Gemcitabine Hydrochloride and Tanespimycin in Treating Patients With Stage IV Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial is studying three different schedules of gemcitabine hydrochloride and tanespimycin to see how well they work in treating patients with stage IV pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and tanespimycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To assess the effect of gemcitabine hydrochloride and tanespimycin (17-AAG) on 6-month survival rate in patients with stage IV pancreatic adenocarcinoma. SECONDARY OBJECTIVES: I. To determine the overall survival of these patients. II. To determine the time to disease progression (TTP) in these patients. III. To determine the confirmed response rate and duration of response in these patients. IV. To determine the time to treatment failure in these patients. V. To determine the adverse events in these patients. TERTIARY OBJECTIVES: I. To determine the effects of treatment on molecular targets, such as CDK4, akt, phospho-akt, Hsp90, Hsp70, and CHK1, and correlate these with clinical endpoints, including survival at 6 months, TTP, response rate, and overall survival. II. To determine the effect of gemcitabine hydrochloride metabolizing enzyme genotype on toxicity, and clinical outcome. OUTLINE: This is a multicenter study. Patients are stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, or 2). Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on day 9 of course one. ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9 of course one. ARM III: Patients receive gemcitabine hydrochloride IV over 30 minutes on day 8 and tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and periodically during treatment for pharmacogenetic studies. Tumor tissue samples that are available are also collected for laboratory studies. Samples are analyzed for number of circulating tumor cells, levels of intracellular targets (e.g., CDK4, akt, phospho-akt, Hsp90, Hsp70, and CHK1), single nucleotide DNA polymorphisms, and Vav1 expression. Samples are analyzed by reverse transcriptase-polymerase chain reaction, immunofluorescence, and immunohistochemistry. After completion of study treatment, patients are followed periodically for up to 2 years.

Official Title
-----------------
A Phase II Trial of 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG) in Combination With Gemcitabine in Patients With Metastatic Pancreatic Adenocarcinoma

Conditions
-----------------
Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: gemcitabine hydrochloride
* Drug: tanespimycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed pancreatic adenocarcinoma Clinical stage IV disease No known brain metastases ECOG performance status 0-2 Life expectancy ≥ 12 weeks Absolute Neutrophil Count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin normal Aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2 times ULN (5 times ULN if liver metastases are present) Creatinine normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Ejection fraction > 40% by echocardiogram Patients who received prior anthracyclines must have a normal ejection fraction by echocardiogram Corrected QT interval (QTc) < 500 msec Pulse oximetry > 88% on room air at rest and after gentle exercise (according to Group Medicare Guidelines) No history of allergic reactions attributed to compounds of similar chemical or biologic composition to tanespimycin (17-AAG) or gemcitabine hydrochloride No known allergy to eggs No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements No active ischemic heart disease within the past 12 months No history of uncontrolled dysrhythmias No congenital long QT syndrome No left bundle branch block No other significant cardiac disease, including any of the following: New York Heart Association class III or IV heart failure Myocardial infarction within the past year Poorly controlled angina Uncontrolled dysrhythmias History of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row) No clinically significant interstitial lung disease No symptomatic pulmonary disease requiring medication, including any of the following: Dyspnea Dyspnea on exertion Paroxysmal nocturnal dyspnea Significant pulmonary disease requiring oxygen*, including chronic obstructive/restrictive pulmonary disease No pulmonary or cardiac symptoms ≥ grade 2 No history of cardiac or pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or vincristine) No prior chemotherapy for metastatic disease No prior radiotherapy to the chest No prior radiotherapy that potentially included the heart in the field (e.g.,mantle radiotherapy) More than 3 months since prior adjuvant chemotherapy or chemotherapy for locally advanced disease More than 3 weeks since prior radiotherapy No concurrent medications that prolong or may prolong QTc No concurrent antiarrhythmic drugs No concurrent prophylactic colony-stimulating factors No other concurrent investigational agents No other concurrent anticancer therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (combination chemotherapy)<br>Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9. | Drug: gemcitabine hydrochloride<br>* 750 mg/m2 Given IV<br>* Other names: Gemzar;Drug: tanespimycin<br>* 154 mg/m2 Given IV<br>* Other names: 17-N-Allylamino-17-Demethoxygeldanamycin;|
| Experimental: Arm II (combination chemotherapy)<br>Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9. | Drug: gemcitabine hydrochloride<br>* 750 mg/m2 Given IV<br>* Other names: Gemzar;Drug: tanespimycin<br>* 154 mg/m2 Given IV<br>* Other names: 17-N-Allylamino-17-Demethoxygeldanamycin;|
| Experimental: Arm III (combination chemotherapy)<br>Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9. | Drug: gemcitabine hydrochloride<br>* 750 mg/m2 Given IV<br>* Other names: Gemzar;Drug: tanespimycin<br>* 154 mg/m2 Given IV<br>* Other names: 17-N-Allylamino-17-Demethoxygeldanamycin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six Month Survival Rate | A patient that is alive at 6 months is considered a treatment success. Estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | Overall Survival time is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier. | Assessed up to 2 years from registration | 
| Time to Disease Progression | The time to disease progression is defined as the time from registration to the time of confirmed disease progression using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD. | Time from registration to documentation of disease progression, assessed up to 2 years | 
| Confirmed Response Rate | A confirmed response is defined as a complete response (CR) or partial response (PR) observed in two consecutive evaluations at least 4 weeks apart using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD.Evaluated using RECIST criteria. | 2 consecutive evaluations at least 4 weeks, up to 6 courses of treatment |