This phase Ib/II trial finds out the best dose and effect of cladribine and low dose cytarabine when given in combination with uproleselan in treating patients with treated secondary acute myeloid leukemia. Chemotherapy drugs, such as uproleselan, cladribine, and low dose cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Cladribine | 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251 | Treatment (uproleselan, cladribine, cytarabine) |
| Cytarabine | .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453 | Treatment (uproleselan, cladribine, cytarabine) |
| Uproleselan | GMI-1271 | Treatment (uproleselan, cladribine, cytarabine) |
PRIMARY OBJECTIVE:
I. To determine the safety, tolerability, and recommended phase II dose (RP2D) of uproleselan
combined with cladribine + low dose cytarabine (LDAC) in patients with treated-secondary
acute myeloid leukemia (AML) (ts-AML).
SECONDARY OBJECTIVES:
I. To assess the efficacy (overall response rate [ORR], complete response [CR], complete
response without blood count recovery [CRi], CR with partial hematologic recovery [CRh],
partial response [PR], or morphologic leukemia-free state of uproleselan combined with
cladribine + LDAC in patients with ts-AML.
II. To assess the rate of minimal residual disease (MRD) negativity by flow cytometry at
response.
III. To assess overall survival (OS), remission duration (CRd), and progression-free survival
(PFS) in patients with ts-AML treated with uproleselan combined with cladribine + LDAC.
IV. To assess the rate of complete cytogenetic response (CCyR) in patients with ts-AML with
abnormal baseline karyotype, treated with uproleselan combined with cladribine + LDAC.
V. To assess toxicity and induction mortality of patients with AML treated with uproleselan
added to cladribine + LDAC.
EXPLORATORY OBJECTIVES:
I. To explore biomarkers of response and resistance in patients with ts-AML treated with
uproleselan combined with cladribine + LDAC.
II. To examine the correlation of E-selectin ligand-forming glycosylation genes of leukemic
blasts with clinical outcome.
OUTLINE: This is a phase I, dose-escalation study of cladribine and cytarabine followed by a
phase II study.
INDUCTION THERAPY: Patients receive uproleselan intravenously (IV) over 20 minutes on day 1
and every (Q) 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine
subcutaneously (SC) twice daily (BID) on days 1-10 in the absence of disease progression or
unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a
second induction cycle.
CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1
and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic
leukemia-free state after induction therapy receive uproleselan IV once daily (QD) on days
1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on
days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Treatment (uproleselan, cladribine, cytarabine) | Experimental | INDUCTION THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine SC BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle. CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic leukemia-free state after induction therapy receive uproleselan IV QD on days 1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. |
|
Inclusion Criteria:
- Patients with a diagnosis of treated secondary-AML (TS-AML) who have not received
therapy for their AML will be eligible
- TS-AML is defined as AML arising from a previously treated antecedent myeloid neoplasm
(myelodysplastic syndrome or myeloproliferative neoplasm)
- Age >= 18 years
- Total bilirubin =< 2mg/dL
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper
limit of normal (ULN) - or < 5 x ULN if related to leukemic involvement
- Creatinine =< 1.5 x ULN
- Known cardiac ejection fraction of > or = 45% within the past 6 months
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- A negative urine or serum pregnancy test is required within 1 week for all women of
childbearing potential prior to enrolling on this trial
- Patient must have the ability to understand the requirements of the study and informed
consent. A signed informed consent by the patient or his legally authorized
representative is required prior to their enrollment on the protocol
Exclusion Criteria:
- Pregnant women are excluded from this study because the agents used in this study have
the potential for teratogenic or abortifacient effects. Because there is a potential
risk for adverse events in nursing infants secondary to treatment of the mother with
the chemotherapy agents, breastfeeding should also be avoided
- Uncontrolled intercurrent illness including, but not limited to active uncontrolled
infection, symptomatic congestive heart failure (New York Heart Association [NYHA]
class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia,
or psychiatric illness/social situations that would limit compliance with study
requirements
- Patients with documented hypersensitivity to any of the components of the chemotherapy
program
- Men and women of childbearing potential who do not practice contraception. Women of
childbearing potential and men must agree to use contraception prior to study entry
and for the duration of study participation
- Prior treatment with uproleselan
- Patients with a diagnosis of acute promyelocytic leukemia (AML-M3) will be excluded
from this study
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Incidence of adverse events |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | The severity of the toxicities will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 whenever possible. Will follow standard reporting guidelines for adverse events. Safety data will be summarized by category, severity and frequency. |
| Measure: | Overall response rate |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | Complete response (CR) |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | CR without blood count recovery (CRi) |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | CR with partial hematologic recovery |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | Partial response |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | Morphologic leukemia-free state |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: | Will be estimated along with the 95 percent credible interval. |
| Measure: | Rate of minimal residual disease (MRD) negativity |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: |
| Measure: | Overall survival |
| Time Frame: | From treatment start to the date of death or last follow-up, whichever occurred first, assessed up to 4.5 years |
| Safety Issue: | |
| Description: | Assessed using Kaplan-Meier method. |
| Measure: | Remission duration |
| Time Frame: | From date of CR/CRi to date of disease relapse, death or last follow-up, whichever occurred first, assessed up to 4.5 years |
| Safety Issue: | |
| Description: | Assessed using Kaplan-Meier method. |
| Measure: | Progression-free survival |
| Time Frame: | From treatment start to date of death, relapse or last follow-up, whichever occurred first, assessed up to 4.5 years |
| Safety Issue: | |
| Description: | Assessed using Kaplan-Meier method. |
| Measure: | Rate of complete cytogenetic response |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: |
| Measure: | Toxicity |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: |
| Measure: | Induction mortality |
| Time Frame: | Up to 4.5 years |
| Safety Issue: | |
| Description: |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | M.D. Anderson Cancer Center |
June 29, 2021
