Study of Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients With Acute Myelogenous Leukemia (AML)
Information source: University of Pittsburgh
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Acute Myelogenous Leukemia
Intervention: dasatinib (SPRYCEL) (Drug); all trans retinoic acid (VESANOID) (Drug)
Phase: Phase 1
Sponsored by: University of Pittsburgh
Official(s) and/or principal investigator(s):
Robert Redner, MD, Principal Investigator, Affiliation: University of Pittsburgh
Robert Redner, MD, Phone: 412-623-3257, Email: firstname.lastname@example.org
This is an open label, prospective, single institution dose-escalation study. The patient
population includes non-induction candidate elderly patients with AML and/or patients with
high-risk or relapsed/refractory AML. Five dose cohorts will be evaluated using a fixed
dose of ATRA in combination with an escalating dose of dasatinib. The investigators will
treat with an escalating dose of dasatinib from 70mg to 140mg daily. Dose escalation will
proceed in a standard 3+3 fashion. A de-escalation to a 50 mg total daily dose of dasatinib
is planned if DLT is greater than or equal to 33% is observed at the first dose level. Once
the MTD for the combination of the drugs has been established, up to 6 additional patients
will be enrolled at the MTD level to obtain additional safety information about the
combination and to allow for preliminary laboratory correlate analysis.
Official title: A Phase 1, Open-label, Dose-escalation Study of Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients With Acute Myelogenous Leukemia
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: To determine the MTD and DLTs of dasatinib in combination with ATRA given the proposed dose escalation plan.
Assessment of Differentiation. Bone marrow biopsies and aspirates will be obtained pre-treatment, on day 14, and day 28. These will be subjected to morphologic, cytochemical, and routine flow cytometric analyses.
Assess treatment effects on SFK (Src family kinase) activation and expression of RARA target genes.
PK parameters including peak concentration (Cmax),Tmax, Cmin, the area under the curve (AUC), volume of distribution, clearance terms, elimination rate constant, and elimination half-life (t1/2) will be analyzed.
1. To determine the safety and tolerability of the combination of dasatinib and ATRA in
relapsed or elderly, non-induction candidate acute myelogenous leukemia (AML) patients and
to identify the maximally tolerated dose (MTD), dose-limiting toxicities (DLT).
1. To determine the pharmacokinetic (PK) profiles of dasatinib and ATRA when administered
as combination therapy for patients with AML
2. To determine if the combination therapy of dasatinib and ATRA promotes differentiation
of AML .
Minimum age: 18 Years.
Maximum age: N/A.
- Signed informed consent form (ICF) indicating that the subject has been informed of
the procedures to be followed, the experimental nature of the therapy, alternatives,
potential benefits, side-effects, risks, and discomforts
- Confirmed diagnosis of non-APL AML (WHO criteria) that is refractory to available
therapy (i. e., has failed two induction regimens)-or- that has relapsed within six
months of attaining a remission. Patients who relapse more than six months after
achieving a remission, who cannot achieve a second remission after two standard
re-induction chemotherapy regimens, will also be candidates. Patients who develop
AML after a pre-existing hematologic disease (myelodysplastic syndrome,
myeloproliferative syndrome) or after prior exposure to chemotherapy (secondary AML)
will be considered eligible for study. Additionally we will include patients age 65
years or older with relapsed or de novo AML who are not candidates for induction
chemotherapy, given the inferior prognosis in this group of patients.
- Confirmed diagnosis of non-APL AML in a patient age 65 or older
- Males or non-pregnant, non-breastfeeding females 18 years of age or older
- ECOG Performance Status less than or equal to 3
- Life expectancy of at least 2 months
- Subjects with reproductive capability must agree to practice adequate contraception
methods. Males must be surgically sterilized or be willing to use condoms from the
first dose of study drug until at least 30 days after the last dose. Females must be
surgically sterilized, postmenopausal for at least 1 year, or willing to use an
appropriate double barrier method or oral, patch, implant, or injectable
contraception from the first dose of study drug until at least 30 days after the last
- Adequate baseline laboratory assessments:
- Total bilirubin level ≤1. 5 times institutional upper limit of normal (ULN), alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2. 5 x ULN
- Estimated plasma creatinine clearance of ≥50 mL/min (using the Cockroft-Gault
equation) (Cockroft-Gault, 1976): CLcreat = ((140 - age) x body mass x 0. 85 if
female) / 72 x creatinine where age is given in years, body mass is given in kg, and
creatinine is given in mg/dL
- Patient with a diagnosis of Acute Promyelocytic Leukemia
- Known or clinically suspected CNS involvement
- Treatment with an investigational agent within 30 days prior to the first dose of
dasatinib/ATRA or planning to receive an investigational agent during the study
- Currently receiving anticancer therapy
- Screening ECG QTc interval ≥500 msec for females, ≥470 msec for males.
- Chronic diarrhea
- Gastrointestinal diseases that could affect drug absorption including post surgical
states such as gastric bypass
- Gastrointestinal diseases that could alter the assessment of safety, including
irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic
- Positive HIV serology
- Uncontrolled, life-threatening infection that is not responding to antimicrobial
- Pregnant or Breastfeeding
- A diagnosis of another active malignancy with the exception of non-melanoma skin
cancer or cervical cancer
- History of psychiatric disorder which may compromise compliance
Locations and Contacts
Robert Redner, MD, Phone: 412-623-3257, Email: email@example.com
University of Pittsburgh Cancer Institute - Hillman Cancer Center, Pittsburgh, Pennsylvania 15232, United States; Recruiting
Starting date: April 2011
Last updated: January 31, 2013