A Phase I Study Of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, (17-DMAG) (NSC 707545) In Patients With Advanced Solid Tumors
A Phase I Study Of 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin, (17-DMAG) (NSC 707545) In Patients With Advanced Solid Tumors
This phase I trial is studying the side effects and best dose of 17-DMAG in treating patients with metastatic or unresectable solid tumors or lymphomas. Drugs used in chemotherapy, such as 17-DMAG, work in different ways to stop cancer cells from dividing so they stop growing or die
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in patients with metastatic or unresectable solid tumors or lymphomas.
II. Determine the safety and toxicity of this drug in these patients. III. Determine the pharmacokinetics and pharmacodynamics of this drug in these patients.
IV. Determine the recommended phase II dose of this drug for future studies.
SECONDARY OBJECTIVES:
I. Determine tumor response in patients treated with this drug.
OUTLINE: This is a dose-escalation, multicenter study.
Patients receive 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) IV over 1-6 hours on days 1-3 or 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 1-2 patients receive accelerated escalating doses of 17-DMAG until at least 1 of 2 patients experience dose-limiting toxicity (DLT). Cohorts are then expanded to 3-6 patients who receive escalating doses (in a standard manner) of 17-DMAG 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 DLT.
Patients are followed at 4 weeks.
Inclusion Criteria:
Histologically confirmed solid tumor or lymphoma
Standard curative or palliative measures do not exist or are no longer effective
No known brain metastases
Performance status - ECOG 0-2
Performance status - Karnofsky 60-100%
More than 12 weeks
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9.0 g/dL
ALT and AST ≤ 1.5 times upper limit of normal (ULN)
Bilirubin ≤ normal
Creatinine ≤ 1.25 times ULN
Creatinine clearance ≥ 60 mL/min
QTc < 450 msec for male patients (470 msec for female patients)
LVEF > 40% by MUGA
No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
No myocardial infarction or active ischemic heart disease within the past year
No New York Heart Association class III or IV congestive heart failure
No poorly controlled angina
No uncontrolled dysrhythmia requiring medication
No left bundle branch block
No history of congenital long QT syndrome
No other significant cardiac disease
Pulse oximetry at rest or on exercise > 88%
No symptomatic pulmonary disease (e.g., chronic obstructive or restrictive pulmonary disease, etc.) or any of the following are allowed:
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double barrier contraception 1 week before, during, and for at least 2 weeks after study participation
No uncontrolled illness
No active or ongoing infection
No history of allergic reaction attributed to compounds of similar chemical or biological composition to 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG)
No psychiatric illness or social situation that would preclude study compliance
No concurrent routine colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
Concurrent hormonal therapy allowed
At least 4 weeks since prior radiotherapy and recovered
No prior radiation that included the heart in the field (e.g., mantle)
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent anticancer agents or therapies
No concurrent medication that would prolong the QTc interval
No other concurrent investigational agents