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

Sponsored by University of Pittsburgh

Phase Quota
Phase 1

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.

Study Start Date: April 2011

Estimated Completion Date: February 2016

Specialties: Oncology: Leukemia/Lymphoma,Pharmacology/Therapy Pharmacy: Chemotherapy/Oncology Physician Assistant: Hematology/Oncology

Interventions

  • Drug: dasatinib (SPRYCEL)
  • Drug: all trans retinoic acid (VESANOID)

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

Study Locations And Contact Information

  • University of Pittsburgh Cancer Institute Hillman Cancer Center, Pittsburgh Pennsylvania
  • University of Pittsburgh Cancer Institute Hillman Cancer Center, Pittsburgh Pennsylvania

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