Study of Dasatinib and All-Trans Retinoic Acid for Relapsed/Refractory and/or Elderly Patients With Acute Myelogenous Leukemia (AML)

Condition(s) targeted: Acute Myelogenous Leukemia

Intervention: dasatinib (SPRYCEL) (Drug); all trans retinoic acid (VESANOID) (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Robert Redner, MD, Principal Investigator, Affiliation: University of Pittsburgh

Overall contact:
Robert Redner, MD, Phone: 412-623-3257, Email: rednerrl@upmc.edu

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 40mg to 140mg daily. Dose escalation will proceed in a standard 3+3 fashion. A de-escalation to a 20 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: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Primary outcome: To determine the MTD and DLTs of dasatinib in combination with ATRA given the proposed dose escalation plan.

Secondary outcome:

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.

Detailed description: Primary Objective:

1. To perform a Phase I clinical trial of dasatinib and ATRA in relapsed or elderly, non-induction candidate acute myelogenous leukemia (AML) patients to determine the maximally tolerated dose, dose-limiting toxicities (DLT), and other side effects of this regimen.

Secondary Objectives:

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 blasts as measured by flow cytometric analysis and morphologic assessment of serial bone marrow biopsies and aspirates

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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 dose

- 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

Exclusion Criteria:

- 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 coloproctitis.

- Positive HIV serology

- Uncontrolled, life-threatening infection that is not responding to antimicrobial

therapy

- 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

Robert Redner, MD, Phone: 412-623-3257, Email: rednerrl@upmc.edu

University of Pittsburgh Cancer Institute - Hillman Cancer Center, Pittsburgh, Pennsylvania 15232, United States

Starting date: July 2009
Ending date: July 2011
Last updated: May 1, 2009