Clinical trial NCT00397579: DT388IL3 Fusion Protein in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes
Official title: Therapy Targeting the Interleukin-3 Receptor (IL3R) for Patients With Relapsed or Refractory and Elderly or Poor-Risk Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome With DTIL3 (IND# 11314): a Phase I/II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Myelodysplastic Syndromes
Blastic Plasmacytoid Dendritic Cell Neoplasm
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
untreated adult acute myeloid leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
blastic plasmacytoid dendritic cell neoplasm
plasmacytoid dendritic cell leukemia
CD123+
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2006-11-09
Enrollment: 11
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: RATIONALE: Combinations of biological substances in DT388IL3 fusion protein may be able to carry cancer killing substances directly to the cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of DT388IL3 fusion protein and to see how well it works in treating patients with acute myeloid leukemia or myelodysplastic syndromes.

Detailed description: OBJECTIVES:

* Determine the maximum tolerated dose of DT_388IL3 fusion protein in patients with refractory or relapsed or poor-risk acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS).
* Define the dose-limiting toxicities of this regimen in these patients.
* Measure the pharmacokinetics of this regimen in these patients.
* Measure the immune responses in patients treated with this regimen.
* Evaluate response and correlate with disease type (relapsed/refractory or poor-risk de novo AML or high-risk MDS), pretreatment marrow blast percentage, and leukemia blast interleukin-3 receptor density.

OUTLINE: This is a phase I, multicenter, dose-escalation study followed by a phase II, open-label study.

* Phase I: Patients receive DT_388IL3 IV over 15 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of DT_388IL3 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

* Phase II: An additional 15 patients receive DT_388IL3 at the MTD as in phase I. Patients undergo serum and blast collection periodically for laboratory studies, including analysis of expression of interleukin-3 receptors and anti-DT_388IL3 antibodies at baseline. Samples are also analyzed by immunoenzyme assays and flow cytometry.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following:

  * Histologically or morphologically confirmed acute myeloid leukemia (AML), meeting 1 of the following criteria:

    * Relapsed or refractory AML after treatment with ≥ 1 prior conventional induction therapy

      * Patients in early first relapse must not have a matched donor available and/or be ineligible for allogeneic stem cell transplantation
    * Poor-risk AML, as defined by any of the following criteria:

      * Treatment-related AML, unless associated with favorable cytogenetics (e.g., inversion 16, t\[16;16\], t\[8;21\], t\[15;17\]), and ineligible for stem cell transplantation
      * Antecedent hematological disease (e.g., myelodysplastic syndromes, myelofibrosis, or polycythemia vera) that evolved to AML (≥ 20% blasts) and ineligible for stem cell transplantation
      * De novo AML (must be \> 70 years of age)
      * AML with unfavorable cytogenetics (e.g., abnormalities of chromosomes -7, -5, 7q-, or 5q-; complex \[≥ 3\] abnormalities; or abnormalities of 11q23, excluding t\[9;11\], t\[9;22\], inversion 3, t\[3;3\], and t\[6;9\]), regardless of age, and ineligible for allogeneic stem cell transplantation
  * High-risk myelodysplastic syndromes diagnosed by morphologic, histochemical, or cell surface marker criteria

    * Resistant or intolerant to chemotherapy
    * Ineligible for or unwilling to undergo immediate allogeneic stem cell transplantation
* Bone marrow index (i.e., percent cellularity × percent blasts) ≤ 40% at time of treatment
* No active CNS leukemia

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Bilirubin ≤ 1.5 mg/dL
* ALT and AST \< 2.5 times upper limit of normal
* Albumin ≥ 3 mg/dL
* Creatinine ≤ 1.5 mg/dL
* LVEF ≥ 50%
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 2 weeks after completion of study treatment
* No complicated medical or psychiatric problems that would preclude study compliance
* No concurrent serious uncontrolled infection or disseminated intravascular coagulation
* No myocardial infarction within the past 6 months
* No allergies to diphtheria toxin
* No requirement for oxygen

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No other concurrent antineoplastic drugs
* No concurrent radiotherapy
* No concurrent corticosteroids as antiemetics
* No concurrent hematopoietic growth factors (e.g., epoetin alfa, interleukin-11, filgrastim \[G-CSF\], or sargramostim \[GM-CSF\])
* No concurrent intravenous immunoglobins

Primary outcomes:
measure: Overall Response Rate (CR+PR+SD): Percentage of Participants Experiencing Response
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 months
Secondary outcomes:
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Arthur E. Frankel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Frankel AE, Woo JH, Ahn C, Pemmaraju N, Medeiros BC, Carraway HE, Frankfurt O, Forman SJ, Yang XA, Konopleva M, Garnache-Ottou F, Angelot-Delettre F, Brooks C, Szarek M, Rowinsky E. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood. 2014 Jul 17;124(3):385-92. doi: 10.1182/blood-2014-04-566737. Epub 2014 May 23.