A Phase I Trial Of 17-Allylaminogeldanamycin (17-AAG) And PS341 In Advanced Malignancies
A Phase I Trial Of 17-Allylaminogeldanamycin (17-AAG) And PS341 In Advanced Malignancies
This phase I trial is studying the side effects and best dose of giving tanespimycin together with bortezomib in treating patients with advanced solid tumors or lymphomas. (Accrual for lymphoma patients closed as of 11/27/09) Drugs used in chemotherapy, such as tanespimycin, work in different ways to stop cancer cells from dividing so they stop growing or die. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It may also increase the effectiveness of tanespimycin by making cancer cells more sensitive to the drug. Combining tanespimycin with bortezomib may kill more cancer cells.
OBJECTIVES:
I. Determine the dose-limiting toxicity and maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin) and bortezomib in patients with advanced solid tumors or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09).
II. Determine changes in biomarkers (e.g., HSP70, client proteins, and ubiquitination of proteins) in peripheral blood mononuclear cells and tumor specimens from patients with advanced solid tumors or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09) treated with this regimen.
III. Determine responses in patients treated with this regimen. IV. Determine the toxic effects of this regimen in these patients.
OUTLINE: This is a dose-escalation, multicenter study.
Patients receive tanespimycin intravenously (IV) over 1-2 hours and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tanespimycin and bortezomib 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. Once the MTD is determined, at least 12 additional patients are treated as above* at the MTD.
NOTE: *Bortezomib is not administered on day 1 of course 1 only. Patients are followed at 3 months.
Inclusion Criteria:
Histologically confirmed solid tumor or lymphomas (Accrual for Lymphoma Patients Closed as of 11/27/09)
Refractory to standard treatment OR no standard treatment that is potentially curative or capable of prolonging life expectancy exists
Tumor amenable to biopsy (patients accrued at the MTD only)
No CNS metastases
Performance status - ECOG 0-2
At least 12 weeks
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9.0 g/dL
Bilirubin ≤ 2 times upper limit of normal (ULN)
AST ≤ 2.5 times ULN
Alkaline phosphatase ≤ 2 times ULN (5 times ULN if due to liver involvement)
Creatinine ≤ 2 times ULN
QTc < 500 msec for men (470 msec for women)
LVEF > 40% by echocardiogram
Ejection fraction normal by echocardiogram (for patients who have received prior anthracycline therapy)
No cardiac symptoms ≥ grade 2
No New York Heart Association class III or IV heart failure
No myocardial infarction within the past year
No active ischemic heart disease within the past year
No congenital long QT syndrome
No left bundle branch block
No history of uncontrolled dysrhythmias or requiring antiarrhythmic drugs
No history of cardiac toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
No poorly controlled angina
No history of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
No other significant cardiac disease
Pulse oximetry at rest and exercise < 88% (per Medicare guidelines)
No pulmonary symptoms ≥ grade 2
No significant pulmonary disease requiring oxygen supplementation or causing a severe limitation in activity
No symptomatic pulmonary disease requiring medication including any of the following:
No home oxygen use that meets the Medicare criteria
No history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
No seizure disorder
No sensory peripheral neuropathy > grade 1
No neuropathic pain of any etiology
No uncontrolled infection
No prior serious allergic reaction to eggs
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Willing to return to Mayo Clinic Rochester, Mayo Clinic Arizona, or Mayo Clinic Florida for follow up
More than 4 weeks since prior immunotherapy or biologic therapy
No concurrent prophylactic colony-stimulating factors
No concurrent immunotherapy, biologic therapy, or gene therapy
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
No other concurrent chemotherapy
Concurrent steroids (at a stable dose for ≥ 4 weeks) for comorbid conditions (e.g., adrenal insufficiency or rheumatoid arthritis) allowed
More than 4 weeks since prior radiotherapy
No prior radiotherapy that potentially included the heart in the field (e.g., mantle) or chest
No prior radiotherapy to > 25% of bone marrow
No prior radiopharmaceuticals
No concurrent radiotherapy
Recovered from prior therapy
More than 8 weeks since prior UCN-01
No concurrent warfarin
No concurrent medications that prolong or may prolong QTc interval
No other concurrent investigational therapy