Uproleselan, Cladribine, and Low Dose Cytarabine for the Treatment of Patients With Treated Secondary Acute Myeloid Leukemia

Phase 1

Completed

Conditions: Secondary Acute Myeloid Leukemia

Interventions: Drug: Cladribine
Drug: Cytarabine
Drug: Uproleselan

Registration Number: NCT04848974

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

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 that has been previously treated with hypomethylating agents).
Patients must be at least 7 days from their last therapy for the antecedent myeloid neoplasm
Age >/= 18 years.
Adequate organ function as defined below:
- liver function (total bilirubin < 2mg/dL, AST and/or ALT <3 x ULN - or <5 x ULN if related to leukemic involvement)
- kidney function (creatinine < 1.5 x ULN ).
- known cardiac ejection fraction of > or = 45% within the past 6 months
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 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 (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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ph 1 Treatment Dose Level -1 Cladaribine 3.75mg/m^2	Cladribine	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.
Ph 1 Treatment Dose Level -1 Cladaribine 3.75mg/m^2	Cytarabine	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.
Ph 1 Treatment Dose Level -1 Cladaribine 3.75mg/m^2	Uproleselan	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.
Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Cladribine	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.
Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Cytarabine	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.
Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Uproleselan	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.
Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Cladribine	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.
Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Cytarabine	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.
Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2	Uproleselan	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.

Primary Outcome Measures

Name	Time	Method
Recommended Phase II Dose	Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days	During safety lead-in, we will use the Bayesian optimal interval (BOIN) design to identify the RP2D of the combination therapy. If the observed DLT rate at the current dose is . 0.236, escalate the dose to the next higher dose level; . if the observed DLT rate at the current dose is . 0.359, de-escalate the dose to the next lower dose level; otherwise, stay at the current dose.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Response	Up to 3 years, 4 months and 14 days	Response is Complete Remission (CR) + Complete Remission Without Count Recovery (CRi) + Morphologic Leukemia-Free State (MLFS) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L). MLFS is Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L \& platelet count . 100 x 10\^9/L.
Number of Participants With Complete Response (CR)	Up to 3 years, 4 months and 14 days	Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts.
Number of Participants With Complete Remission Without Blood Count Recovery (CRi)	Up to 3 years, 4 months and 14 days	Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L).
Number of Minimal Residual Disease (MRD) Negativity in Responders	Up to 3 years, 4 months and 14 days	Measures the Minimal Residual Disease (MRD) negativity in participants who achieve Complete Remission (CR) or Complete remission without count recovery (CRi) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L).
Number of Participants to Reach Morphologic Leukemia-free State (MLFS)	Up to 3 years, 4 months and 14 days	Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L \& platelet count . 100 x 10\^9/L.
Overall Survival	From treatment start to the date of death or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days	Time from date of treatment start until date of death due to any cause.
Complete Remission Duration	From date of CR/CRi to date of disease relapse, death or last follow-up, whichever occurred first, assessed up to 4.5 years	The date of Complete Response to the date of loss of response or last follow-up.
Induction Mortality, Number of Participants	Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days	Number of participants who died during the induction period of therapy.
Event-free Survival	From treatment start to date of death, relapse or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days	Time from date of treatment start until the date of failure or death from any cause.
The Number of Participants With Complete Cytogenetic Response (CCyR)	Up to 3 years, 4 months and 14 days	To assess the rate of complete cytogenetic response (CCyR) in patients with abnormal baseline karyotype, treated with uproleselan combined with cladribine + LDAC. Participants were evaluated for abnormal baseline karyotype and evaluated again after treatment.