A Phase I Study of 17-N-Allylamino-17-Demethoxy Geldanamycin (17-AAG, NSC# 330507, IND# 57,966) in Combination With Docetaxel in Patients With Advanced Solid Tumors
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)
- Patients who have not undergone surgical orchiectomy should continue
on medical therapies to maintain castrate levels of testosterone
- 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:
- Development of new lesions or an increase in pre-existing lesions by bone
scintigraphy, CT scan, MRI, positron emission tomography, or physical
examination
- Patients whose sole criterion for progression is an increase in a
biochemical marker (e.g., carcinoembryonic antigen or CA 15-3) or an
increase in symptoms are not eligible
- 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:
- Myocardial infarction > 1 year ago
- NYHA class I or II CHF
- Atrial fibrillation
- Right or left bundle branch block by EKG
- 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
- Calcium blockers and beta blockers allowed
- No other concurrent investigational agents
- No other concurrent anticancer agents or therapies (investigational or commercial)
- No concurrent CYP3A4 inhibitors, including any of the following:
- Fluconazole
- Itraconazole
- Ketoconazole
- Macrolide antibiotics (azithromycin, clarithromycin, erythromycin, or
troleandomycin)
- Nifedipine
- Verapamil
- Diltiazem
- Cyclosporine
- Grapefruit juice
- No concurrent CYP3A4 inducers, including any of the following:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampin
- No concurrent herbal extracts or tinctures with CYP3A4 inhibitory activity, including
any of the following:
- Hydrastis canadensis (goldenseal)
- Hypericum perforatum (St. John's wort)
- Uncaria tomentosa (cat's claw)
- Echinacea angustifolia roots
- Trifolium pratense (wild cherry)
- Matricaria chamomilla (chamomile)
- Glycyrrhiza glabra (licorice)
- Dillapiol
- Hypericin
- Naringenin
- Concurrent CYP3A4 substrates allowed