Clinical trial NCT04848974: Uproleselan, Cladribine, and Low Dose Cytarabine for the Treatment of Patients With Treated Secondary Acute Myeloid Leukemia
Official title: Phase Ib/II Study of Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) Induction Followed by Consolidation With Uproleselan Plus Cladribine Plus LDAC in Patients With Treated Secondary AML (TS-AML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Secondary Acute Myeloid Leukemia
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
First posted: 2021-04-19
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Patients with a diagnosis of treated secondary-AML (TS-AML) who have not received therapy for their AML will be eligible.
2. 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).
3. Patients must be at least 7 days from their last therapy for the antecedent myeloid neoplasm
4. Age \>/= 18 years.
5. 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
6. ECOG performance status of ≤ 2.
7. A negative urine or serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial.
8. 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:

1. 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.
2. 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.
3. Patients with documented hypersensitivity to any of the components of the chemotherapy program.
4. 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.
5. Prior treatment with uproleselan.
6. Patients with a diagnosis of acute promyelocytic leukemia (AML-M3) will be excluded from this study.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 4.5 years
measure: Recommended phase II dose
timeFrame: Up to 4.5 years
Secondary outcomes:
measure: Overall response rate
timeFrame: Up to 4.5 years
measure: Complete response (CR)
timeFrame: Up to 4.5 years
measure: CR without blood count recovery (CRi)
timeFrame: Up to 4.5 years
measure: CR with partial hematologic recovery
timeFrame: Up to 4.5 years
measure: Partial response
timeFrame: Up to 4.5 years
measure: Morphologic leukemia-free state
timeFrame: Up to 4.5 years
measure: Rate of minimal residual disease (MRD) negativity
timeFrame: Up to 4.5 years
measure: Overall survival
timeFrame: From treatment start to the date of death or last follow-up, whichever occurred first, assessed up to 4.5 years
measure: Remission duration
timeFrame: From date of CR/CRi to date of disease relapse, death or last follow-up, whichever occurred first, assessed up to 4.5 years
measure: Progression-free survival
timeFrame: From treatment start to date of death, relapse or last follow-up, whichever occurred first, assessed up to 4.5 years
measure: Rate of complete cytogenetic response
timeFrame: Up to 4.5 years
measure: Toxicity
timeFrame: Up to 4.5 years
measure: Induction mortality
timeFrame: Up to 4.5 years
Other outcomes:
Locations:
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Tapan M Kadia
role: PRINCIPAL_INVESTIGATOR
References: