A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered CNF1010 )17-(Allylamino)-17-Demethoxygeldanamycin [17-AAG]) in Patients With Gleevec-Resistent Chronic Myelogenous Leukemia
18 Years
N/A
Both
Leukemia
Trial Information
A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered CNF1010 )17-(Allylamino)-17-Demethoxygeldanamycin [17-AAG]) in Patients With Gleevec-Resistent Chronic Myelogenous Leukemia
OBJECTIVES:
Primary
- Determine the maximum tolerated dose and dose-limiting toxicity of
17-N-allylamino-17-demethoxygeldanamycin (17-AAG), in terms of frequency, severity, and
duration of treatment-emergent adverse events, in patients with imatinib
mesylate-resistant Philadelphia chromosome (Ph)-positive chronic phase chronic
myelogenous leukemia.
- Determine the pharmacokinetics of this drug and its primary metabolite
(17-amino-17-demethoxygeldanamycin) in these patients.
Secondary
- Determine the hematologic response rate, in terms of WBC count, platelet count, and
assessment of blast cells in peripheral blood, in patients treated with this drug.
- Determine the cytogenic response rate, in terms of Ph-positive progenitor cells in the
bone marrow, in patients treated with this drug.
- Assess the effect of this drug on pharmacodynamic markers (i.e., CRKL phosphorylation,
BCR-ABL kinase activity, and BCR-ABL, RAF kinase, and HSP70 expression) in these
patients.
OUTLINE: This is an open label, dose-escalation, multicenter study.
Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 15 minutes or 1
hour (depending on the dose administered) once on days 1, 4, 8, 11, 15, 18, 22, and 25.
Treatment repeats every 28 days for up to 3 courses in the absence of unacceptable toxicity
or disease progression. Eligible patients may receive additional courses of 17-AAG at the
discretion of the investigator.
Cohorts of 3-6 patients receive escalating doses of 17-AAG 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. Up to 10 additional patients are treated at the
MTD.
Patients are followed for 1 month.
PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Diagnosis of chronic phase chronic myelogenous leukemia
- Philadelphia chromosome (Ph)-positive disease
- Hematologic resistence after treatment with imatinib mesylate (400 mg per day or
maximum tolerated dose [MTD]) as defined by 1 of the following criteria:
- Loss of complete hematologic response, defined as WBC count OR platelet count >
upper limit of normal (ULN) on 2 separate occasions at least 2 weeks apart that
cannot be attributed to other etiologies
- Absolute increase of ≥ 30% in Ph-positive cells while on a stable dose of
imatinib mesylate for at least 6 months* NOTE: *Patients meeting this criterion
are not eligible for enrollment into the expanded MTD cohort
- Less than 15% blasts in peripheral blood or bone marrow AND < 30% blasts and
promyelocytes in peripheral blood or bone marrow
PATIENT CHARACTERISTICS:
Age
- 18 and over
Performance status
- ECOG 0-2
Life expectancy
- At least 6 months
Hematopoietic
- See Disease Characteristics
Hepatic
- Bilirubin < 1.5 times ULN (3 mg/dL for patients with Gilbert's syndrome)
- ALT or AST < 2 times ULN
- No known hepatitis positivity
Renal
- Creatinine < 1.5 times ULN OR
- Creatinine clearance > 60 mL/min
Cardiovascular
- No New York Heart Association class III or IV cardiac disease
Pulmonary
- No severe debilitating pulmonary disease, including any of the following:
- Dyspnea at rest
- Significant shortness of breath
- Chronic obstructive pulmonary disease
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 1 month after study
participation
- No known HIV positivity
- No psychological or social condition that would preclude study compliance
- No addictive disorder that would preclude study compliance
- No family problems that would preclude study compliance
- No known allergy or sensitivity to soy or other excipient components of study drug
- No other illness or condition that may affect safety of study treatment or evaluation
of study endpoints
PRIOR CONCURRENT THERAPY:
Biologic therapy
- More than 2 weeks since prior interferon
- No concurrent interferon
Chemotherapy
- More than 2 weeks since prior cytarabine (4 weeks for doses > 100 mg)
- More than 6 weeks since prior busulfan
- No concurrent cytarabine
- No concurrent hydroxyurea during the second study treatment course and beyond
- No concurrent anagrelide during the second study treatment course and beyond
Endocrine therapy
- Not specified
Radiotherapy
- Not specified
Surgery
- Not specified
Other
- More than 2 days since prior imatinib mesylate
- More than 1 week since prior and no concurrent drugs that alter metabolism by
cytochrome P450 3A4, including the following:
- Diltiazem
- Nifedipine
- Verapamil
- Fluconazole
- Itraconazole
- Ketoconazole
- Lovastatin
- Simvastatin
- Indinavir
- Nelfinavir
- Ritonavir
- Alprazolam
- Diazepam
- Midazolam
- Triazolam
- Phenobarbital
- Phenytoin
- Carbamazepine
- Azithromycin
- Clarithromycin
- Erythromycin
- Rifampin
- Rifamycin
- Astemizole
- Terfenidine
- Amiodarone
- Cimetidine
- Cisapride
- Cyclosporine
- Grapefruit juice
- Hypericum perforatum (St. John's wort)
- Warfarin
- More than 4 weeks since prior investigational drugs and recovered
- No concurrent imatinib mesylate
Type of Study:
Interventional
Study Design:
Masking: Open Label, Primary Purpose: Treatment
Principal Investigator
Charles Sawyers, MD
Investigator Role:
Study Chair
Investigator Affiliation:
Jonsson Comprehensive Cancer Center
Authority:
United States: Federal Government
Study ID:
UCLA-0408048-01
NCT ID:
NCT00100997
Start Date:
October 2004
Completion Date:
October 2006
Related Keywords:
- Leukemia
- chronic myelogenous leukemia, BCR-ABL1 positive
- chronic phase chronic myelogenous leukemia
- relapsing chronic myelogenous leukemia
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Leukemia, Myeloid, Chronic-Phase
Name | Location |
|---|---|
| Jonsson Comprehensive Cancer Center at UCLA | Los Angeles, California 90095-1781 |
