Gemcitabine Hydrochloride and Tanespimycin in Treating Patients With Recurrent Advanced Ovarian Epithelial or Peritoneal Cavity Cancer

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of gemcitabine hydrochloride and tanespimycin in treating patients who have recurrent advanced ovarian epithelial or primary peritoneal cavity cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and tanespimycin, work in different ways to stop tumor cells from dividing so they stop growing or die.

Detailed Description
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OBJECTIVES: I. Determine the response rate, time to progression, and survival of patients with recurrent advanced ovarian epithelial or primary peritoneal cavity cancer treated with gemcitabine hydrochloride and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin). II. Determine the toxicity of this regimen in these patients. III. Correlate the effect of 17-AAG alone on chaperone and client proteins in tumor samples and peripheral blood mononuclear cells with response, time to progression, and survival of these patients. OUTLINE: This is a multicenter study. Patients are stratified according to gemcitabine hydrochloride therapy (gemcitabine hydrochloride-naive/no prior exposure to gemcitabine hydrochloride vs gemcitabine hydrochloride-resistant/prior exposure to gemcitabine hydrochloride as a single agent with disease progression while on treatment). Patients receive tanespimycin intravenously (IV) over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

Official Title
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A Phase II Trial Of Gemcitabine in Combination With 17-Allylaminogeldamycin (17-AAG) In Advanced Epithelial Ovarian And Primary Peritoneal Carcinoma

Conditions
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Primary Peritoneal Cavity Cancer, Recurrent Ovarian Epithelial Cancer, Stage III Ovarian Epithelial Cancer, Stage IV Ovarian Epithelial Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ovarian epithelial or primary peritoneal cavity cancer Relapsed disease Persistent disease Platinum-resistant disease, defined as having evidence of disease that would be expected to be non-responsive to additional platinum-containing regimens or contraindication to platinum-based chemotherapy and 1 of the following: Failure to obtain a complete response to initial platinum therapy Recurrence < 6 months after completing a platinum-containing regimen for initial or recurrent disease Any of the above situations and following treatment with additional chemotherapy regimens (e.g., non-platinum containing regimens) Relative or absolute contraindication to platinum-based chemotherapy regimens (e.g., platinum allergy) as determine by the investigator Measurable or evaluable disease Patients with a rising CA 125 level, even in the absence of other indicators of disease, allowed provided CA 125 is ≥ 2 times upper limit of normal (ULN) Patients with accessible disease must be willing to undergo tumor biopsies No CNS metastases Performance status - ECOG 0-2 WBC ≥ 3,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9.0 g/dL Bilirubin normal Alkaline phosphatase ≤ 2.5 times ULN AST ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN Ejection fraction > 40% by ECHO for patients with prior anthracycline therapy No significant cardiac disease including any of the following: New York Heart Association class III or IV heart disease History of myocardial infraction within the past year Uncontrolled dysrhythmias or requirement for antiarrhythmic drugs Poorly controlled angina No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row) No history of QTc ≥ 500 msec No active ischemic heart disease within the past 12 months No congenital long QT syndrome No left bundle branch block No cardiac symptoms ≥ grade 2 No history of cardiac toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone, bleomycin, or carmustine) Does not meet the medicare criteria for home oxygen No pulse oximetry at rest and exercise < 88% No symptomatic pulmonary disease requiring medication including any of the following: Dyspnea on or off exertion Paroxysmal nocturnal dyspnea Oxygen requirement Significant pulmonary disease (e.g., chronic obstructive/restrictive pulmonary disease) No pulmonary symptoms ≥ grade 2 No history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone, bleomycin, or carmustine) K+, Mg ++, and Ca ++ normal No seizure disorder No uncontrolled infection No history of serious allergic reaction to eggs More than 4 weeks since prior immunotherapy More than 4 weeks since prior biologic therapy No concurrent immunotherapy No concurrent routine or prophylactic colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) See Disease Characteristics More than 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered Prior gemcitabine hydrochloride allowed provided 1 of the following criteria is met: Patients have no prior exposure to gemcitabine hydrochloride Patients who have prior exposure to gemcitabine hydrochloride as a single agent have experienced progressive disease while on treatment No other concurrent chemotherapy No prior radiotherapy to > 25% of bone marrow No history of radiotherapy that potentially included the heart in the field (e.g., mantle) Chest wall irradiation or other radiotherapy techniques that do not include the heart in the radiation field area allowed More than 4 weeks since prior radiotherapy More than 4 weeks since prior radiopharmaceuticals No concurrent radiotherapy No other concurrent investigational therapy No concurrent medications that may prolong QTc

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy)<br>Patients are stratified according to gemcitabine hydrochloride therapy (gemcitabine hydrochloride-naive/no prior exposure to gemcitabine hydrochloride vs gemcitabine hydrochloride-resistant/prior exposure to gemcitabine hydrochloride as a single agent with disease progression while on treatment). Patients receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: tanespimycin<br>* Given IV<br>* Other names: 17-AAG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Experience a Confirmed Response According to Modified RECIST Criteria. | Objective response will be measured using the modified RECIST criteria. A confirmed response requires an objective status of complete or partial response on 2 consecutive evaluations occurring 4 or more weeks apart. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers. Partial Response (PR): At least a 30% decrease in the sum of the target lesions from the baseline. | Participants were evaluated every 6 weeks on treatment, with median treatment length of 12 weeks (3 week minimum and 42 week maximum). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Times to Progression | Defined as the time from registration to the date of progression or last follow-up, whichever comes first. Estimated using the method of Kaplan-Meier | Participants were evaluated every 6 weeks on treatment (maximum 42 weeks), and followed up to 5 years from registration. | 
| Overall Survival | Defined as the time from registration to date of last follow-up or death due to any cause. Estimated using the method of Kaplan-Meier. | Every 3 months until disease progression and then every 6 months for up to 5 years. | 
| Toxicity | Defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as an adverse event classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. | Participants were evaluated every 6 weeks on treatment (maximum 42 weeks) |