A Phase I Trial Of Gemcitabine, 17-Allylaminogeldanamycin (17-AAG) And Cisplatin In Advanced Solid Tumor Patients
A Phase I Trial Of Gemcitabine, 17-Allylaminogeldanamycin (17-AAG) And Cisplatin In Advanced Solid Tumor Patients
This phase I trial studies the side effects, best way to give, and best doses of tanespimycin with or without gemcitabine hydrochloride and cisplatin in treating patients with advanced solid tumors. Drugs used in chemotherapy, such as tanespimycin, gemcitabine hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Using more than one drug (combination chemotherapy) may kill more tumor cells.
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose (MTD) of 17-AAG (tanespimycin) when given on days 1 and 8 of every 3 weeks cycle in combination with Gemzar (gemcitabine hydrochloride) and CDDP (cisplatin) (cohorts A, B, and E).
II. To determine the MTD of 17-AAG plus Gemzar when Gemzar is given on days 1 and 8 and 17-AAG is given on days 2 and 9 every 3 weeks (cohort C).
III. To determine the MTD of 17-AAG plus CDDP when given on days 1 and 8 every 3 weeks (cohort D).
IV. To define the dose-limiting toxicity of 17-AAG when used in combination with Gemzar and CDDP.
V. To assess the effect of 17-AAG on surrogate markers when used in combination with Gemzar and CDDP.
VI. To report any responses observed.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 treatment cohorts.
Cohort A (closed to accrual as of 3/2/04)*: Patients receive escalating doses of gemcitabine hydrochloride intravenously (IV) over 30 minutes, tanespimycin IV over 1 hour, and cisplatin IV over 2 hours on days 1 and 8. NOTE: *The maximum tolerated dose (MTD) of this 3-drug combination has been determined as of 3/2/04.
Cohort B (closed to accrual as of 3/2/05): Patients receive gemcitabine hydrochloride** IV over 30 minutes, tanespimycin IV over 1 hour, and cisplatin** IV over 2 hours on days 1 and 8.
Cohort C: Patients receive gemcitabine hydrochloride** IV over 30 minutes and tanespimycin IV over 1-2 hours on days 2 and 9.
Cohort D: Patients receive cisplatin** IV over 2 hours and tanespimycin IV over 1-2 hours on days 1 and 8.
Cohort E: Patients receive gemcitabine hydrochloride***, tanespimycin***, and cisplatin*** as in cohort B.
In all cohorts, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 3 months.
NOTE: **Gemcitabine hydrochloride and cisplatin dosage is constant, while 17-AAG is escalated in cohorts B, C, and D.
NOTE: ***Gemcitabine hydrochloride dosage is constant, 17-AAG is started at a higher dose level than all other cohorts, and cisplatin dosage is escalated in cohort E.
Inclusion Criteria:
Exclusion Criteria:
Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
ECOG performance status (PS) 2, 3 or 4
Uncontrolled infection
Any of the following prior therapies:
Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
Significant cardiac disease including:
Active ischemic heart disease =< 12 months prior to study entry
Congenital long QT syndrome
Left bundle branch block
Central nervous system (CNS) metastases or seizure disorder
Any of the following:
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
History of serious allergic reactions to eggs
Concurrent use of drugs known to be inhibitors of the 3A4 enzyme
>= grade 2 peripheral neuropathy, as defined by the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0
Significant underlying pulmonary disease as manifested by requirement for oxygen or pulmonary fibrosis on chest x-ray
Use of concomitant medications that prolong or may prolong corrected QT interval (QTc)
History of serious ventricular arrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF], >= 3 beats in a row), QTc >= 450 msec for men and 470 msec for women, or left ventricular ejection fraction (LVEF) =< 40% by MUGA
Patients with symptomatic pulmonary disease requiring medication including the following: dyspnea, dyspnea on exertion, paroxysmal nocturnal dyspnea, oxygen requirement and significant pulmonary disease, including chronic obstructive/restrictive pulmonary disease; note: patients that meet the Medicare criteria for home oxygen should be excluded from the protocol
Patients with a prior history of cardiac or pulmonary toxicity after receiving anthracyclines such as doxorubicin, daunorubicin, mitoxantrone, bleomycin or carmustine (BCNU)
Patients with greater or equal to grade 2 pulmonary or cardiac symptoms