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A Phase I Trial Of Gemcitabine, 17-Allylaminogeldanamycin (17-AAG) And Cisplatin In Advanced Solid Tumor Patients


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Trial Of Gemcitabine, 17-Allylaminogeldanamycin (17-AAG) And Cisplatin In Advanced Solid Tumor Patients


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of tanespimycin, gemcitabine hydrochloride, and cisplatin, determined by incidence of dose-limiting toxicity (DLT) graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Charles Erlichman

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01429

NCT ID:

NCT00047047

Start Date:

August 2002

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

Mayo Clinic Rochester, Minnesota  55905