induction/re-induction chemotherapy.
• Have newly diagnosed disease or disease in first relapse that is refractory (defined as marrow with \>1% leukemic blasts by MDF or persistence of extramedullary disease) to at least 2 cycles of induction/re-induction chemotherapy.
• This sample will be used for eligibility as well as correlative biomarkers. Please see section 9.2 for details regarding collection, processing, and shipping of the sample.

You may not qualify if:

• Participants who have had a previous hematopoietic stem cell transplantation
• Participants who have had prior treatment with uproleselan
• CNS 3 disease at time of admission for HSCT. Patients previously diagnosed CNS 3 disease that has improved (CNS1 or CNS2) will be eligible. (See Section 3.3 for definitions).
• Down Syndrome
• Fanconi Anemia, Dyskeratosis Congenita and other disorders associated with excess risk for transplant related toxicities
• Acute Promyelocytic Leukemia
• Multiply relapsed (≥2) disease
• Pregnancy (positive serum beta-HCG) or breastfeeding Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with uproleselan, breastfeeding should be discontinued if the mother is treated with uproleselan. These potential risks also apply to other agents used in this study.
• Absolute neutrophil count \<300/μL due to treatment (chemotherapy or immunotherapy).
• Patients with neutropenia due to disease related marrow dysfunction (refractory disease, underlying myelodysplasia or an underlying marrow failure disorder) will be eligible regardless of the absolute neutrophil count. However, enrolling centers must provide clear evidence that the neutrophil count is not rising, that the patient does not have an inadequately controlled infection (see section 3.2.15), and that the patient is on broad anti-fungal prophylaxis. Given the serious risk associated with starting conditioning in patients with severe neutropenia, centers are encouraged to delay transplant if they have any reason to believe that the absolute neutrophil count may improve.
• Estimated GFR of \<60 mL/min/1.73 m2. Estimated GFR may be calculated using the CKD-EPI Creatinine Equation (2009) for patients ≥19 years or creatinine-based Bedside Schwartz equation (2009) for patients \<19 years. It is recommended that estimates be determined using the calculators found on the National Kidney Foundation website. the (https://www.kidney.org/professionals/KDOQI/gfr\_calculator). Any patient for whom these equations yields a GFR less than 90 mL/min/1.73 m2 should have radionucleotide testing. Measurement of 24-hour urine creatinine clearance is not an acceptable substitute for radionucleotide testing.
• Cardiac ejection fraction \<50% or shortening fraction \<27%
• Total bilirubin (with elevated direct bilirubin) or ALT \>2 X ULN.
• Pulmonary disease with FVC, FEV1 or DLCO (corrected for hemoglobin) \<50 % predicted or requiring supplemental oxygen. Children who are developmentally unable to perform pulmonary function testing will be assessed solely on their need for supplemental oxygen
• Active hepatitis B or C infection

Sponsors & Collaborators

• Malika Kapadia: lead
• GlycoMimetics Incorporated: collaborator

Study Sites (5)

University of Alabama Birmingham

Birmingham, Alabama, 35233, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Helen DeVos Children's Hospital/Spectrum Health

Grand Rapids, Michigan, 49503, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10174, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasms

Interventions

uproleselan; fludarabine; fludarabine phosphate; Clofarabine; Busulfan

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Malika Kapadia, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 27, 2022
• First Posted: October 6, 2022
• Study Start: October 6, 2022
• Primary Completion: October 5, 2023
• Study Completion: December 6, 2023
• Last Updated: August 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu BCH - Contact the Technology \& Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu

Locations

US (5)