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A Phase I Study Of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG) With Evaluation Of Hsp90 Client Proteins In Subjects With Solid Tumors And Lymphomas


Phase 1
18 Years
N/A
Not Enrolling
Both
Lymphoma, Small Intestine Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study Of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG) With Evaluation Of Hsp90 Client Proteins In Subjects With Solid Tumors And Lymphomas


OBJECTIVES:

Primary

- Determine the maximum tolerated dose of
17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in patients with an
advanced malignant solid tumor or lymphoma.

- Determine the dose-limiting toxic effects and toxicity profile of this drug in these
patients.

Secondary

- Compare the effects of this drug on heat shock protein 90 (Hsp90) client proteins when
assayed in peripheral blood mononuclear cells (PBMC) vs tumor tissue from patients
treated with this drug.

- Correlate disturbances in key signaling pathways with administration of this drug in
these patients.

- Determine the dose that alters key proteins in the majority of patients treated with
this drug.

- Correlate serum proteomic patterns with target interactions or DMAG clinical effects in
patients treated with this drug.

- Determine the pharmacokinetics of this drug in these patients.

OUTLINE: This is a single-center, dose-escalation study.

Patients receive 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) IV over 1-2
hour on days 1 and 4 or days 2 and 5 weekly for 4 weeks. Treatment repeats every 4 weeks in
the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of 17-DMAG until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of up to 6
patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional
patients are treated at the MTD.

PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study within 2 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed malignant solid tumor OR lymphoma

- Metastatic or unresectable disease

- Standard curative or palliative measures are not available OR are associated with
minimal survival benefit

- No known brain metastases

- Treated brain metastases allowed provided they have been stable ≥ 6 months
without steroids or anti-seizure medications

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-2 OR

- Karnofsky 60-100%

Life expectancy

- More than 3 months

Hematopoietic

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- WBC ≥ 3,000/mm^3

- Hemoglobin > 8 g/dL

Hepatic

- AST and ALT ≤ 2 times upper limit of normal

- Bilirubin ≤ 1.5 times normal

- PT and PTT ≤ 1.5 times normal (unless due to the presence of lupus anticoagulant or
stable anticoagulation)

Renal

- Creatinine normal OR

- Creatinine clearance ≥ 60 mL/min

Cardiovascular

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No orthostatic hypotension > grade 2 (requiring more than brief fluid replacement or
other therapy OR with physiological consequences)

- No New York Heart Association class III or IV heart failure

- LVEF ≥ 40% by MUGA

- QTc ≤ 450 msec (470 msec for women)

- No congenital long QT syndrome

- No myocardial infarction within the past year

- No active ischemic heart disease within the past year

- No history of uncontrolled dysrhythmias

- No history of serious ventricular arrhythmia (ventricular fibrillation or ventricular
tachycardia > 3 premature ventricular contractions in a row)

- Not requiring antiarrhythmic drugs

- No poorly controlled angina

- No left bundle branch block

Pulmonary

- No uncontrolled symptomatic pulmonary disease, including any of the following:

- Dyspnea off or on exertion

- Paroxysmal nocturnal dyspnea

- Severe chronic obstructive/restrictive pulmonary disease requiring daily chronic
medications and oxygen

- Must not meet the Medicare criteria for home oxygen

- No sufficiently compromised pulmonary status as measured by baseline pulmonary
function tests and DLCO

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 2 months after study
participation

- No known HIV positivity

- No hyponatremia indicated by sodium < 130 mmol/L

- No known immunodeficiency syndromes

- No history of allergic reaction attributed to compounds of similar chemical or
biological composition to 17-dimethylaminoethylamino-17-demethoxygeldanamycin
(geldanamycin or 17-AAG)

- No concurrent uncontrolled illness

- No active or ongoing uncontrolled infection

- No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

- More than 4 weeks since prior biologic therapy and recovered

- No concurrent prophylactic growth factors

Chemotherapy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin, 8
weeks for UCN-01) and recovered

Endocrine therapy

- See Disease Characteristics

- Concurrent hormonal therapy for prostate cancer allowed provided patient has
metastatic disease that has progressed despite prior hormonal therapy

Radiotherapy

- More than 4 weeks since prior radiotherapy and recovered

- No prior radiotherapy that included the heart in the field (e.g., mantle
radiotherapy)

Surgery

- At least 4 weeks since prior major surgery

Other

- At least 2 weeks since prior participation in a phase 0 study

- Concurrent bisphosphonates for any cancer allowed

- Concurrent preventative doses of aspirin or non-steroidal anti-inflammatory drugs
allowed

- No concurrent drugs that may prolong QTc interval

- No concurrent full anticoagulation on a regular basis

- No concurrent prophylactic antiemetics

- No other concurrent investigational agents or therapies

- No other concurrent anticancer agents or therapies

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Shivaani Kummar, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NCI - Medical Oncology Branch

Authority:

United States: Food and Drug Administration

Study ID:

040218

NCT ID:

NCT00088868

Start Date:

June 2004

Completion Date:

December 2010

Related Keywords:

  • Lymphoma
  • Small Intestine Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • anaplastic large cell lymphoma
  • intraocular lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent mantle cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • stage III adult Burkitt lymphoma
  • stage III adult diffuse large cell lymphoma
  • stage III adult diffuse mixed cell lymphoma
  • stage III adult diffuse small cleaved cell lymphoma
  • stage III adult Hodgkin lymphoma
  • stage III adult immunoblastic large cell lymphoma
  • stage III adult lymphoblastic lymphoma
  • stage III grade 1 follicular lymphoma
  • stage III grade 2 follicular lymphoma
  • stage III grade 3 follicular lymphoma
  • stage III mantle cell lymphoma
  • stage III marginal zone lymphoma
  • stage III small lymphocytic lymphoma
  • stage IV adult Burkitt lymphoma
  • stage IV adult diffuse large cell lymphoma
  • stage IV adult diffuse mixed cell lymphoma
  • stage IV adult diffuse small cleaved cell lymphoma
  • stage IV adult Hodgkin lymphoma
  • stage IV adult immunoblastic large cell lymphoma
  • stage IV adult lymphoblastic lymphoma
  • stage IV grade 1 follicular lymphoma
  • stage IV grade 2 follicular lymphoma
  • stage IV grade 3 follicular lymphoma
  • stage IV mantle cell lymphoma
  • stage IV marginal zone lymphoma
  • stage IV small lymphocytic lymphoma
  • recurrent mycosis fungoides/Sezary syndrome
  • stage III mycosis fungoides/Sezary syndrome
  • stage IV mycosis fungoides/Sezary syndrome
  • recurrent adult Burkitt lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult Hodgkin lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • angioimmunoblastic T-cell lymphoma
  • small intestine lymphoma
  • Waldenström macroglobulinemia
  • recurrent cutaneous T-cell non-Hodgkin lymphoma
  • stage III cutaneous T-cell non-Hodgkin lymphoma
  • stage IV cutaneous T-cell non-Hodgkin lymphoma
  • recurrent adult T-cell leukemia/lymphoma
  • stage III adult T-cell leukemia/lymphoma
  • stage IV adult T-cell leukemia/lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, Large-Cell, Immunoblastic
  • Duodenal Neoplasms
  • Ileal Neoplasms
  • Jejunal Neoplasms
  • Neoplasms
  • Intestinal Neoplasms

Name

Location

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral OfficeBethesda, Maryland  20892-1182