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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


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia

Thank you

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 UCLALos Angeles, California  90095-1781