Tanespimycin, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Advanced Solid Tumors

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

• Histologic proof of cancer that is now considered clinically unresectable
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelets (PLT) >= 100,000/uL
• Total bilirubin =< 2 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) =< 2.5 x ULN
• Creatinine =< 1.5 x ULN
• Alkaline phosphatase =< 2 x ULN or =< 5 x ULN if liver involvement
• Hemoglobin (Hgb) >= 9.0 g/dL
• Ability to provide informed consent
• Willingness to return to Mayo Clinic Rochester for follow up
• Life expectancy >= 12 weeks
• Willingness to provide all biologic specimens as required by the protocol; this is the mandatory translational research component
• Prior treatment with gemcitabine or cisplatin or both is allowed
• Patients who have had prior anthracycline must have a normal ejection fraction on multi gated acquisition scan (MUGA)
• Women of childbearing potential only: negative serum pregnancy test done =< 7 days prior to registration

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:

• Chemotherapy =< 4 weeks prior to study entry
• Mitomycin C/nitrosoureas =< 6 weeks prior to study entry
• Immunotherapy =< 4 weeks prior to study entry
• Biologic therapy =< 4 weeks prior to study entry
• Radiation therapy =< 4 weeks prior to study entry, or any radiation that potentially included the heart in the field (e.g., mantle)
• Radiation to > 25% of bone marrow
• Radiopharmaceuticals
• Chest radiation
• Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
• Significant cardiac disease including:

• Heart failure that meets New York Heart Association classification III or IV
• History of myocardial infarction =< one year of study entry
• Uncontrolled dysrhythmias or requiring antiarrhythmic drugs, or
• Poorly controlled angina
• 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:

• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, injections, intrauterine device [IUD], or abstinence, etc.) Note: Concurrent use of oral contraceptives is contraindicated
• 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