A Phase I Study of 17-N-Allylamino-17-Demethoxy Geldanamycin (17-AAG, NSC# 330507) in Combination With Docetaxel in Patients With Advanced Solid Tumors
A Phase I Study of 17-N-Allylamino-17-Demethoxy Geldanamycin (17-AAG, NSC# 330507) in Combination With Docetaxel in Patients With Advanced Solid Tumors
This phase I trial is studying the side effects and best dose of combination chemotherapy in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as docetaxel and 17-N-allylamino-17-demethoxygeldanamycin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.
OBJECTIVES:
I. Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) administered with docetaxel in patients with progressive metastatic prostate cancer or other progressive metastatic or unresectable solid tumors.
II. Determine the pharmacokinetics of this regimen in these patients.
OUTLINE: This is a dose-escalation study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG). Patients are assigned to 1 of 2 treatment groups.
Group 1: Patients receive docetaxel IV over 1 hour and 17-AAG IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Group 2: Patients receive docetaxel IV over 30 minutes and 17-AAG as in group 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients per group 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 20 additional patients (10 per group) are treated at the MTD.
Patients are followed every 2-3 months.
Inclusion Criteria:
Histologically confirmed metastatic or unresectable malignancy for which standard curative or palliative therapy does not exist or is no longer effective
Progressive disease manifested by the following parameters
For prostate cancer:
Must have castrate, metastatic disease defined by disease progression after surgical castration or treatment with a gonadotropin-releasing hormone (GnRH) analog (testosterone level less than 50 ng/mL)
Progressive metastatic disease on imaging studies (bone scan, CT scan, or MRI) OR metastatic disease and a rising prostate-specific antigen (PSA)
Biochemical progression indicated by at least 3 rising PSA values (obtained at least 1 week apart) from a baseline OR 2 rising PSA values (more than 1 month apart), where the percentage increase over the range of values is at least 25%
Patients who have received an antiandrogen as part of first-line hormonal therapy must have shown progression of disease off of the antiandrogen prior to study enrollment
For other solid tumors:
Patients with metastatic disease must not be progressing to the extent as to require palliative treatment within 4 weeks of study entry
No active brain metastases
Performance status - Karnofsky 70-100%
More than 6 months
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT < 1.5 times ULN
PT ≤ 1.1 times ULN
Creatinine no greater than 1.4 mg/dL or within ULN
Creatinine clearance greater than 55 mL/min
No prior history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
No dyspnea ≥ grade 2 at rest on room air
No requirement for supplementary oxygen therapy or oxygen saturations ≤ 88%
No clinically significant pulmonary comorbidities that require medication (e.g., severe chronic obstructive pulmonary disease that could predispose patient to pulmonary toxicity)
QTc ≤ 450 msec for male patients (470 for female patients)
LVEF > 40% by echocardiogram or MUGA
Echocardiogram or MUGA required for patients with any of the following:
No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
No myocardial infarction within the past year
No active ischemic heart disease within the past year
No New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)
No poorly controlled angina
No uncontrolled dysrhythmia
No congenital long QT syndrome
No left bundle branch block
No other significant cardiac disease
No prior history of cardiac toxicity after receiving anthracyclines such as doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of severe hypersensitivity reaction to paclitaxel, docetaxel, or polysorbate 80
No ongoing or active infection
No psychiatric illness or social situation that would preclude study compliance
No grade 2 or greater symptomatic peripheral neuropathy
No allergy to eggs or egg products
No other concurrent uncontrolled illness
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
See Disease Characteristics
At least 4 weeks since prior radiotherapy and recovered
No concurrent radiotherapy to sole measurable lesion
No prior mantle-field radiotherapy
See Disease Characteristics
No concurrent surgery for sole measurable lesion
Recovered from prior therapy
At least 1 week since prior ketoconazole and recovered
At least 4 weeks since prior investigational anticancer therapeutic drugs
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent medications that prolong QTc interval
No concurrent medication used to control arrhythmias
No other concurrent investigational agents
No other concurrent anticancer agents or therapies (investigational or commercial)
No concurrent CYP3A4 inhibitors, including any of the following:
No concurrent CYP3A4 inducers, including any of the following:
No concurrent herbal extracts or tinctures with CYP3A4 inhibitory activity, including any of the following:
Concurrent CYP3A4 substrates allowed