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

Sponsor

John Horan, MD (Other)

Overall Status

Recruiting

CT.gov ID

NCT05569512

Collaborator

GlycoMimetics Incorporated (Industry)

Enrollment

Locations

Arm

73.9

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Pediatric Cancer	Drug: Uproleselan Drug: Fludarabine Drug: Clofarabine Drug: Busulfan	Phase 1/Phase 2

Detailed Description

This is a single arm, multi-center, phase 1/2 trial involving the use of the study drug, uproleselan, as part of the pre stem cell transplant conditioning regimen for pediatric patients with acute myeloid leukemia (AML). This study is looking to learn what dose of uproleselan should be given and the safety of uproleselan when combined with other drugs as part of the pre stem cell transplant conditioning regimen.

The U.S. Food and Drug Administration (FDA) has not approved uproleselan as a treatment for any disease. This is the first time that uproleselan will be given to children. Uproleselan is expected to treat acute myeloid leukemia (AML) by making AML cells sensitive to chemotherapy drugs that are part of standard of care pre-transplant conditioning regimen which could help make the transplant more effective..The standard of care conditioning regimen will include the drugs busulfan, clofarabine, and fludarabine. The standard of care drugs tacrolimus, and either methotrexate or mycophenolate mofetil will be used during the stem cell transplant course.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

Participants will receive study drug doses for 7 days before their stem cell transplant and will be followed for 2 years following their stem cell transplant.

It is expected that about 28 people will take part in this research study.

GlycoMimetics, Inc., a pharmaceutical company, is supporting this research study by providing the study drug (uproleselan) and funding for some of the laboratory tests.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

28 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Trial of Uproleselan Combined With High Dose Busulfan Pre-Transplant Conditioning in Hematopoietic Stem Cell Transplantation for Patients With Chemotherapy Resistant Acute Myeloid Leukemia

Actual Study Start Date :

Oct 6, 2022

Anticipated Primary Completion Date :

Dec 1, 2027

Anticipated Study Completion Date :

Dec 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Uproleselan with pre-transplant conditioning 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 Administered by intravenous infusion Drug: Fludarabine Administered by intravenous infusion Other Names: Fludara Drug: Clofarabine Administered by intravenous infusion Other Names: Clolar Drug: Busulfan Administered by intravenous infusion Other Names: Busulfex Myleran

Arm

Intervention/Treatment

Experimental: Uproleselan with pre-transplant conditioning

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

Administered by intravenous infusion

Drug: Fludarabine

Administered by intravenous infusion

Other Names:

Fludara

Drug: Clofarabine

Administered by intravenous infusion

Other Names:

Clolar

Drug: Busulfan

Administered by intravenous infusion

Other Names:

Busulfex

Myleran

Outcome Measures

Primary Outcome Measures

Recommend Phase 2 Dose [Day -8 pre- transplant through post-transplant Day +30]
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)
Dose Limiting Toxicity (DLT) Phase 1 [Transplant Day 0 through post-transplant Day +30]
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.
Dose Limiting Toxicity (DLT) Phase 2 [Transplant Day 0 through post-transplant Day +30]
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.

Secondary Outcome Measures

Uproleselan Pharmacokinetics [Day -8 pre-transplant to day -4 pre- transplant]
Blood samples will be drawn for measurement of uproleselan plasma levels with the day -8 dose and the first day -4 dose. Four 1 ml samples will be drawn each day for patients less than 6 years. Five 2 ml samples will be drawn each day for patients 6 years and older. Measurements will be used to estimate uproleselan area under the curve.
12-month Leukemia-Free Survival (LFS) [12 months]
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria:
Overall Survival (OS) [Date of transplant (Day 0) to 2 years post stem cell transplant]
Overall Survival (OS) is based on the Kaplan-Meier method and defined as the time from study entry to death or censored at date last known alive per immune RECIST (iRECIST)
Relapse Rate at the RP2D [Up to 2 years]
Rate of Relapse defined as the proportion of patients that has relapse on treatment or during the follow-up period
Number of Patients with Severe Oral or Gastrointestinal Mucositis [Between day 0 and post-transplant day 14]
Defined as all grade 3 or higher oral or gastrointestinal mucositis related adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv5.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Months to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥12 months and ≤ 30 years
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.

Graft and Donor Types:
Patients must be receiving bone marrow or peripheral blood stem cells from a HLA identical related or HLA matched unrelated (allele level matched at A, B, C and DRB1 loci) donor.
Eligibility of prospective donors should be determined in compliance with requirements of 21 CFR Part 1271. This should include donor screening for COVID-19 exposure or infection. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/update d-information-human-cell-tissue-or-cellular-or-tissue-based-product-hctp-establis hments
Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document.

Exclusion Criteria:

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.
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
Active, poorly controlled infections
Patients with a known history of HIV are excluded, unless they meet all of the following conditions:
No history of HIV complications with the exception of CD4 count <200 cells/mm3
No antiretroviral therapy with overlapping toxicity such as myelosuppression
CD4 count >500 cells/mm3 prior to the diagnosis of relapsed AML
HIV viral loads below the limit of detection
No history of highly active antiretroviral therapy (HAART)-resistant HIV
Patients who have received another investigational drug within 28 days or 5 half-lives (whichever is longer).