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

NCT00892190 | Completed Phase 1 DMC

• 1 other identifier: UPCI 08-160
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label, prospective, single institution dose-escalation study. The patient population includes non-induction candidate elderly patients with AML or MDS and/or patients with high-risk or relapsed/refractory AML or MDS. 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.

Conditions

Acute Myelogenous Leukemia; Myelodysplastic Syndrome

Keywords

AML; Dasatinib; all trans retinoic acid; relapsed AML; refractory AML; Relapsed/Refractory Acute myelogenous leukemia; Elderly subjects (age 65 or older) with acute myelogenous leukemia; Myelodysplastic Syndrome; MDS

Outcome Measures

Primary Outcomes (1)

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

  1.5 years

Secondary Outcomes (3)

• 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.

  1.5 years

• Assess treatment effects on SFK (Src family kinase) activation and expression of RARA target genes.

  1.5 years

• 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.

  1.5 years

Study Arms (1)

dasatinib (SPRYCEL) and all trans retinoic acid (VESANOID)

EXPERIMENTAL

Dasatinib DL0 - 50 mg every 24 hours DL1 (START)- 70 mg every 24 hours DL2 - 100 mg every 24 hours DL3 - 140 mg every 24 hours ATRA 22.5mg/m2 every 12 hours

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

Interventions

dasatinib (SPRYCEL) DRUG

DL0 - 50 mg every 24 hours DL1 (START)- 70 mg every 24 hours DL2 - 100 mg every 24 hours DL3 - 140 mg every 24 hours

dasatinib (SPRYCEL) and all trans retinoic acid (VESANOID)

all trans retinoic acid (VESANOID) DRUG

22.5mg/m2 every 12 hours

dasatinib (SPRYCEL) and all trans retinoic acid (VESANOID)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent
• Performance Status (ECOG) less than or equal to 3
• Subjects ages 18 or older
• Confirmed diagnosis of non-APL AML (WHO criteria) or high-risk MDS (IPSS criteria INT-2 or High)
• For subjects Age \<65: Refractory AML or AML relapse within six months of attaining remission or AML relapse more than six months after achieving a remission, who cannot achieve a second remission or Untreated subjects who develop AML after preexisting hematologic disease or Secondary AML or high-risk MDS who either are not a candidate for hypomethylating agents or who have failed one or more hypomethylating agent
• For subjects Age ≥65: De novo AML not candidates for induction chemotherapy or Refractory AML or AML relapse within six months of attaining remission or AML relapse more than six months after achieving a remission, who cannot achieve a second remission or Untreated subjects who develop AML after preexisting hematologic disease Secondary AML or high-risk MDS who either are not a candidate for hypomethylating agents or who have failed one or more hypomethylating agent
• Life expectancy of at least 2 months
• Adequate Organ Function: Total bilirubin \< 2.0 times the institutional Upper Limit of Normal (ULN), Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN, Serum Creatinine \< 2.0 times the institutional ULN
• Ability to take oral medication (dasatinib must be swallowed whole)
• Concomitant Medications: Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib). Patient agrees that IV bisphosphonates will be withheld for the 4 weeks of dasatinib therapy due to risk of hypocalcemia.
• Age and Sex: Men and women, age 18-100. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 30 days after the last dose of study drug to minimize the risk of pregnancy. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as: Amenorrhea that has lasted for \>= 12 consecutive months without another cause, or For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product. A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study \[and for up to 30 days after the last dose of study drug\] to minimize the risk of pregnancy. A barrier method is recommended.

You may not qualify if:

• Sex and Reproductive Status: WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug. Women who are pregnant or breastfeeding. Women with a positive pregnancy test. Sexually active fertile men not using effective birth control if their partners are WOCBP.
• Target Disease Exceptions: Subjects with a diagnosis of Acute Promyelocytic Leukemia, Known or clinically suspected CNS involvement, HIV Positivity, A diagnosis of another active malignancy with the exception of non-melanoma skin cancer or cervical cancer in situ., Gastrointestinal conditions that could affect drug absorption including post surgical states such as gastric bypass, History of psychiatric disorder which may compromise compliance, Stem cell transplant within 60 days., Subjects who have undergone stem cell transplant who are undergoing treatment or prophylaxis for Graft versus host disease
• Physical and Laboratory Test Findings: Chronic diarrhea, Uncontrolled, life-threatening infection that is not responding to antimicrobial therapy
• Allergies and Adverse Drug Reactions: History of allergic reaction to ATRA, History of allergic reaction to dasatinib
• Prohibited Treatments and/or Therapies: Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes or prolonge QT interval including: (Patients must discontinue drug 7 days prior to starting dasatinib) (See section 5.6.1.2) quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycin, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine, azithromycin, citalopram, escitalopram, flecainide, mesoridazine, sevoflurane. Potent inhibitors of CYP3A4 (see section 5.6.1.1 for more details). Proton pump inhibitors and H2 inhibitors (see section 5.6.2.3). St. John's Wort (see section 5.6.2.4). Medications that inhibit platelet function and anticoagulants (see section 5.6.2.5). Currently receiving anticancer therapy. Use of hydroxyurea within 7 days prior to screening labs. Treatment with a an investigational agent within 30 days prior to the first dose of dasatinib/ATRA or planning to receive an investigational agent during the study. Growth factors within 14 days prior to screening labs

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (1)

University of Pittsburgh Cancer Institute - Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Dasatinib; Tretinoin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Robert Redner, MD

  University of Pittsburgh Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2009
• First Posted: May 4, 2009
• Study Start: April 1, 2011
• Primary Completion: January 1, 2016
• Study Completion: February 1, 2016
• Last Updated: February 10, 2016

Record last verified: 2016-02

Locations

US (1)